F. Stöckmann

Gabexate mesilate in human acute pancreatitis

Abstract Background: A multicenter controlled study was performed to evaluate the effect of high doses of the low molecular weight protease inhibitor gabexate mesilate on mortality and complications associated with moderate and severe acute pancreatitis. Methods: Two hundred twenty-three patients from 29 hospitals were entered in the randomized, double-blind trial. Admission to the study was based on strict criteria excluding mild acute pancreatitis. The patients received placebo or 4 g gabexate mesilate per day intravenously for 7 days. All patients were followed up for 90 days after randomization. The analysis was based on 14 complications, including death. Results: There was no statistical difference in either mortality or complications associated with acute pancreatitis between the placeboand gabexate mesilate groups. Conclusions: The results show that gabexate mesilate was not effective in preventing complications and mortality in acute pancreatitis.

Long-Term Omeprazole Treatment in Man: Effects on Gastric Endocrine Cell Populations

36 patients with chronic gastric or oesophageal peptic ulceration (including 6 with antrectomy), resistant to high-dose ranitidine treatment for at least 3 months, were successfully treated with 40-60 mg of omeprazole daily for periods between 1 and 2 years. Fasting serum gastrin levels were monitored at regular intervals during therapy and multiple gastric mucosal biopsies were taken during gastroscopy every 3-6 months. Gastrin levels increased significantly during the first 6 months of therapy from a medium level of 81.5 to 206 pg/ml, a slight decrease was seen thereafter. In 10 patients investigated before the start of the treatment and after 1 and 2 years, the volume density of argyrophilic cells in the oxyntic mucosa increased from 0.43 +/- 0.08 to 0.91 +/- 0.14% during the first year; this change was statistically significant. No further increase was observed thereafter. No such difference could be demonstrated between a larger group of 18 patients investigated before and after 1 year of treatment with omeprazole (0.806 +/- 0.1 vs. 0.93 +/- 0.08%) and between a larger group of 22 untreated patients and 17 patients treated for 17-24 months with omeprazole (0.73 +/- 0.1 vs. 0.86 +/- 0.09%). The volume density of argyrophilic cells found in 8 patients with gastrinoma amounted to 1.37 +/- 0.22%. No clusters of endocrine cells were found in omeprazole-treated patients. The D cell volume density in the antral mucosa decreased significantly during the first months of treatment, but steadily increased thereafter to reach pretreatment values after 17 months. There was no change in G cell volume density under therapy. No changes in gastrin levels or oxyntic argyrophilic cells were observed in the antrectomized patients. It is concluded that the hyperplasia of argyrophilic cells observed in some patients during long-term omeprazole treatment is mediated by hypergastrinaemia.

Secretin-pancreozymin test (SPT) and endoscopic retrograde cholangiopancreatography (ERCP) : both are necessary for diagnosing or excluding chronic pancreatitis

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 (p = 0.04). 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 only reflect 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.

Effect of Short- and Long-Term Feeding of Omeprazole on Rat Gastric Endocrine Cells

Rats were tube-fed with omeprazole (40 mumol/kg body weight twice daily) for 30 and 60 days. As a result, fasting plasma gastrin levels were significantly elevated, while plasma somatostatin levels remained normal. Gastrin concentrations in the antral mucosa were unchanged after 30 days, but significantly elevated after 60 days. The relative stomach weight and the area of the antral and oxyntic mucosa increased significantly; however, the oxyntic mucosa thickness and the volume density of the parietal cells did not increase. Highly significant changes occurred in the endocrine cells of the antrum and corpus. The volume density of the argyrophilic (Grimelius technique) cells of the oxyntic mucosa increased time-dependently, and so did the volume density of the antral G cells, while the volume density of the antral D cells decreased. This resulted in a remarkable increase in the G/D cell ratio. All functional and morphological changes are reversed 42 days after omeprazole feeding for 60 days. The findings in the endocrine cells of the antral mucosa are explained by the omeprazole-induced permanent elevation of the intragastric pH and in the endocrine cells of the oxyntic mucosa by the following hypergastrinaemia.

Etiology and Age Have Only a Limited Influence on the Course of Acute Pancreatitis

In a retrospective study of 602 patients with a first attack of acute pancreatitis, it was investigated whether the etiology of the disease and age of the patient are negative factors. There was no significant difference concerning hospital stay, respiratory and renal insufficiency, indication for surgery, or mortality rate among the different etiological groups. However, pancreatic pseudocysts developed significantly more frequently in alcoholics than in patients with other etiologies (p < 0.001 to p = 0.007). There was also no difference concerning hospital stay and respiratory insufficiency among the age groups. The increased incidence of renal insufficiency probably is related to physiological alteration with age, but the indication for dialysis did not increase. Pancreatic pseudocysts were more frequent in patients between 31 and 40 years of age, which was also the peak age group of alcoholics. Indication for surgery was the same for all age subgroups. The increase in mortality rate with age was weakly significant (p = 0.049). For the etiological subgroups, an increase in mortality with age was found only for biliary pancreatitis patients (p = 0.003). It is concluded that etiology and age of the patient have only limited influences on the course of acute pancreatitis.

Measurement and partial characterization of the multiple forms of neurokinin A-like immunoreactivity in carcinoid tumours

An antiserum raised against neurokinin A has been used to demonstrate storage and release of neurokinin A-like immunoreactivity by carcinoid tumours. The antiserum showed reactivity towards members of the tachykinin family of polypeptides in the order: neurokinin A greater than eledoisin greater than neurokinin B greater than kassinin greater than substance P greater than physalaemin but the magnitude of the cross-reactivity with substance P and physalaemin was less than 1% of that of neurokinin A. A sensitive (IC50 238 fmol/ml; minimum detectable concentration, 9 fmol/ml) radioimmunoassay was set up using this antiserum. Extracts of metastatic tumour tissue from four patients with a primary carcinoid tumour in the midgut contained both neurokinin A-like immunoreactivity (NKA-LI) and substance P-like immunoreactivity (SP-LI). The concentrations (pmol/g wet weight) of NKA-LI and SP-LI in the tumours were: patient A 210, 201; patient B 2276, 6849; patient C 1198, 834 and patient D 424, 379. Analysis of the tumour extracts by reverse phase HPLC indicated that the NKA-LI was heterogeneous. Under two different conditions of chromatography, one component was eluted with the same retention time as neurokinin A. Two further components were more hydrophobic than neurokinin A but were not eluted with the retention time of neurokinin B. Analysis of these components by gel filtration indicated a molecular weight in the 3000-4000 range suggesting that they may be related to neuropeptide K, an N-terminally extended form of neurokinin A. NKA-LI and SP-LI were undetectable in the plasma of patients A and D but were elevated in patient B (NKA-LI 1005 +/- 114; SP-LI 345 +/- 85 fmol/ml) and patient C (NKA-LI 80 +/- 31; SP-LI 21 +/- 13 fmol/ml).

Circulating Tachykinins (Substance P, Neurokinin A, Neuropeptide K) and the Carcinoid Flush

Antisera of defined regional specificity have been used to measure the concentration of substance P-like immunoreactivity (SP-LI) and neurokinin A-like immunoreactivity (NKA-LI) during a meal-induced flush in 10 patients with metastatic carcinoid tumours. Although all patients flushed, NKA-LI levels in five patients and SP-LI in six patients were not elevated relative to healthy subjects (NKA-LI, less than 3 pg/ml; SP-LI, less than 10 pg/ml) both in the fasted state and after food. In the patients with elevated basal plasma tachykinin levels, increases in NKA-LI and SP-LI after food were erratic and did not correspond to a defined digestive phase or the occurrence of the flush. Chromatographic analysis of plasma demonstrated the presence of neuropeptide K and neurokinin A, and the detection of COOH-terminal fragments of substance P is consistent with the higher levels of circulating SP-LI measured with a COOH-terminally directed antiserum compared with an NH2-terminally directed antiserum. Subcutaneous injection of the somatostatin analogue SMS 201-995 (50 micrograms) alleviated symptoms of flush in two of three patients but only partially suppressed NKA-LI and SP-LI concentrations. It is concluded that circulating tachykinins cannot be solely responsible for the meal-induced carcinoid flush.

Effect of a Specific Serine Protease Inhibitor on the Rat Pancreas: Systemic Administration of Camostate and Exocrine Pancreatic Secretion

Camostate, a synthetic serine protease inhibitor, specifically inhibits the trypsin activity in vitro. Immediately after intravenous administration of camostate (5, 2.5, 0.5, and 0.1 mg/kg body weight/h) the trypsin activity in the biliary-pancreatic juice was diminished dose-dependently in anaesthetized rats. The amylase release was not influenced. Camostate and its metabolites were detected by high-pressure liquid chromatography in the pancreatic juice and tissue; in plasma, only the metabolites were found. Therefore, the inhibitory action of camostate on the trypsin activity in the biliary-pancreatic juice may be due to penetration of camostate into the juice.

Trypsin Radioimmunoassay in the Diagnosis of Chronic Pancreatitis

Serum immunoreactive trypsin (IRT) determination has been recommended as a screening test in chronic pancreatitis. Using a commercial radioimmunoassay kit (RIA--gnost Trypsin; Behring-Werke, Marburg/Lahn, FRG) the interassay coefficient of variation was 26--44% for three different test sera. Gel filtration chromatography profiles revealed immunoreactivity in the position of 125I-trypsin and (less than 50%) in the void volume. The test was evaluated in controls (n = 90), chronic relapsing pancreatitis (CRP;n = 60) and after total pancreatectomy (n = 5). In 65% of the CRP cases decreased IRT values were found, whereas during acute attacks of CRP supranormal and normal values were found. After total pancreatectomy IRT levels were undetectable. It is concluded that the sensitivity of this IRT test is limited and that the available test system needs improvement.

Quantitative Studies of Gastric Endocrine Cells in Patients Receiving Long-term Treatment with Omeprazole

A total of 36 patients with chronic gastric or oesophageal peptic ulceration (including 6 with antrectomy), resistant to high-dose ranitidine treatment for at least 3 months, were successfully treated with omeprazole 20-60 mg/day, for periods up to 3 years. Fasting serum gastrin levels were monitored at regular intervals during therapy and multiple gastric mucosal biopsies were taken during gastroscopy every 3-6 months. Gastrin levels increased significantly during the first 6 months of therapy from a mean of 81.5 to 206 pg/ml; a slight decrease was observed thereafter. There was no significant increase in the volume density of argyrophilic cells in the oxyntic mucosa. No clusters of endocrine cells were found in the oxyntic mucosa and no change of G-cell volume density occurred in the antral mucosa under therapy. Omeprazole therapy did not result in any changes in gastrin levels or oxyntic argyrophilic cells in the antrectomized patients. It is concluded that the moderate hypergastrinaemia observed during long-term omeprazole treatment in man does not induce hyperplasia of argyrophilic cells in the oxyntic mucosa.