P. Malfertheiner

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.

The coccoid forms of Helicobacter pylori. Criteria for their viability.

The fact that Helicobacter pylori can revert to a coccoid form has stimulated speculation about its role in transmission and as a possible cause of reinfection in duodenal ulcer disease. Bismuth subcitrate (32 micrograms/ml), bismuth subsalicylate (64 micrograms/ml), amoxicillin (0.05 micrograms/ml) and erythromycin (4 micrograms/ml) inhibited the growth of H. pylori and stimulated the formation of basically respiring but non-culturable coccoid structures. The presence of polyphosphates as energy and phosphorus source permits a certain level of endogenous metabolism to preserve RNA and DNA, as well as structural components like cell wall, cell membrane and cytoplasma for at least 3 months. However, the applied standard laboratory methods were insufficient for regrowth of H. pylori out of the coccoid form.

PMN-elastase in comparison with CRP, antiproteases, and LDH as indicators of necrosis in human acute pancreatitis.

We analyzed the role of polymorphonuclear granulocytes (PMN)-elastase in predicting the prognosis of patients with acute pancreatitis in comparison with C-reactive protein (CRP), lactate dehydrogenase (LDH), and the two antiproteases α1-antitrypsin (α1-AT) and α2-macroglobulin (α2-M). Fifty-two patients with acute pancreatitis were subdivided according to morphological criteria into 29 patients with edematous pancreatitis and 23 patients with necrotizing pancreatitis. Within 5 days after the onset of acute pancreatitis, the accuracy rates for detecting necrotizing pancreatitis were 86%, 84%, 82%, 72%, and 69%, using cutoff levels of 120 mg/L for CRP, 120 pg/L for PMN-elastase, 270 UIL for LDH, 1.5 g/L for α2-M, and 3.5 g/L for α1AT, respectively. The median peak value of PMN-elastase was reached on day 1 of acute pancreatitis in contrast to the median peak of CRP, which was at its highest between days 3 and 4. PMN-elastase represents a reliable indicator, comparable with CRP, for the staging of acute pancreatitis. The advantage of PMN-elastase over CRP appears to be its earlier increase and the greater dynamism of its serum course. Finally, the results suggest that CT scanning for the evaluation of the extent of intra- and extrapancreatic necrosis could be restricted to those patients with increased values of PMN-elastase and CRP.

A randomised, double blind, multicentre trial of octreotide in moderate to severe acute pancreatitis

BACKGROUND The pharmacological inhibition of exocrine pancreatic secretion with the somatostatin analogue octreotide has been advocated as a specific treatment of acute pancreatitis. AIM To investigate the efficacy of octreotide in acute pancreatitis in a randomised, placebo controlled trial. METHODS 302 patients from 32 hospitals, fulfilling the criteria for moderate to severe acute pancreatitis within 96 hours of the onset of symptoms, were randomly assigned to one of three treatment groups: group P (n=103) received placebo, while groups O1 (n=98) and O2 (n=101) received 100 and 200 μg of octreotide, respectively, by subcutaneous injection three times daily for seven days. The primary outcome variable was a score composed of mortality and 15 typical complications of acute pancreatitis. RESULTS The three groups were well matched with respect to pretreatment characteristics. An intent to treat analysis of all 302 patients revealed no significant differences among treatment groups with respect to mortality (P: 16%; O1: 15%; O2: 12%), the rate of newly developed complications, the duration of pain, surgical interventions, or the length of the hospital stay. A valid for efficacy analysis (251 patients) also revealed no significant differences. CONCLUSIONS This trial shows no benefit of octreotide in the treatment of acute pancreatitis.

Role of phospholipase A2 in human acute pancreatitis.

In a prospective clinical trial, 85 patients with acute pancreatitis, including 50 with acute interstitial-edematous pancreatitis and 35 with necrotizing pancreatitis, were recruited. Serum pancreatic immunoreactive phospholipase A2 (IR-PLA2), serum phospholipase A catalytic activity (CA-PLA), and serum phospholipase A2 catalytic activity (CA-PLA2) were determined daily between day 1 and day 10 after the onset of the disease. The serum course of IR-PLA2 values for patients with acute interstitial-edematous pancreatitis was comparable to that for patients with necrotizing pancreatitis. In contrast, the determination of CA-PLA and of CA-PLA2 specific activity in the serum revealed a high differentiation between patients with interstitial edematous and those with necrotizing pancreatitis. The overall accuracy for differentiating patients with necrotizing pancreatitis from those with the interstitial-edematous type was 79% for CA-PLA and 77% for CA-PLA2 (cut-off level: CA-PLA, 15 U/L, day 1-5; CA-PLA2, 3.5 U/L, day 1-5). Patients with pancreatitis-associated pulmonary complications showed significantly higher CA-PLA and CA-PLA2 values in the serum. This study demonstrates the role of serum catalytic phospholipase A2 in human acute pancreatitis where the development of pancreatic necrosis and pulmonary failure is concerned.

Pathogenetic Implications of Ultrastructural Findings in Campylobacter pylori Related Gastroduodenal Disease

There is now substantial evidence that Campylobacter pylori (Cp) is able to colonize the gastroduodenal mucosa and is responsible for active chronic gastritis, its role in duodenitis, gastric ulceration and duodenal ulceration is still under debate. Cp has a lot of characteristics which are prerequisites for a pathogen: the typical S-shape, the corkscrew-like movement and the powerful urease and protease enzymes. These features allow a rapid movement through the mucous layer to permit access to the apical membranes of the surface mucous cells. There they adhere directly to the membranes and induce several ultrastructural alterations: degeneration of microvilli, depletion of mucous granules and an increase in sialic-acid rich glycoproteins in the apical part of the cytoplasma. Cp weakens the tight-junction complex and is found between the cells and sometimes intracellularly. Cp is phagocytized by invading polymorphonuclear leukocytes and causes an intense inflammatory response. These observations clearly demonstrate pathological alterations which in the cellular level induced by Cp with the result of a disrupted mucosal barrier of the stomach and the duodenum.

Sensitivity of antiproteases, complement factors and C-reactive protein in detecting pancreatic necrosis. Results of a prospective clinical study.

SummaryThirty-five patients with acute pancreatitis underwent serum monitoring of α-1-protease inhibitor, α-2-macroglobulin, complement factors C3+C4, and C-reactive protein (CRP). Edematous interstitial pancreatitis was shown to be present in 13 patients by contrast-enhanced computed tomography (CT) and laparotomy (n=3). Necrotizing pancreatitis was confirmed by laparotomy (n=21) and contrast-enhanced CT. There were significant differences between the serum values of all measured parameters in the two morphologically defined pancreatitis groups. The best discriminating factors were CRP and α-2-macroglobulin, showing 95% and 85% overall detection rates for pancreatic necrosis, respectively.

Hyperlipidemia in acute pancreatitis

Whether hyperlipidemia is a pre-existing metabolic disorder or a consequence of acute pancreatitis is still debated. Mild to moderate elevation of serum triglyceride levels are likely to be an epiphenomenon of the pancreatic disease. A marked hyperchylomicronemia and hypertrygliceridemia would be needed to trigger acute pancreatitis; a relevant defect in the lipid catabolism and clearance should therefore pre-exist. The aim of the present study was to investigate whether patients with acute pancreatitis and marked hyperlipidemia have an impaired clearance capacity of exogenous lipids, which would define the hyperlipidemia as a preexistent abnormality and therefore a potential cause of the pancreatic disease. With this aim, the kinetics of the removal of exogenous triglycerides from the circulation have been analyzed. Twenty patients with acute pancreatitis have been studied. Ten of them suffered from an episode of acute pancreatitis with marked hyperlipidemia (serum triglyceride levels>20mmol/L). Four to six months after recovery from the pancreatitis, a two-stage infusion of Intralipid 20% was carried out and the fractional removal rate (K2) and the maximal clearance capacity (K1) of exogenous triglycerides were calculated. At low infusion rates a first order kinetics for removal was observed, whereas at high infusion rates a zero order kinetics was operating. All patients with a previous attack of normolipidemic acute pancreatitis had normal K2 and K1 values. Five patients with previous hyperlipidemic acute pancreatitis had an abnormally low clearance capacity of exogenous triglycerides, whereas the remaining five had normal removal values. The present study provides new information in the association between hyperlipidemia and acute pancreatitis by showing that even a marked elevation of serum lipid levels should not be invariably considered as the etiological factor of the pancreatic disease, even if other potential causes are not evident.

The Penetration of Antibiotics into Human Pancreas

SummaryIn order to analyse the penetration of two antibiotics (mezlocillin and metronidazole) which cover the spectrum of microorganisms involved in pancreatic infection, we determined their concentration in pancreatic tissue, juice and cyst fluid in 16 patients undergoing pancreatic surgery. In addition, the external pancreatic fistula fluid of one patient was analysed for antibiotic concentration and bacterial counts during a seven-day treatment with mezlocillin, metronidazole and netilmicin (i.v.). Antibiotic concentrations were determined by HPLC between 16 and 210 (median 74) min after i.v. administration of 4 g mezlocillin and 500 mg metronidazole, respectively. The median concentration of mezlocillin was 23.2 (range: 3.1–37.4) mg/kg, 15.9 (range: 4.2–55.0) mg/l and 9.9 (range: 5.2–14.8) mg/l in pancreatic tissue, juice and cyst fluid, respectively. The median concentration of metronidazole was 5.1 (range: 1.8–13.0) mg/kg, 8.5 (range: 3.6–16.2) mg/l and 1.2 (0.9–1.4) mg/l in pancreatic tissue, juice and cyst fluid, respectively. From the fistula patient, seven different bacteria were cultured (five aerobic and two anaerobic isolates); their concentration in fistula fluid ranged from 105 to 107 CFU/ml. The bacteria sensitive for mezlocillin and metronidazole disappeared after four days of i.v. treatment, whereas the two isolates sensitive for netilmicin showed continuous growth seven days after i.v. treatment. The peak concentrations for mezlocillin, metronidazole and netilmicin in the fistula fluid were 6.8 mg/l, 5.6 mg/l and <0.1 mg/l, respectively.ZusammenfassungBei 16 Patienten wurden im Rahmen von operativen Eingriffen an der Bauchspeicheldrüse die Konzentrationen von Mezlocillin und Metronidazol im humanen Pankreasgewebe, Pankreassaft und Zystenflüssigkeit bestimmt. Die beiden Substanzen wurden analysiert, da sie das Spektrum an Bakterien abdecken, welche im Rahmen von Infektionen an der Bauchspeicheldrüse relevant sind. Zusätzlich wurde bei einem Patienten mit einer superinfizierten pankreatikokutanen Fistel das Fistelsekret bezüglich der Konzentrationen von Mezlocillin, Metronidazol und Netilmicin untersucht. Die Antibiotika-Konzentrationen in den verschiedenen Bauchspeicheldrüsenkompartimenten wurden mittels HPLC bestimmt nach intravenöser Injektion von 4g Mezlocillin, 500 mg Metronidazol bzw. 150 mg Netilmicin. Der mediane Bestimmungszeitpunkt lag bei 74 min. (16–210 min.) nach intravenöser Gabe des jeweiligen Antibiotikums. Die mediane Konzentration für Mezlocillin entsprach 23,2 mg/kg (3,1–37,4) in humanem Pankreasgewebe, 15,9 mg/l (4,2–55,0) im Pankreassaft und 9,9 mg/l (5,2–14,8) in der Zystenflüssigkeit. Die entsprechenden medianen Konzentrationen für Metronidazol waren 5,05 mg/kg (1,8–13,0) im Pankreasgewebe, 8,5 mg/l (3,6–16,2) im Pankreassaft und 1,15 mg/l (0,9–1,4) im Pankreaspseudozysteninhalt. Bei dem Fistelpatienten wurden sieben verschiedene Keime (fünf aerobe und zwei anaerobe) in Konzentrationen zwischen 105–107 KBE/ml isoliert. Die Keime, welchein vitro für Mezlocillin und Metronidazol empfindlich waren, verschwanden aus dem Fistelsekret innerhalb von vier Tagen nach intravenöser Therapie. Demgegenüber zeigten diein vitro für Netilmicin empfindlichen Keime ein verstärktes Wachstum im Fistelsekret. Die Spitzen-Konzentrationen für Mezlocillin, Metronidazol und Netilmicin in der Fistelflüssigkeit wurden mit 6,8 mg/ml, 5,6 mg/l und >0,1 mg/l ermittelt.

A Metastatic Endocrine-Neurogenic Tumor of the Ampulla of Vater with Multiple Endocrine Immunoreaction Malignant Paraganglioma?

The present case report demonstrates the history of a 50-year-old man with a mixed endocrine-neurogenous tumor of the ampulla of Vater. The tumor was localized endoscopically after an attack of melena. There were no signs of endocrinopathy. A local resection with suturing of the pancreatic duct was performed. Morphologically, there were two different tissue types (neurogenous and carcinoid-like) with numerous cells and nerve fibers reacting immunohistochemically with somatostatin and neurotensin antisera: some immunoreactivity to PP-antibodies was observed. Still, after 20 months, the patient seems to have been cured by local resection.