ceruletide and Chronic-Disease

Faecal elastase 1 (FE1) and the pancreolauryl test (PLT) are widely used for the non-invasive diagnosis of exocrine pancreatic insufficiency (EPI). Whether one of these two tests is superior for the detection of mild-to-moderate EPI is the subject of controversy. The aim of this study was to compare the diagnostic performance of the PLT and FE1 for the detection of EPI in patients with chronic pancreatitis.. Forty consecutive patients (27 males, 13 females, 23-72 years) with chronic pancreatitis based on imaging procedures (computed tomography, endoscopic retrograde pancreatography and endoscopic ultrasound) were admitted to the study. A secretin-caerulein test (SCT) was performed after an overnight fast by giving secretin (1 U/kg/h) and caerulein (100 ng/kg/h) intravenously over 90 min. Duodenal contents were aspirated at 15 min intervals and analysed for pH, bicarbonate, amylase, lipase and elastase. EPI was graded on the basis of the results of the SCT as absent, mild, moderate or severe. A serum PLT was performed in accordance with a modified protocol previously described. A commercial ELISA was used for determination of FE1. The cut-off values were > or = 4.5 mg/l for PLT and > or = 200 microg/g for FE1. and 13 severe) on the basis of the results of the SCT. The sensitivity of the PLT for diagnosing EPI of all degrees of severity was 82% (27/33), compared with 50% for FE1 (16/ 33). In patients with severe EPI, the PLT was abnormal in 100% (13/13) and FE1 was abnormal in 85% (11/13) of the cases. The sensitivity decreases for both tests in the group of mild/moderate EPI (PLT 70% (14/20), FE1 35% (7/20)). In all seven patients with normal exocrine pancreatic function, both PLT and FE1 were also normal.. The PLT is more sensitive than FE1 for the diagnosis of mild-to-moderate EPI, and is therefore more appropriate for completing the staging of chronic pancreatitis.

Topics: Adult; Aged; Ceruletide; Chronic Disease; Feces; Female; Fluoresceins; Humans; Male; Middle Aged; Pancreas; Pancreatic Elastase; Pancreatic Function Tests; Pancreatitis; Secretin; Sensitivity and Specificity; Severity of Illness Index

Caerulein (CRL) (5 micrograms i.m.) and morphine (10 mg i.m.) have been tested for their analgesic activity in a double blind randomized study in a total of 36 patients with medium to severe tumor pains. A decrease of more than 20 mm on a visual analogue scale (VAS) was taken as a criterion for successful therapy. This was the case in 67% of the patients treated with morphine and 50% of those treated with CRL. This difference is statistically not significant, but CRL has significantly fewer side-effects than morphine. The present data do not permit a definitive judgement on the value of CRL in the treatment of tumor pains. Further studies with more patients and different doses and administration routes are warranted.

Topics: Adult; Aged; Aged, 80 and over; Ceruletide; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Morphine; Neoplasms; Pain; Pain Measurement; Random Allocation

In order to determine whether the doses of cerulein generally used in the secretin-cerulein test are supramaximal, the pancreatic secretion of enzymes and bicarbonate in response to intravenous infusion of cerulein plus secretin was studied in 6 subjects on two separate days at the respective doses of 50 ng/kg/h and 0.5 CU/kg/h on one day, and 100 ng/kg/h and 1 CU/kg/h on the other. In all subjects studied, the infusion of cerulein at the dose of 100 ng/kg/h caused a pancreatic enzyme response significantly higher than that produced by 50 ng/kg/h, demonstrating that the doses of cerulein generally used in clinical practice to explore the exocrine pancreatic function are not supramaximal.

Topics: Adult; Bicarbonates; Ceruletide; Chronic Disease; Chymotrypsin; Clinical Trials as Topic; Exocrine Pancreatic Insufficiency; Humans; Infusions, Intravenous; Lipase; Male; Middle Aged; Pancreatic Function Tests; Pancreatitis; Random Allocation

We evaluated ceruletide, a cholecystokininlike peptide, in a double-blind, placebo-controlled study of 20 male chronic schizophrenic patients. After baseline investigations, 10 patients received 0.3 microgram/kg body weight ceruletide, and 10 patients received placebo (normal saline) intramuscularly once weekly for 3 consecutive weeks. Psychopathology was rated on the Brief Psychiatric Rating Scale and the Nurses' Observation Scale for Inpatient Evaluation. Blood was drawn on the same days for estimation of norepinephrine, epinephrine, beta-endorphin, cortisol, and prolactin. There were no significant changes in biochemical parameters. With regard to psychopathology, no significant differences in behavioral ratings were found between the ceruletide- and placebo-treated groups. Furthermore, there was no changes in either positive or negative symptoms of schizophrenia secondary to ceruletide. Contrary to uncontrolled studies, we failed to show antipsychotic properties of ceruletide.

Topics: Adult; Ceruletide; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Humans; Male; Middle Aged; Psychopathology; Schizophrenia

Ceruletide, an analog of cholecystokinin (CCK), has been reported to have neuroleptic-like activity in mice, and, in three open studies, to benefit schizophrenic patients. This study evaluated ceruletide in schizophrenia using a double-blind design. Subjects were 17 chronic schizophrenics with residual symptoms following stabilization with neuroleptics. Patients randomly received two injections, 1 week apart, of either ceruletide (0.6 microgram/kg im) or placebo, while continuing neuroleptics; this regimen was found helpful in earlier studies. Evaluation included ratings of 29 variables related to prognosis in schizophrenia (e.g., age, number of previous hospitalizations), regular BPRSs and SCL-90s, and psychiatrist, patient, and relative ratings of global improvement. Results showed few significant differences between ceruletide and placebo, with exceptions as likely to favor placebo as ceruletide. Among the patients on ceruletide, no predictors of benefit were found. Possible reasons for the negative results are discussed.

Topics: Antipsychotic Agents; Ceruletide; Chronic Disease; Double-Blind Method; Humans; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Topics: Adult; Ceruletide; Cholecystokinin; Chronic Disease; Clinical Trials as Topic; Female; Humans; Long-Term Care; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia

Eight neuroleptic-resistant schizophrenic patients were treated with ceruletide diethylamine, a cholecystokininlike peptide, in a placebo-controlled, double-blind, cross-over study. Ceruletide or placebo was administered intramuscularly twice a day for four consecutive days while patients received a constant dose of fluphenazine hydrochloride. Cholecystokinin octapeptide was also administered to four different schizophrenic patients in a double-blind, cross-over study. Cholecystokinin or placebo was administered as a slow intravenous infusion daily for four days. There were no changes in either the positive or negative symptoms of schizophrenia between the periods of placebo, ceruletide, or cholecystokinin administration. Furthermore, there was no tendency for the patients' conditions to either improve or worsen during the course of ceruletide or cholecystokinin treatment. In contrast to previous reports from uncontrolled studies, cholecystokininlike peptides appear to be devoid of antipsychotic properties when administered parenterally.

Topics: Adult; Ceruletide; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Sincalide

Topics: Ceruletide; Chronic Disease; Clinical Trials as Topic; Humans; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Topics: Ceruletide; Chronic Disease; Clinical Trials as Topic; Humans; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Secretin (1 CU/Kg) plus Caerulein (100 ng/Kg) or Cholecystokinin (1 or 2 IvyU/Kg) were given by rapid intravenous injection (Schedule 1) or by continuous infusion (Schedule 2) to 63 control subjects (C) and 69 patients affected by chronic pancreatitis (CP). Duodenal juice was collected for two and four 30-minute periods in schedule 1 and schedule 2, respectively. Volume, bicarbonate, and enzyme content were measured. Secretin-Daerulein, by rapid intravenous injection, showed a strong overlapping between C and CP values and led to some side-effects. Secretin-Caerulein by continuous intravenous infusion gave almost identical results as the Secretin-Cholecystokinin.

Topics: Adolescent; Adult; Aged; Bicarbonates; Ceruletide; Cholecystokinin; Chronic Disease; Clinical Trials as Topic; Duodenum; Female; Humans; Injections, Intravenous; Male; Middle Aged; Pancreas; Pancreatic Juice; Pancreatitis; Secretin

Chronic pancreatitis is associated with recurrent inflammation, pain, fibrosis, and loss of exocrine and endocrine pancreatic function and risk of cancer. We hypothesized that activation of the CCK receptor contributes to pancreatitis and blockade of this pathway would improve chronic pancreatitis.. Two murine models were used to determine whether CCK receptor blockade with proglumide could prevent and reverse histologic and biochemical features of chronic pancreatitis: the 6-week repetitive chronic cerulein injection model and the modified 75% choline-deficient ethionine (CDE) diet. In the CDE-fed model, half the mice received water supplemented with proglumide, for 18 weeks. After chronic pancreatitis was established in the cerulein model, half the mice were treated with proglumide and half with water. Histology was scored in a blinded fashion for inflammation, fibrosis and acinar ductal metaplasia (ADM) and serum lipase levels were measured. RNA was extracted and examined for differentially expressed fibrosis genes.. Proglumide therapy decreased pancreatic weight in the CDE diet study and the cerulein-induced chronic pancreatitis model. Fibrosis, inflammation, and ADM scores were significantly reduced in both models. Lipase values improved with proglumide but not in controls in both models. Proglumide decreased pancreas mRNA expression of amylase, collagen-4, and TGFβR2 gene expression by 44, 38, and 25%, respectively, compared to control mice.. New strategies are needed to decreased inflammation and reduce fibrosis in chronic pancreatitis. CCK receptor antagonist therapy may improve chronic pancreatitis by reversing fibrosis and inflammation. The decrease in ADM may reduce the risk of the development of pancreatic cancer.

Topics: Animals; Ceruletide; Chronic Disease; Disease Models, Animal; Fibrosis; Inflammation; Lipase; Mice; Pancreas; Pancreatitis, Chronic; Proglumide; Receptors, Cholecystokinin

Inhibitory κB kinase (IKK)/nuclear factor κB (NF-κB) signalling has been implicated in the pathogenesis of pancreatitis, but its precise function has remained controversial. Here, we analyse the contribution of IKK/NF-κB signalling in epithelial cells to the pathogenesis of pancreatitis by targeting the IKK subunit NF-κB essential modulator (NEMO) (IKKγ), which is essential for canonical NF-κB activation.. Mice with a targeted deletion of NEMO in the pancreas were subjected to caerulein pancreatitis. Pancreata were examined at several time points and analysed for inflammation, fibrosis, cell death, cell proliferation, as well as cellular differentiation. Human samples were used to corroborate findings established in mice.. In acute pancreatitis, NEMO deletion in the pancreatic parenchyma resulted in minor changes during the early phase but led to the persistence of inflammatory and fibrotic foci in the recovery phase. In chronic pancreatitis, NEMO deletion aggravated inflammation and fibrosis, inhibited compensatory acinar cell proliferation, and enhanced acinar atrophy and acinar-ductal metaplasia. Gene expression analysis revealed sustained activation of profibrogenic genes and the CXCL12/CXCR4 axis in the absence of epithelial NEMO. In human chronic pancreatitis samples, the CXCL12/CXCR4 axis was activated as well, with CXCR4 expression correlating with the degree of fibrosis. The aggravating effects of NEMO deletion were attenuated by the administration of the CXCR4 antagonist AMD3100.. Our results suggest that NEMO in epithelial cells exerts a protective effect during pancreatitis by limiting inflammation and fibrosis and improving acinar cell regeneration. The CXCL12/CXCR4 axis is an important mediator of that effect and may also be of importance in human chronic pancreatitis.

Topics: Acute Disease; Animals; Biomarkers; Ceruletide; Chemokine CXCL12; Chronic Disease; Disease Progression; Epithelial Cells; Fibrosis; Humans; Intracellular Signaling Peptides and Proteins; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B; Pancreas; Pancreatitis; Receptors, CXCR4; Regeneration

Chronic pancreatitis is a significant risk factor for pancreatic cancer. Previously, we demonstrated that the pancreatic cancer cells show enhanced expression of collapsin response mediator protein 4 (CRMP4) that strongly correlates with severe venous invasion, liver metastasis, and poor prognosis. However, involvement of CRMP4 in acute or chronic pancreatitis remains unknown.. Acute and chronic pancreatitis mice models were developed by periodic injection of caerulein. The expression levels of CRMP4 and its phosphorylation were examined.. Elevated CRMP4 levels were observed in the infiltrated lymphocytes as well as in the pancreas parenchyma of both acute and chronic pancreatitis. The expression pattern of phosphorylated CRMP4 was similar to that of CRMP4. Cdk5 partially co-localized with the phosphorylated CRMP4.. Pancreatitis induces CRMP4 expression in the pancreas parenchyma and in the infiltrated lymphocytes. Overlapping expression of CRMP4 and Cdk5 may suggest that the Cdk5 is at least, in part, responsible for the phosphorylation of CRMP4. The results suggest that CRMP4 is involved in the inflammatory response in pancreatitis. Understanding the mechanisms of CRMP4 would help us to develop novel therapeutic strategies against acute or chronic pancreatitis, and pancreatic cancer.

Topics: Acute Disease; Animals; Biopsy, Needle; Cell Transformation, Neoplastic; Ceruletide; Chronic Disease; Cyclin-Dependent Kinase 5; Disease Models, Animal; Gene Expression Regulation; Humans; Immunohistochemistry; Mice; Nerve Tissue Proteins; Pancreatic Neoplasms; Pancreatitis; Phosphorylation; Precancerous Conditions; RNA, Small Interfering

Acinar cells represent the primary target in necroinflammatory diseases of the pancreas, including pancreatitis. The signaling pathways guiding acinar cell repair and regeneration following injury remain poorly understood. The purpose of this study was to determine the importance of Hepatocyte Growth Factor Receptor/MET signaling as an intrinsic repair mechanism for acinar cells following acute damage and chronic alcohol-associated injury. Here, we generated mice with targeted deletion of MET in adult acinar cells (MET-/-). Acute and repetitive pancreatic injury was induced in MET-/- and control mice with cerulein, and chronic injury by feeding mice Lieber-DeCarli diets containing alcohol with or without enhancement of repetitive pancreatic injury. We examined the exocrine pancreas of these mice histologically for acinar death, edema, inflammation and collagen deposition and changes in the transcriptional program. We show that MET expression is relatively low in normal adult pancreas. However, MET levels were elevated in ductal and acinar cells in human pancreatitis specimens, consistent with a role for MET in an adaptive repair mechanism. We report that genetic deletion of MET in adult murine acinar cells was linked to increased acinar cell death, chronic inflammation and delayed recovery (regeneration) of pancreatic exocrine tissue. Notably, increased pancreatic collagen deposition was detected in MET knockout mice following repetitive injury as well alcohol-associated injury. Finally, we identified specific alterations of the pancreatic transcriptome associated with MET signaling during injury, involved in tissue repair, inflammation and endoplasmic reticulum stress. Together, these data demonstrate the importance of MET signaling for acinar repair and regeneration, a novel finding that could attenuate the symptomology of pancreatic injury.

Topics: Acinar Cells; Acute Disease; Alcohol Drinking; Animals; Ceruletide; Chronic Disease; Collagen; Disease Models, Animal; Gene Deletion; Humans; Inflammation; Macrophages; Mice, Inbred C57BL; Pancreas; Pancreatitis, Chronic; Proto-Oncogene Proteins c-met; Regeneration; Wound Healing

Diabetes and fibrosis can be concurrent processes in several diseases such as cystic fibrosis or chronic pancreatitis. To evaluate whether diabetes can influence fibrosis and thus aggravate the pathological process, the progression of chronic pancreatitis was assessed in diabetic and non diabetic mice. For this purpose, insulin producing beta-cells in C57Bl/6J mice were selectively impaired by administration of streptozotocin. Chronic pancreatitis was then induced by repetitive administration of cerulein in normoglycaemic and hyperglycaemic mice. Diabetes caused enhanced collagen I deposition within three weeks of the onset of chronic pancreatitis and increased the proliferation of interstitial cells. This was accompanied by an increased number of interlobular fibroblasts, which expressed S100A4 (fibroblast-specific protein-1) and stimulation of α-smooth muscle actin expression of pancreatic stellate cells. In addition, the observed aggravation of chronic pancreatitis by diabetes also led to a significantly enhanced atrophy of the pancreas, increased infiltration of inflammatory chloracetate esterase positive cells and enhanced acinar cell death. We conclude that diabetes has a detrimental influence on the progression of chronic pancreatitis by aggravating fibrosis, inflammation and pancreatic atrophy.

Topics: Actins; Animals; Ceruletide; Chronic Disease; Collagen Type I; Diabetes Mellitus, Experimental; Fibrosis; Mice; Pancreas; Pancreatitis; S100 Calcium-Binding Protein A4; S100 Proteins; Streptozocin

Glucagon-like peptide-1 (GLP-1) promotes insulin release; however, the relationship between the GLP-1 signal and chronic pancreatitis is not well understood. Here we focus on chemokine (C-C motif) ligand 2 (CCL2) and its receptor (CCR2) axis, which regulates various immune cells, including macrophages, to clarify the mechanism of GLP-1-mediated insulin secretion in chronic pancreatitis in mice. One and multiple series of repetitive cerulein administrations were used to induce acute and chronic cerulein pancreatitis, respectively. Acute cerulein-administered CCR2-knockout (KO) mice showed suppressed infiltration of CD11b(+)Gr-1(low) macrophages and pancreatic inflammation and significantly upregulated insulin secretion compared with paired wild-type (WT) mice. However, chronic cerulein-administered CCR2-KO mice showed significantly increased infiltration of CD11b(+)/Gr-1(-) and CD11b(+)/Gr-1(high) cells, but not CD11b(+)/Gr-1(low) cells, in pancreas with severe inflammation and significantly decreased insulin secretion compared with their WT counterparts. Furthermore, although serum GLP-1 levels in chronic cerulein-administered WT and CCR2-KO mice were comparably upregulated after cerulein administrations, GLP-1 receptor levels in pancreases of chronic cerulein-administered CCR2-KO mice were significantly lower than in paired WT mice. Nevertheless, a significantly higher hyperglycemia level in chronic cerulein-administered CCR2-KO mice was markedly restored by treatment with a GLP-1 analog to a level comparable to the paired WT mice. Collectively, the CCR2/CCL2 axis-mediated CD11b(+)-cell migration to the pancreas is critically involved in chronic pancreatitis-mediated hyperglycemia through the modulation of GLP-1 receptor expression and insulin secretion.

Topics: Acute Disease; Animals; CD11b Antigen; Ceruletide; Chronic Disease; Disease Models, Animal; Female; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; Hyperglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Pancreatitis, Chronic; Receptors, CCR2; Receptors, Glucagon

To investigate chronic stress as a susceptibility factor for developing pancreatitis, as well as tumor necrosis factor-α (TNF-α) as a putative sensitizer.. Rat pancreatic acini were used to analyze the influence of TNF-α on submaximal (50 pmol/L) cholecystokinin (CCK) stimulation. Chronic restraint (4 h every day for 21 d) was used to evaluate the effects of submaximal (0.2 μg/kg per hour) cerulein stimulation on chronically stressed rats.. In vitro exposure of pancreatic acini to TNF-α disorganized the actin cytoskeleton. This was further increased by TNF-α/CCK treatment, which additionally reduced amylase secretion, and increased trypsin and nuclear factor-κB activities in a protein-kinase-C δ and ε-dependent manner. TNF-α/CCK also enhanced caspases' activity and lactate dehydrogenase release, induced ATP loss, and augmented the ADP/ATP ratio. In vivo, rats under chronic restraint exhibited elevated serum and pancreatic TNF-α levels. Serum, pancreatic, and lung inflammatory parameters, as well as caspases'activity in pancreatic and lung tissue, were substantially enhanced in stressed/cerulein-treated rats, which also experienced tissues' ATP loss and greater ADP/ATP ratios. Histological examination revealed that stressed/cerulein-treated animals developed abundant pancreatic and lung edema, hemorrhage and leukocyte infiltrate, and pancreatic necrosis. Pancreatitis severity was greatly decreased by treating animals with an anti-TNF-α-antibody, which diminished all inflammatory parameters, histopathological scores, and apoptotic/necrotic markers in stressed/cerulein-treated rats.. In rats, chronic stress increases susceptibility for developing pancreatitis, which involves TNF-α sensitization of pancreatic acinar cells to undergo injury by physiological cerulein stimulation.

Topics: Actins; Adenosine Diphosphate; Adenosine Triphosphate; Amylases; Animals; Antibodies; Calcium Signaling; Caspases; Ceruletide; Cholecystokinin; Chronic Disease; Cytoskeleton; Disease Models, Animal; Enzyme Activation; Lung Injury; Male; Necrosis; NF-kappa B; Pancreas, Exocrine; Pancreatitis; Protein Kinase C-delta; Protein Kinase C-epsilon; Protein Transport; Rats; Rats, Wistar; Restraint, Physical; Severity of Illness Index; Stress, Psychological; Tissue Culture Techniques; Trypsin; Tumor Necrosis Factor-alpha

Alcohol consumption is a risk factor for chronic pancreatitis (CP), but the mechanism in humans remains obscure because prolonged alcohol consumption in most humans and animal models fails to produce alcoholic chronic pancreatitis (ACP). We hypothesize that the process leading to ACP is triggered by a sentinel acute pancreatitis (AP) event; this event causes recruitment of inflammatory cells, which initiates fibrosis driven by the anti-inflammatory response to recurrent AP and/or chronic oxidative stress. The aim was to determine whether chronic alcohol consumption accelerates fibrosis in response to cerulein-induced pancreatitis in the rat. Wistar male rats were pair-fed control (C) or 5% ethanol (E) Lieber-DeCarli liquid diets. Animals were studied without pancreatitis (P0), with cerulein pancreatitis induced once (P1), or with cerulein-induced pancreatitis weekly for 3 weeks (P3). AP markers, inflammation, and fibrosis were measured histologically, by gene expression profiling and protein expression. Macrophage infiltration was reduced in EP0 versus CP0 rats, but the pattern was reversed after AP. Microabscess, severe necrosis, and early calcification were only induced in the EP3 rats. Fibrosis was significantly induced in the EP3 rats versus EP1, CP1, and CP3 by histology, hydroxyproline content, and mRNA expression for collagen alpha1(1) and procollagen alpha2(1). Proinflammatory cytokine mRNAs were up-regulated shortly after induction of AP, while the anti-inflammatory cytokines (interleukin-10 and transforming growth factor-beta) were strongly up-regulated later and in parallel with fibrogenesis, especially in the EP3 rats. Pancreatic fibrosis develops after repeated episodes of AP and is potentiated by alcohol. Expression of fibrosis-associated genes was associated with expression of anti-inflammatory cytokines in alcohol-fed rats.

Topics: Alcohol Drinking; Alcoholism; Animals; Ceruletide; Chronic Disease; Disease Models, Animal; DNA Primers; Fibrosis; Gene Expression Regulation; Male; Pancreatitis; Polymerase Chain Reaction; Rats; Rats, Wistar; RNA, Messenger

Peroxisome proliferator-activated receptor (PPAR)-gamma controls growth, differentiation, and inflammation. PPAR-gamma agonists exert anti-inflammatory effects in vitro and inhibit the activation of pancreas stellate cells, implicated in the formation and progression of fibrosis. We determined the influence of troglitazone, a ligand for PPAR-gamma, on pancreatic damage and fibrosis in experimental chronic pancreatitis. Mice received six hourly intraperitoneal injections with 50 microg/kg of cerulein or saline, three times a week for 6 weeks. One week after the last injection all mice were sacrificed. Untreated mice were compared with mice treated with troglitazone either during weeks 1 to 6 or weeks 4 to 6. All mice that received cerulein injections displayed histopathological signs of chronic pancreatitis at week 7. Troglitazone treatment improved all markers for severity of pancreatitis. Moreover, early and postponed troglitazone treatments were equally effective in diminishing intrapancreatic fibrosis as quantified by Sirius red staining, hydroxyproline content, and laminin staining as well as the increased number of pancreatic stellate cells and pancreas levels of transforming growth factor-beta. Thus, troglitazone attenuated pancreatic damage and inflammation in experimental chronic pancreatitis and remained beneficial in a therapeutic setting when given after initial damage had been established.

Topics: Actins; Animals; Cell Differentiation; Ceruletide; Chromans; Chronic Disease; Collagen; Disease Models, Animal; Fibrosis; Inflammation; Interleukin-6; Ligands; Mice; Mice, Inbred C57BL; Muscle, Smooth; Pancreatitis; Platelet Aggregation Inhibitors; PPAR gamma; Receptors, Tumor Necrosis Factor, Type I; Sodium Chloride; Thiazolidinediones; Transforming Growth Factor beta; Transforming Growth Factor beta1; Troglitazone

Oxygen free radicals (OFRs) mediate an important step in the initiation of experimental acute pancreatitis and several clinical findings suggested the possible contribution of OFRs to the pathogenesis of pancreatic fibrosis. So far, there are no studies which reporting potential role of OFRs in development of chronic pancreatitis with the prevention with antioxidants. This study was aimed to establish the mice model of chronic fibrosing pancreatitis and to prove the involvement of OFRs in chronic pancreatitis with fibrosis.. Repeated intraperitoneal cerulein injection was performed to induce chronic pancreatitis in mice. Histological changes in the pancreas were examined, and markers for oxidative stress were measured in the pancreatic tissue and serum of the mice. DA-9601, a phytochemical possessing anti-inflammatory and antioxidative action, was given together with cerulein to the mice.. Repeated intraperitoneal injection of cerulein provoked significant severity of chronic fibrosing pancreatitis after 5 weeks. After treatment of DA-9601, the extents of pancreatic fibrosis were statistically significantly decreased in accordance with lessened pancreatic inflammations. The NF-kappaB binding activities were increased in chronic pancreatitis, which were significantly attenuated after DA-9601 treatment. The levels of myeloperoxidase and iNOS activities were also significantly decreased in DA-9601-treated group compared to the pancreatitis only group. Cytoprotective proteins such as heat shock protein-70 (HSP) and metallothionein were significantly increased in the DA-9601-treated group. DA-9601 decreased the expressions of alpha-SMA and type I collagen in cultured pancreatic stellate cells.. Oxidative stress was principally involved in the pathogenesis of chronic pancreatitis with fibrosis.

Topics: Animals; Antioxidants; Artemisia; Cells, Cultured; Ceruletide; Chronic Disease; Disease Models, Animal; Fibrosis; Free Radicals; Male; Mice; Mice, Inbred ICR; Oxidative Stress; Pancreatitis; Plant Extracts

The majority of patients with chronic pancreatitis are alcoholics. Our goal was to develop a mouse model of alcohol dependent chronic pancreatitis.. Mice were fed either the non-alcohol containing Lieber-DeCarli diet or the Lieber-DeCarli diet containing 24% of calories as ethanol. After eight weeks and while on their respective diets, mice were subjected to repeated episodes of acute pancreatitis elicited by administration of caerulein. They were sacrificed 1, 3, and 5 weeks after the last dose of caerulein. Pancreatic morphology and collagen deposition were evaluated in samples stained with haematoxylin-eosin and Sirius red. Collagen content was quantitated by measuring OH-proline. Gene expression was determined by quantitative polymerase chain reaction.. Both groups of mice gained weight at the same rate. Those receiving the alcohol containing diet had serum alcohol levels of approximately 100 mM. No histological or gene expression differences were found in mice that were not subjected to acute pancreatitis, regardless of their diet. Necrosis, Sirius red staining, OH-proline content, and expression of alpha-1 collagen I, alpha-smooth muscle actin, transforming growth factor beta1, and tissue inhibitor of metalloproteinase 1 were all increased in mice fed the alcohol containing diet and given caerulein compared with those fed the control diet and given caerulein. Matrix metalloproteinase 9 expression was transiently decreased in mice fed ethanol and given caerulein compared with the group given caerulein but not fed ethanol.. We have developed a mouse model of alcohol dependent chronic pancreatic fibrosis. This mouse model may be useful in studies examining the effects of genetic manipulation on chronic pancreatitis.

Topics: Animals; Ceruletide; Chronic Disease; Collagen; Diet; Disease Models, Animal; Ethanol; Fibrosis; Gene Expression Regulation; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C3H; Pancreas; Pancreatitis; Weight Gain

Oxidative stress plays a role in the development of pancreatic fibrosis.. In the present study, we hypothesized that the administration of an antioxidant complex could ameliorate cerulein and cyclosporin A pancreatic fibrosis, assessed by changes in oxidative stress and a histopathological study in an experimental rat model.. Four groups of ten rats each. In Group A, the rats served as controls and were treated with intraperitoneal saline solution. In Group B, six courses of cerulein pancreatitis were induced at weekly intervals. In Group C, the rats received cyclosporin A the day before and the day on which pancreatitis was induced in Group B. In Group D, the rats were treated as in Group C but also received antioxidants. All rats were sacrificed at the seventh week.. The presence of fibrosis was evaluated according to a scoring system. Glutathione peroxidase was utilized as an indicator of oxidative stress and total antioxidant status as an indicator of total antioxidant tissue capacity.. The rats in Groups B and C showed more pancreatic fibrosis than those in Groups A and D (90%, 70%, 0%, and 20%, respectively). The glutathione peroxidase increased in Group B (455+/-196 mU/g protein) and Group C (243+/-206 mU/g protein) with respect to those in Group A (137+/-80 mU/g protein) and Group D (135+/-105 mU/g protein). Total antioxidant status was significantly higher in Groups B (1.41+/-0.96 mmol/g protein) and D (1.28+/-0.09 mmol/g protein) with respect to Groups A (0.10+/-0.06 mmol/g protein) and C (0.15+/-0.09 mmoL/g protein).. The administration of cerulein and cyclosporin A caused fibrosis, whereas antioxidant administration showed preventive effects regarding cerulein and cyclosporin A-induced pancreatic fibrosis.

Topics: Animals; Antioxidants; Ceruletide; Chronic Disease; Cyclosporine; Fibrosis; Glutathione Peroxidase; Male; Oxidative Stress; Pancreas; Pancreatitis; Rats; Rats, Wistar

The effects of R-102444 ((2R, 4R)-4-lauroyloxy-2-[2-[2-[2-(3-methoxy)phenyl]ethyl]phenoxy]ethyl-1-methylpyrrolidine hydrochloride) and its active metabolite R-96544 ((2R, 4R)-2-[2-[2-[2-(3-methoxy)phenyl]ethyl]phenoxy]ethyl-4-hydroxy-1-methylpyrrolidine hydrochloride), potent and selective 5-hydroxytryptamine 2A (5-HT2A) receptor antagonists, on development of pancreatitis were investigated in experimental models of acute and chronic pancreatitis. Rat acute pancreatitis was induced by caerulein (20 microg/kg) intraperitoneal injection and by pancreatic duct ligation. In both the models, serum amylase and lipase activities were markedly increased. R-102444 dose-dependently reduced these enzyme activities at a dose range of 10 to 100 mg/kg (p.o.) for the caerulein model and 0.3 to 10 mg/kg (p.o.) for the ligation model. In a mouse model of acute pancreatitis induced by a choline-deficient, ethionine (0.5%)-supplemented diet, subcutaneous administration of R-96544 (10-100 mg/kg, bid) reduced serum amylase activity. Histological analysis showed that R-96544 dose-dependently attenuated pancreatic necrosis, inflammation and vacuolization. The effect of R-102444 was further examined in male Wistar Bonn/Kobori rats (4-9 months of age) which spontaneously show pancreatic fibrosis and parenchymal destruction compatible with human chronic pancreatitis. In Wistar Bonn/Kobori rats (from 3 to 9 months of age) fed a diet containing 0.017% and 0.17% of R-102444, pancreatic weight, pancreatic protein and amylase content were higher compared to those in non-treated pancreatitis control rats. Histological analysis showed that R-102444 suppressed parenchymal destruction and replacement with adipose tissue, indicating inhibition of pancreatic atrophy. These results clearly indicate that R-102444 and R-96544 inhibit the progression of acute and chronic pancreatitis and support the contention of possible involvement of 5-HT2A receptors in the progression of experimental pancreatitis.

Topics: Acute Disease; Amylases; Animals; Ceruletide; Choline; Chronic Disease; Dietary Supplements; Ethionine; Injections, Intraperitoneal; Ligation; Lipase; Male; Organ Size; Pancreas; Pancreatic Ducts; Pancreatitis; Pyrrolidines; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Time Factors

The secretin-caerulein test (SCT) is generally considered the gold standard for evaluation of the exocrine pancreatic function. Problems related to enzyme inactivation in the aspirated duodenal juice limit the clinical applicability of the test. Pancreatic zinc, which is mainly secreted as constituent of metalloenzymes, is stable in duodenal juice and easy to quantify. The aim of this study was to analyze the accuracy of the secretin-caerulein-stimulated pancreatic zinc output as pancreatic function test in comparison with the standard SCT.. Forty consecutive patients with suspected chronic pancreatitis and 28 healthy subjects were studied. A SCT was performed after overnight fast by infusing intravenously secretin (1 U/kg/h) and caerulein (100 ng/kg/h) over 90 min. The duodenal content was continuously aspirated and separated at 15-min intervals and immediately analyzed for pH, bicarbonate, amylase, lipase, elastase, carboxypeptidase A, and zinc. Correlation and concordance between standard SCT and quantification of zinc output and the accuracy of the latter for diagnosing and grading the exocrine pancreatic dysfunction were calculated.. The pancreatic zinc output correlated significantly with enzyme and bicarbonate output (r ranging from 0.670 to 0.855; p < 0.001). A highly significant concordance was found between the degree of exocrine pancreatic dysfunction based on the standard SCT (bicarbonate and enzymes output) and that based only on zinc output (k = 0.831; p < 0.001). Quantification of the stimulated pancreatic zinc output has a sensitivity of 97% and a specificity of 91% in the diagnosis of exocrine pancreatic dysfunction.. The determination of pancreatic zinc output during secretin and caerulein stimulation is a simple and accurate method for evaluation of the exocrine pancreatic function. Zinc is stable in duodenal juice, and its determination as a single parameter simplifies the clinical applicability of the SCT.

Topics: Adolescent; Adult; Aged; Amylases; Bicarbonates; Carboxypeptidases A; Ceruletide; Chronic Disease; Duodenum; Female; Humans; Hydrogen-Ion Concentration; Linear Models; Lipase; Male; Middle Aged; Pancreas; Pancreatic Elastase; Pancreatic Function Tests; Pancreatitis; Secretin; Sensitivity and Specificity; Suction; Zinc

The objective was to investigate the effects of vitamin E on collagen deposition induced by Cyclosporin A (CsA) administration in rats with caerulein (Cr) pancreatitis. CsA transforms the fully regenerative, self-limited form of Cr pancreatitis into a chroniclike disease in conjunction with increased transforming growth factor (TGF)-beta and myofibroblast proliferation. Vitamin E inhibits TGF-beta release in mesangial cells and reduces CsA cytotoxicity. Wistar rats received CsA daily (20 mg/kg), and CR pancreatitis was induced on days 1 and 8 (Cr + CsA group). In a separate group, vitamin E (600 mg.kg(-1).day(-1)) was administered starting 4 days before CsA. Three other groups received either vehicle, CsA, or Cr alone. Thiobarbituric acid-reactive substance (TBARS), 8-isoprostanes, and hyaluronic acid were measured in plasma obtained on the day the animals were killed (day 15). Pancreases were weighed and processed for light microscopy to assess connective tissue and myofibroblast number. Pancreatic homogenates were also assayed for collagen (hydroxyproline) and TBARS content. TBARS, 8-isoprostane, and TGF-beta were elevated in CsA and Cr + CsA rats. Vitamin E treatment greatly decreased these parameters. Vitamin E also decreased the fall in pancreatic weight observed in Cr + CsA pancreas. Pancreatic hydroxyproline and plasma hyaluronic acid were increased in Cr + CsA rats but were effectively reduced by vitamin E. Morphology showed improvement in fibrosis score and a decreased number of myofibroblasts in vitamin E-treated rats. Vitamin E reduces oxidative stress and collagen deposition during the development of experimental chronic pancreatitis. Adjuvant antioxidants may be of value in the treatment of chronic pancreatitis.

Topics: Animals; Ceruletide; Chronic Disease; Collagen; Cyclosporine; Fibroblasts; Fibrosis; Lipid Peroxidation; Lipoproteins; Male; Myocytes, Smooth Muscle; Pancreas; Pancreatitis; Rats; Rats, Wistar; Vitamin E

A mouse model using repetitive acinar cell injury caused by supraphysiologic doses of cerulein to induce the characteristic fibrosis and loss of acinar cell mass found in human chronic pancreatitis was employed to identify early changes in gene expression. A gene array was used to detect changes in 18,000 expressed sequence tags; changes in specific transcripts were confirmed by RNase protection assays. These methods identified SPINK3, the mouse homologue of human and rat protease inhibitor genes, as being highly expressed in the pancreas and induced after pancreatic injury. Because SPINK3 may be an important serine protease inhibitor, its up-regulation may reflect an important endogenous cytoprotective mechanism in preventing further injury. The up-regulation of SPINK3 was specific; the mouse homologue of the zymogen-processing protein ZG-16p was also highly expressed in the pancreas but sharply down-regulated early in the course of injury. These findings suggest that the pancreatic acinar cell may respond to injury with a program of self-preservation and loss of normal function.

Topics: Amino Acid Sequence; Animals; Ceruletide; Chronic Disease; Female; Gene Expression Profiling; Gene Expression Regulation; Glycoproteins; Lectins; Membrane Proteins; Mice; Molecular Sequence Data; Oligonucleotide Array Sequence Analysis; Pancreas; Pancreatitis; Prostatic Secretory Proteins; RNA, Messenger; Sequence Alignment; Sequence Homology, Amino Acid; Trypsin Inhibitor, Kazal Pancreatic; Trypsin Inhibitors

Transforming growth factor-beta (TGF-beta) is an important cytokine in the fibrogenesis in many organs, including the pancreas. Using an adenoviral vector expressing the entire extracellular domain of type II human TGF-beta receptor (AdTbeta-ExR), we investigated whether inhibition of TGF-beta action is effective against persistent pancreatic fibrosis, and whether it exerts a beneficial effect on the pancreas in the process of chronic injury. To induce chronic pancreatic injury and pancreatic fibrosis, mice were subjected to three episodes of acute pancreatitis induced by six intraperitoneal injections of 50 microg/kg body weight cerulein at hourly intervals, per week for 3 consecutive weeks. Mice were infected once with AdTbeta-ExR, or with a control adenoviral vector expressing bacterial beta-galactosidase (AdLacZ). Pancreatic fibrosis was evaluated by histology and hydroxyproline content. Activation of pancreatic stellate cells (PSCs) was assessed by immunostaining for alpha-smooth muscle actin. Apoptosis and proliferation of acinar cells were assessed by immunostaining of ssDNA and Ki-67, respectively. Three-week cerulein injection induced pancreatic fibrosis and pancreatic atrophy with proliferation of activated PSCs. In AdTbeta-ExR-injected mice, but not AdLacZ-injected mice, pancreatic fibrosis was significantly attenuated. This finding was accompanied by a reduction of activated PSCs. AdTbeta-ExR, but not AdLacZ, significantly increased pancreas weight after chronic pancreatic injury. AdTbeta-ExR did not change the proportion of proliferating acinar cells, whereas it reduced the number of apoptotic acinar cells. Our results demonstrate that inhibition of TGF-beta action not only decreases pancreatic fibrosis but also protects the pancreas against chronic injury by preventing acinar cell apoptosis.

Topics: Animals; Ceruletide; Chronic Disease; Disease Models, Animal; Fibrosis; Male; Mice; Mice, Inbred BALB C; Mice, Transgenic; Pancreatic Diseases; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta

Diabetes occurs in 20-30% of patients above forty years old with chronic pancreatitis (CP). The aim of the present study was to determine the relationship between development of diabetes mellitus in CP patients and insufficiency of pancreatic exocrine secretion as well as changes in composition of pancreatic juice. Ninety CP patients with diagnosis confirmed by endoscopic retrograde pancreatography (ERP) were studied. They were divided into 3 groups in dependency on ERP changes (according to Cambridge classification) and oral glucose tolerance test (OGTT): group A--equivocal or mild changes in ERP and normal OGTT (control group); group B--moderate or marked changes in ERP and normal OGTT: group C--moderate or marked changes in ERP and diabetes mellitus. The exocrine pancreatic function was determined by the secretin-caerulein test; volume of duodenal content and bicarbonate, protein, alpha-amylase activity outputs were measured.. All exocrine pancreatic function parameters were diminished in B and C groups compared with A group--differences were statistically significant. However in group C values of volume and bicarbonate, protein and amylase activity were especially low.. Exocrine pancreatic insufficiency is strongly associated with anatomical changes of the pancreas but also depends on endocrine function.

Topics: Adult; Aged; Ceruletide; Cholangiopancreatography, Endoscopic Retrograde; Chronic Disease; Diabetes Mellitus; Female; Glucose Tolerance Test; Humans; Male; Middle Aged; Pancreas; Pancreatitis; Secretin

Leptin released by adipocytes has been implicated in the control of food intake but recent detection of specific leptin receptors in the pancreas suggests that this peptide may also play some role in the modulation of pancreatic function. This study was undertaken to examine the effect of exogenous leptin on pancreatic enzyme secretion in vitro using isolated pancreatic acini, or in vivo in conscious rats with chronic pancreatic fistulae. Leptin plasma level was measured by radioimmunoassay following leptin administration to the animals. Intraperitoneal (i.p.) administration of leptin (0.1, 1, 5, 10, 20 or 50 microg/kg), failed to affect significantly basal secretion of pancreatic protein, but markedly reduced that stimulated by feeding. The strongest inhibition has been observed at dose of 10 microg/kg of leptin. Under basal conditions plasma leptin level averaged about 0.15 +/- 0.04 ng/ml and was increased by feeding up to 1.8 +/- 0.4 ng/ml. Administration of leptin dose-dependently augmented this plasma leptin level, reaching about 0.65 +/- 0.04 ng/ml at dose of 10 microg/kg of leptin. This dose of leptin completely abolished increase of pancreatic protein output produced by ordinary feeding, sham feeding or by diversion of pancreatic juice to the exterior. Leptin (10(-10)-10(-7) M) also dose-dependently attenuated caerulein-induced amylase release from isolated pancreatic acini, whereas basal enzyme secretion was unaffected. We conclude that leptin could take a part in the inhibition of postprandial pancreatic secretion and this effect could be related, at least in part, to the direct action of this peptide on pancreatic acini.

Topics: Animals; Bethanechol Compounds; Ceruletide; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation, Preclinical; Drug Therapy, Combination; Eating; Gastric Fistula; Injections, Intraperitoneal; Leptin; Pancreas; Pancreatic Fistula; Pancreatic Juice; Postprandial Period; Rats; Rats, Wistar

The role of repetitive acute injury in the pathogenesis of chronic pancreatitis remains unknown. To determine if repetitive injury induced by pancreatic hyperstimulation would reproduce the characteristic features of human chronic pancreatitis, acute reversible pancreatic injury was induced in mice by twice weekly cerulein treatment, 50 microg/kg/hr x 6 hr, for 10 weeks. Procollagen alpha1(I) mRNA was markedly increased by week 2. Sirius red staining of interstitial collagen demonstrated progressive accumulation of extracellular matrix surrounding acinar units and in interlobular spaces. Atrophy, transdifferentiation of acinar units to ductlike tubular complexes, and dilatation of intraacinar lumina also developed. Electron microscopy demonstrated the presence of stromal cells in areas of fibrosis with morphologic characteristics of pancreatic stellate cells. These findings demonstrate that, in a murine model, repetitive acute injury to the pancreas by hyperstimulation can reproduce the major morphological characteristics of human chronic pancreatitis.

Topics: Acute Disease; Animals; Atrophy; Ceruletide; Chronic Disease; Extracellular Matrix; Female; Fibrosis; Gene Expression Regulation; Humans; Mice; Microscopy, Electron; Pancreatitis; Procollagen

The clinical relevance of the 13C-starch breath test was evaluated in comparison to the secretin-caerulein test as the "gold standard" of pancreatic function testing, fecal elastase concentration, and fecal chymotrypsin activity in 30 patients with mild (n = 15) or severe (n = 15) exocrine pancreatic insufficiency. 23 patients with gastrointestinal diseases of non-pancreatic origin and 31 healthy volunteers served as controls. 50 g of natural starch of maize were orally administered after a 12-h fast and breath samples were taken before and in 30 min intervals for five hours after oral ingestion and the increase of 13C/12C-isotopic ratio was analyzed by mass spectrometry. Specificity of fecal elastase (93%) and fecal chymotrypsin (93%) for impaired pancreatic function were much higher compared to the various parameters of the 13C-starch breath test (69-74%). Sensitivities of the 13C-starch breath test for all and separately for mild and severe exocrine pancreatic insufficiency were higher (total 70-77%) compared to fecal chymotrypsin (total 60%), but lower compared to fecal elastase (total 93%). With regard to the higher sensitivity and specificity, the higher practicability, and the lower costs determination of fecal elastase concentrations is superior to the 13C-starch breath test and therefore remains to be the most reliable indirect pancreatic function test available today.

Topics: Adult; Breath Tests; Carbon Radioisotopes; Ceruletide; Chronic Disease; Exocrine Pancreatic Insufficiency; Female; Humans; Male; Mass Spectrometry; Middle Aged; Pancreatic Function Tests; Pancreatitis; Reference Values; Secretin; Sensitivity and Specificity; Starch

Pancreatic exocrine hypofunction is markedly deteriorated during acute exacerbation in a rat model with chronic pancreatitis.. Little is known about pancreatic exocrine function during acute exacerbation in patients with chronic pancreatitis. We investigated changes in pancreatic exocrine function after inducing acute pancreatitis in an animal model of spontaneous chronic pancreatitis.. WBN/Kob rats with chronic pancreatitis sequentially underwent pancreatic exocrine function test 1-6 d after surgical preparation with external pancreatic fistula. We induced acute pancreatitis in another WBN/Kob rats by i.v. administration of cerulein at a rate of 10 micrograms/kg/h for 4 h 4 d after surgical preparation. Pancreatic exocrine function test was undertaken in a conscious state 1 d before and after cerulein administration.. In WBN/Kob rats not given cerulein, pancreatic exocrine function remained almost constant at 3-6 d after surgery. Marked hyperamylasemia developed immediately after cerulein administration. After its administration, the pancreas microscopically showed prominent interstitial edema and intracellular vacuolization of acinar cells in addition to the finding of pre-existing chronic pancreatitis. Basal and cholecystokinin-stimulated flow rate, bicarbonate output, and protein output, which were substantially impaired 1 d before cerulein administration, were further reduced 1 d after its administration.

Topics: Acute Disease; Amylases; Animals; Ceruletide; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Pancreas; Pancreatic Function Tests; Pancreatic Juice; Pancreatitis; Rats; Rats, Inbred Strains; Sincalide

To establish a new experimental model of chronic pancreatitis (CP) with diabetes, we investigated pancreatic endocrine function, blood flow, and histopathology in CP induced by repetition of cerulein injection plus water immersion stress in rats. CP rats were treated with water immersion stress for 5 hr and two intraperitoneal injections of 20 micrograms/kg body weight of cerulein once a week for 16 weeks. In the CP group, pancreatic contents of protein, amylase, elastase, and lipase significantly decreased to 64, 38, 23, and 68% of the control group, respectively. In oral glucose tolerance test (glucose 2 g/kg body wt), blood glucose level in the CP group was 212.1 +/- 97.8 mg/dl (mean +/- SD) at 30 min and was significantly higher than the control group (126.3 +/- 15.4 mg/dl)(P < 0.05). Two of seven rats in the CP group showed an obvious diabetic insulin in the CP group was 640.1 +/- 148.7 pM, significantly lower than in the control group (1133.4 +/- 242.0 pM)(P < 0.001). However, insulin content in the pancreas was 12.37 nmol/pancreas). In CP rats, winding and dilatation of surface blood vessels and gland atrophy were evident. Marked fibrosis, fatty changes, and destruction of lobular architecture were also demonstrated microscopically, although the structure of each pancreatic islet was preserved and each islet was fully stained with anti-insulin antibody. In the CP group, pancreatic blood flow by the hydrogen gas-clearance method was 197.6 +/- 33.0 ml/min/100 g, which was significantly less than the control group (276.2 +/- 19.1 ml/min/100 g) (P < 0.001). Thus, we conclude that the CP model induced by cerulein plus stress is a new CP model with diabetes in rats, in which the glucose tolerance was impaired without loss of insulin reserve.

Topics: Amylases; Animals; Blood Glucose; Ceruletide; Chronic Disease; Diabetes Mellitus, Experimental; Disease Models, Animal; Lipase; Male; Organ Size; Pancreas; Pancreatic Elastase; Pancreatitis; Proteins; Rats; Rats, Sprague-Dawley; Stress, Physiological

Seventeen Indian patients from Kerala State and 13 Indian controls were submitted to a dietary inquiry. Indian patients and controls had a low fat intake (40.8 g +/- 12.1 and 34.5 g +/- 11.0 per day, respectively) and a moderately low protein intake (52.8 +/- 9.5 and 47.8 +/- 11.3 g per day); 11 patients and 6 controls did not consume cassava. Pure nonactivated pancreatic juice was collected at endoscopy in 10 Indian patients who presented with tropical calcific diabetes, 12 apparently normal controls from the same area, and 23 apparently normal French controls. The only significant differences between Indian and French controls was a decreased pancreatic protein response to cerulein and an increased calcium concentration in the Indian subjects. The pancreatic juice of Indian patients was characterized by decreased volume, normal bicarbonate concentration, increased protein concentration when the acinar cells were not stimulated, with no response to cerulein, increased calcium concentration, and normal citrate concentration. These changes are very similar to the changes observed in French patients with chronic alcoholic pancreatitis. The lesions of 14 surgical resection pancreatic specimens from South Indian patients presenting with tropical pancreatitis were compared to pancreata from French patients presenting with chronic alcoholic pancreatitis. The only difference was that intraductal plugs, lesions of the duct epithelium, and retention cysts or pseudocysts were less frequent in Indians. These results show that the two nutritional forms of pancreatic lithiasis, alcoholic and tropical, have similar histological lesions and biochemical modifications of pancreatic juice.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Alcoholism; Calcinosis; Calcium; Ceruletide; Chronic Disease; Citrates; Diet; Female; Humans; India; Lipase; Male; Pancreatic Juice; Pancreatitis; Proteins

The present study was designed to analyze the underlying mechanism of gallbladder motor disturbance in chronic pancreatitis patients.. Gallbladder emptying to endogenous (oral test meal, Daiyan 13 g) and exogenous stimulation (iv cerulein, 30 ng/kg for 5 min) was examined by real-time ultrasonography in 12 patients with chronic pancreatitis and 10 normal subjects (controls). Plasma cholecystokinin levels during the endogenous stimulation were measured by bioassay.. In chronic pancreatitis patients compared with controls, the fasting gallbladder volume was significantly increased (29.5 +/- 2.2 vs. 21.5 +/- 2.8 ml), whereas the gallbladder emptying (percent change of the basal volume) to oral test meal was significantly decreased. Neither cholecystokinin secretion induced by the test meal, nor the gallbladder emptying response to intravenous cerulein, differed significantly between the two groups. However, when chronic pancreatitis patients were divided according to pathogenesis, it became clear that gallbladder emptying to intravenous cerulein was significantly greater in patients with alcoholic chronic pancreatitis than in patients with idiopathic pancreatitis.. Gallbladder emptying during the intestinal phase is generally reduced in patients with chronic pancreatitis, but gallbladder responsiveness to exogenous stimulation might be heterogeneous according to the pathogenesis.

Topics: Adult; Aged; Ceruletide; Cholecystokinin; Chronic Disease; Eating; Female; Gallbladder Emptying; Humans; Male; Middle Aged; Pancreatitis

We studied the utilization of amino acids by the pancreas after its hormonal stimulation in diseases in which disturbances occur of amino acid and protein metabolism. After 45 minutes of intravenous infusion of secretin (1 CU/kg) and cerulein (75 ng/kg) we found a significantly lower (p 0.05) decrease of amino acid concentration than in healthy individuals, both in chronic pancreatitis and in undernutrition and post-inflammatory cirrhosis with decompensation of liver function. Greatest disturbances in amino acid utilization by the pancreas were found in the case of valine, leucine and isoleucine. The results of studies show certain limitations in the use of this method for the assessment of the exocrine function of the pancreas.

Topics: Adult; Amino Acids; Ceruletide; Chronic Disease; Female; Humans; Infusions, Intravenous; Liver Cirrhosis; Male; Middle Aged; Nutrition Disorders; Pancreas; Pancreatitis; Secretin

Gallbladder dynamics, cholecystokinin (CCK), and pancreatic polypeptide (PP) release were studied in 14 patients with chronic pancreatitis (CP) (2 females, 12 males; age range 24-56 years) and 12 control subjects (4 females, 8 males, 21-50 years). On day 1, gallbladder contractility was investigated after ceruletide intravenous infusion (2.5 ng/kg/min for 10 min). On day 2, a mixed standard test meal (1450 kJ) was administered orally. Gallbladder volume was assessed at three time intervals before (-30, -15, 0 min) and at 5, 10, 20, 30, 40, 50, 60, 80, 100 and 120 min after stimulation by means of ultrasonography. CCK and PP plasma levels were determined at each time interval. Exocrine pancreatic function was assessed using the pancreolauryl serum test (PLT). Six patients with CP had severe exocrine pancreatic insufficiency (EPI) (PLT < 1.8 micrograms/ml) with steatorrhea, eight patients had mild-moderate EPI. Fasting gallbladder volume was increased in CP (32.3 +/- 3.1 cm3) as compared to controls (20.5 +/- 1.2 cm3) (P < 0.01). Peak gallbladder contraction (percent of initial volume) in CP ranged from 5 to 55% (controls: 8-46%) following ceruletide and from 17 to 86% (controls: 27-80%) following the test meal (NS). There was no correlation between the degree of EPI according to PLT and peak gallbladder contraction. Gallbladder emptying in CP patients was not different from controls, although the postprandial CCK response was significantly impaired (P < 0.01). Postprandial PP response in CP was correlated with the PLT result (r = 0.78; P < 0.01) but not with gallbladder emptying or refilling time.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Alcoholism; Ceruletide; Cholecystokinin; Chronic Disease; Female; Food; Gallbladder; Gallbladder Emptying; Humans; Male; Middle Aged; Pancreas; Pancreatic Function Tests; Pancreatic Polypeptide; Pancreatitis; Radioimmunoassay

187 patients were checked up over 4 years by the secretin-ceruletide test. Independently of the test results they were assigned to various disease groups on the basis of clinical assessment. 131 subjects were divided in a pilot investigation into: subjects with a healthy pancreas (n = 55); subjects with chronic pancreatitis (n = 50); subjects whose pancreatic condition could not be classified clearly (n = 26). 8 parameters were compared by univariate and multivariate statistical procedures in order to confirm or rule out the presence of chronic pancreatitis. The discriminatory power of the following parameters in duodenal fluid proved to be sufficiently high, with less than 15% frequency of misclassification: chymotrypsin (activity) and/or; lipase (activity) and/or; amylase (activity); viscosity. Under routine conditions measurement of the activity of two of these enzymes is sufficient. Their contribution to discrimination proved to be approximately equal. The diagnostic sensitivity and specificity of the parameters bicarbonate, lipase (concentration), trypsin (activity) and volume of duodenal fluid are lower. The classification rules derived from the above pilot group were confirmed by a diagnostic study under routine condition in a test group of 38 patients. Limitation to examining only volume and a maximum of 3 parameters which proved best in distinguishing between patients with chronic pancreatitis and healthy subjects, together with the omission of the first-hour samples after a secretin bolus, considerably reduced laboratory workload without altering the discriminatory power of the secretin-ceruletide test.

Topics: Adult; Alcoholism; Amylases; Ceruletide; Chronic Disease; Chymotrypsin; Duodenum; Female; Humans; Intestinal Secretions; Lipase; Male; Middle Aged; Pancreatitis; Reference Values; Secretin; Viscosity

Thirty patients suffering from chronic alcoholic pancreatitis (18 calcified) were entered into a study of exocrine and endocrine pancreatic function based on two maximal stimulation tests, namely the secretin-cerulein test and the glucagon test with serum assays of C peptide. The glucagon test was also performed in 19 control subjects. In addition, 10 chronic pancreatitis patients and nine controls were subjected to an oral glucose tolerance test (OGTT) with serum insulin determinations. C peptide basal values were decreased only in patients with severe pancreatic exocrine insufficiency (P less than 0.001), while delta C peptide values were also reduced in patients with moderate exocrine insufficiency (P less than 0.001). Lipase output correlated very well with delta C peptide values (P less than 0.001). While serum insulin levels during OGTT and C peptide basal values showed no significant differences between the chronic pancreatitis and control groups, delta C peptide values were significantly reduced in chronic pancreatitis patients (P less than 0.02). Both endocrine and exocrine function are impaired in chronic pancreatitis, as demonstrated by maximal tests, even in early stages of the disease.

Topics: Adult; Alcoholism; C-Peptide; Ceruletide; Chronic Disease; Female; Glucagon; Glucose Tolerance Test; Humans; Insulin; Islets of Langerhans; Male; Middle Aged; Pancreas; Pancreatic Function Tests; Pancreatitis; Secretin

We measured total plasma amino acid concentrations before and during pancreatic stimulation with secretin (1 clinical unit/kg/h) and caerulein (50 ng/kg/h) in 28 healthy volunteers, 60 patients with chronic pancreatitis (25 mild to moderate, 35 severe), and 22 patients with non-pancreatic digestive disease. In the healthy volunteers and patients with non-pancreatic digestive disease pancreatic stimulation caused a significant decrease (p less than 0.001) in plasma amino acid concentration, whereas in patients with chronic pancreatitis the decrease did not occur or was only slight. In six healthy volunteers and 24 patients with chronic pancreatitis (nine mild to moderate, 15 severe) repetition of the test using caerulein alone showed no significant differences from combined stimulation. Using the maximal per cent decrease in plasma amino acid concentration as an index of pancreatic function (lower normal limit 14%), 20 of the 25 patients with mild to moderate pancreatitis (80%) and 32 of the 35 with severe pancreatitis (91.4%) had values clearly below normal. The overall sensitivity of the test (86.7%) was significantly greater than that of the pancreolauryl test (64.2%) (p less than 0.02) and that of faecal chymotrypsin (66%) (p less than 0.05). None of the patients with non-pancreatic digestive disease had abnormal values. We conclude that the assessment of the decrease in the plasma amino acid concentration during pancreatic stimulation with secretin and caerulein is a simple, sensitive, and highly specific test of pancreatic function. The data obtained using caerulein stimulation alone suggest that the test can be further simplified, and made less costly, by eliminating the use of secretin.

Topics: Adult; Aged; Amino Acids; Ceruletide; Chronic Disease; Female; Humans; Male; Middle Aged; Pancreatic Function Tests; Pancreatitis; Secretin; Sensitivity and Specificity

Fecal chymotrypsin (FCT) has been measured by a new photometric method (Monotest Chymotrypsin; Boehringer, Mannheim) in 78 patients: 44 with chronic pancreatitis and 34 not affected by any pancreatic disease. The results were compared with those from other tests of pancreatic secretory (secretin-cerulein test) and digestive [serum and urinary p-aminobenzoic acid (PABA) and pancreolauryl] capacity. When FCT values were severely reduced (below 6.7 U/g), from 90 to 100% of the patients also presented abnormal pancreatic secretory and digestive capacity. On the other hand, 87% of the patients with normal FCT (above 20 U/g) presented normal secretory and digestive capacity. Patients with intermediate FCT values (between 6.7 and 20 U/g) showed normal or abnormal pancreatic secretory and digestive capacity with the same probability. Therefore, FCT, carried out as a first test, seems to identify subjects that need no further pancreatic function tests (normal and severely impaired FCT) and patients who need other more complex functional investigations (intermediate FCT values).

Topics: Biomarkers; Ceruletide; Chronic Disease; Chymotrypsin; Clinical Enzyme Tests; Duodenum; Feces; Humans; Pancreas; Pancreatic Function Tests; Pancreatitis; Reference Values; Secretin; Spectrophotometry

To define the characteristics of chronic schizophrenic patients who had responded poorly to treatment with ceruletide, several neuroendocrinological tests were carried out in 5 responders and 5 non-responders. Both thyroid-stimulating hormone and prolactin responses to thyrotropin-releasing hormone stimulation were within normal ranges in all subjects. The luteinizing hormone response to luteinizing hormone-releasing hormone, was slightly weaker in non-responders. There were no differences in the insulin tolerance test between responders and non-responders. Unusually delayed or prolonged growth hormone response to arginine infusion was observed in non-responders. These findings suggest dysfunction of the hypothalamo-pituitary system, especially of the arcuate nucleus and its functionally related areas, in non-responders.

Topics: Antipsychotic Agents; Ceruletide; Chronic Disease; Drug Resistance; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Insulin; Male; Neurosecretory Systems; Schizophrenia; Thyrotropin-Releasing Hormone

We determined by the ninhydrin method the plasma amino acid (AA) levels prior to, during and following, a 1-hour i.v. infusion of 1 U/kg body weight each of secretin and pancreozymin in patients with normal (n = 74) or reduced (n = 39) exocrine pancreatic function, as assessed by the duodenal aspiration test. The results of the two tests correlated significantly with each other (p less than 0.001). A maximum AA decrease of greater than or equal to 12% was observed in all patients with a normally functioning pancreas (specificity 100%), and of less than 12% in all patients with medium to high-grade impairment of pancreatic function (sensitivity 100%). Since, however, low-grade pancreas insufficiency (20-40% of the mean normal enzyme output) is recognized in fewer than one-half of the cases, the overall sensitivity of the AA-consumption test decreases to 69%. The results can, however, be improved by: 1) Calculating the mean percentage AA decrease with a limit value of 5% (sensitivity 90%); 2) determining individual AA with pancreas-specific absorption, such as serine (sensitivity 92%); 3) dropping the lower normal value of exocrine pancreatic function to 25% of the normal mean enzyme output (sensitivity 96%). Diseases that may be associated with the most common condition that causes pancreatic insufficiency--chronic pancreatitis--and which have an influence on AA metabolism, such as cirrhosis of the liver and diabetes mellitus, have no influence on the accuracy of the AA consumption test, which, considered overall, represents a competitive alternative to other tubeless tests of pancreatic function.

Topics: Adult; Aged; Amino Acids; Ceruletide; Cholecystokinin; Chronic Disease; Exocrine Pancreatic Insufficiency; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Nitrogen; Pancreatic Function Tests; Pancreatitis; Secretin

Chronic pancreatic insufficiency (CPI) was induced in male Wistar rats by the injection of a zein-oleic acid-linoleic acid solution into their pancreaticobiliary ducts. Animals injected developed severe pancreatic atrophy with fibrosis and greater than 90% loss of pancreatic enzyme content. The animals also developed malabsorption of fat and bentiromide. Three weeks after the CPI lesion was induced, animals were randomized to receive cerulein 2 micrograms/kg twice daily subcutaneously or saline twice daily subcutaneously for 2 weeks. Cerulein significantly increased pancreatic trypsinogen (p less than 0.03), amylase (p less than 0.01), lipase (p less than 0.02), DNA (p less than 0.02), and RNA (p less than 0.01) content and improved fat and bentiromide malabsorption as compared to saline (p less than 0.05). We conclude that cerulein therapy can cause significant hyperplasia of pancreatic acinar parenchyma in an animal model of CPI and that this therapy can partially reverse malabsorption.

Topics: Animals; Ceruletide; Chronic Disease; Disease Models, Animal; Drug Combinations; Exocrine Pancreatic Insufficiency; Hyperplasia; Linoleic Acid; Linoleic Acids; Male; Oleic Acid; Oleic Acids; Pancreas; Rats; Rats, Inbred Strains; Zein

In the present paper the gastric secretory and motor responsiveness to a gastrin-like peptide, caerulein, was assessed in rats with a chronic gastric ulcer induced by 'isolation', 48 h after completing prolonged treatments (30 and 60 days) with cimetidine (80 and 160 mg/kg), pirenzepine (8 and 16 mg/kg) and sulglycotide (160 mg/kg) administered orally as a single daily dose. After a 30 day pretreatment with both doses of cimetidine, gastric acid secretion was inhibited and the pylorus spasmogenic activity induced by caerulein was enhanced. The gastric effects of the peptide were not modified by pirenzepine pretreatment while an antisecretory action was shown by sulglycotide after the completion of prolonged treatment (60 days). The ulcers were significantly reduced by cimetidine (low dose) and sulglycotide after 30 day pretreatment. The effects are more likely to be related to the treatment than to the presence of the drugs on gastric receptors.

Topics: Animals; Anti-Ulcer Agents; Ceruletide; Chronic Disease; Female; Gastric Acid; Gastric Mucosa; Gastrointestinal Motility; Pepsin A; Rats; Rats, Inbred Strains; Stomach Ulcer

A prospective investigation of the diagnostic value of imaging procedures, computed tomography (CT) and endoscopic retrograde pancreatography (ERP) in comparison with the exocrine pancreatic function test, was done in 109 patients with chronic pancreatitis. The sensitivity of the secretin-ceruletide test (SC) proved to be 87% as compared with 89% for ERP and 78% for CT. The severity of morphological lesions noted in ERP and CT, shows a significant correlation to the degree of the exocrine functional impairment (p less than 0.001). 75% of patients with chronic pancreatitis had corresponding functional and ductal changes in advanced-stage disease, while only 47% of the patients with severe pancreatic insufficiency had CT changes of a corresponding degree. ERP lesions such as ductal obstruction and marked duct dilatation, and CT alterations such as atrophy and ductal dilatation, are almost always coupled with severe pancreatic insufficiency in chronic pancreatitis. Calcific lesions demonstrated by CT are also found in less advanced stages of exocrine insufficiency. Discrepancies between functional and morphological alterations were remarkable in "early" stages of the disease.

Topics: Adult; Aged; Calcinosis; Ceruletide; Cholangiopancreatography, Endoscopic Retrograde; Chronic Disease; Female; Humans; Male; Middle Aged; Pancreatic Ducts; Pancreatic Function Tests; Pancreatitis; Prospective Studies; Secretin; Tomography, X-Ray Computed

Eighteen patients with chronic pancreatitis and 12 healthy controls were subjected to hormonal stimulation by continuous secretin plus cerulein intravenous infusion or a rapid injection of secretin. In both tests total serum amylase, lipase, and TLI (trypsin-like immunoreactive substances) levels were measured. Continuous intravenous infusion does not bring about changes in the serum levels of the enzymes studied; rapid injection of secretin, however, induces changes in the serum levels of TLI and lipase (but not amylase) which makes it possible to distinguish patients with chronic pancreatitis in its early stages from advanced chronic pancreatitis but is of doubtful value in distinguishing healthy subjects from those suffering with chronic pancreatitis.

Topics: Adult; Aged; Amylases; Ceruletide; Chronic Disease; Endopeptidases; Female; Humans; Infusions, Parenteral; Lipase; Male; Middle Aged; Pancreas; Pancreatitis; Secretin

We examined the maximal serum PABA concentration within 3 hrs (MS-PABA) and the 6 hr urinary PABA recovery (6 hr U-PABA) after BT-PABA administration, PABA excretion index, and chymotrypsin secretory response to caerulein-secretin stimulation in ten control subjects and fifteen patients with chronic pancreatitis diagnosed on the basis of pancreatograms. The results suggested that MS-PABA can distinguish the patients with definite irregular dilatation of the main pancreatic duct from the controls, but not those with localized irregular dilatations of the side branches from the controls. MS-PABA showed a significant correlation with 6 hr U-PABA, PABA excretion index, chymotrypsin output and bicarbonate output. This modified method was shown to be useful in the diagnosis of chronic pancreatitis with unequivocally abnormal pancreatograms and/or markedly decreased chymotrypsin secretion. This modification will serve to simplify the BT-PABA test by eliminating urinary collection and shortening the procedure time.

Topics: 4-Aminobenzoic Acid; Adult; Aminobenzoates; Bicarbonates; Ceruletide; Chronic Disease; Chymotrypsin; Female; Humans; Male; Middle Aged; Pancreatitis; para-Aminobenzoates; Secretin

The determination of basal pancreatic serum enzymes is of little value in the diagnosis of chronic pancreatitis. The organ specificity of a recently introduced immunochemical method of determining pancreatic lipase is guaranteed. The diagnostic value of the basal and stimulated serum-lipase determination by the immunochemical assay in chronic pancreatitis was investigated on 84 patients and controls. In 46 patients with chronic pancreatitis the serum increase of pancreatic lipase after secretin stimulation (1 U/kg) was significantly (P less than 0.01) higher than the pancreatic lipase increase in patients with non-pancreatic intestinal disorders and in healthy controls. Patients with chronic pancreatitis deserve to be classified in subgroups, according to the degree of the exocrine pancreatic insufficiency established by means of the secretin-ceruletide test. Of the patients with chronic pancreatitis and a slight to moderate exocrine pancreatic insufficiency 87% show an abnormal serum pancreatic-lipase increase and differ significantly (P less than 0.01) from patients with severe exocrine insufficiency who exhibit an increase of the pancreatic serum lipase only in exceptional cases. Specificity is limited, since an abnormal serum lipase increase after stimulation is found in 20% of controls.

Topics: Adolescent; Adult; Aged; Ceruletide; Chronic Disease; Diagnosis, Differential; Female; Humans; Immunoenzyme Techniques; Lipase; Male; Middle Aged; Pancreatitis; Secretin

The effect of glucagon on human exocrine pancreatic secretion was evaluated in ten patients by analysis of pure pancreatic juice. Pancreatic juice was obtained by endoscopic cannulation of the pancreatic duct at 2-min intervals during constant intravenous infusion of secretin (1 U per kg of body weight per hr) plus caerulein (0.04 micrograms per kg of body weight per hr). Since steady secretion was established 20 minutes after the start of juice collection, a further five 2-min fractions were collected as controls, then constant intravenous infusion of glucagon (15 micrograms per kg of body weight per hr) was commenced. Pancreatic juice was collected for a further 20 minutes. The control fractions and post-glucagon fractions were compared in each patient using Student's test. Glucagon depressed secretin-caerulein-stimulated pancreatic secretions. More uniform reductions were observed in the concentration and output of protein and enzymes. Individual variations were observed in the secretory volume and bicarbonate concentration and output. Amylase and lipase were depressed in a parallel fashion in seven patients and in the remaining three, amylase was more depressed than lipase. The post-glucagon reduction in pancreatic secretion was not proportional to the rise in plasma glucagon and blood glucose.

Topics: Adenocarcinoma; Adult; Aged; Ceruletide; Chronic Disease; Depression, Chemical; Female; Glucagon; Humans; Male; Middle Aged; Pancreas; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Secretin; Secretory Rate; Time Factors

Topics: Adult; Aged; Ceruletide; Chronic Disease; Female; Humans; Male; Middle Aged; Pancreatic Function Tests; Pancreatitis; Secretin; Selenomethionine

Lactoferrin (LF), chymotrypsin and lipase activity were measured in duodenal juice during pancreatic stimulation. Secretin (0.5 CU/kg/h) plus cerulein (75 ng/kg/h) were infused intravenously in 98 subjects: 33 patients without organic diseases (C), 40 patients affected by chronic pancreatitis (CP), and 25 patients with different gastrointestinal diseases (GID). LF was determined by means of a new noncompetitive immunoenzymatic assay with a sensitivity in the duodenal juice of 5 ng/ml. Duodenal LF concentrations were significantly higher in CP than in C or GID (p less than 0.001). LF was in a normal range in acute relapsing pancreatitis due to biliary stones or pancreas divisum. In the diagnosis of the chronic pancreatitis, LF/lipase ratios showed a specificity of 93% and a sensitivity of 95%. Our results show that LF immunoassay in duodenal juice is a sensitive and accurate assay to apply in pancreatic function tests involving duodenal content analysis.

Topics: Adult; Body Fluids; Ceruletide; Chronic Disease; Chymotrypsin; Duodenum; Female; Gastrointestinal Diseases; Humans; Lactoferrin; Lactoglobulins; Lipase; Male; Middle Aged; Pancreatitis; Secretin

Seventy-two chronic alcoholics, 40 (all males) with chronic pancreatitis and 32 (23 males and nine females) with liver cirrhosis, were submitted to liver biopsy, endoscopic retrograde cholangiopancreatography and secretin-caerulein test in order to assess a possible liver involvement in chronic pancreatitis and viceversa, and to evaluate the existence of any relationship between the diseases of these two organs. Chronic pancreatitis patients were younger than cirrhotic patients and drank more than the cirrhotic females. Twenty-nine of the 40 patients had abnormal liver histology, five had micronodular cirrhosis and were older than the others. No relationship was found between the degree of pancreatic impairment and the type of liver injury. Five liver cirrhosis patients had an endoscopic retrograde cholangiopancreatography picture consistent with chronic pancreatitis; two were females with an alcohol intake lower than the one of the other females. In conclusion the association of chronic pancreatitis and liver cirrhosis was observed in a minority of cases, with the same percentage in the two groups, even if the cirrhotic subjects were older than the pancreatitics. Therefore we can postulate that different factors have roles in the pathogenesis of alcoholic cirrhosis and of chronic alcoholic pancreatitis. The association of the two diseases in two women with a relatively low alcohol intake supports this hypothesis.

Topics: Adult; Alcoholism; Ceruletide; Cholangiopancreatography, Endoscopic Retrograde; Chronic Disease; Female; Humans; Liver Cirrhosis, Alcoholic; Male; Pancreatic Ducts; Pancreatic Function Tests; Pancreatitis; Prospective Studies; Secretin

To test the discriminatory potential of certain indices of pancreatic function we performed duodenal perfusion studies and measured trypsin, bicarbonate, and lactoferrin outputs, and plasma concentrations of pancreatic polypeptide and motilin in the basal state and during continuous intravenous stimulation with 100 ng kg-1h-1 Ceruletide and 1 CU kg-1h-1 secretin. The following groups were studied: 12 normal volunteers (NV), seven patients with chronic pancreatitis with steatorrhea (CPS), and seven without steatorrhea (CP). Stimulated trypsin outputs, after 45 min of stimulation, were the best discriminant among the groups (NV versus CPS, p less than 0.0005; NV versus CP, p less than 0.005; CP versus CPS, p less than 0.05). Basal trypsin outputs showed similar patterns but failed to discriminate between NV and CP. Bicarbonate outputs were less discriminatory than trypsin outputs. Lactoferrin outputs failed to discriminate, but transient high peak outputs occurred in the initial stimulation period in all four patients with calcific chronic pancreatitis, suggesting a washout phenomenon. Basal motilin levels were elevated in both groups of pancreatitis (p less than 0.05). Stimulated pancreatic polypeptide levels were lower in CPS (NV versus CPS, p less than 0.05) but higher in CP (NV versus CP, p less than 0.005). These differences were also apparent in the basal state. We conclude that the best discrimination among the three groups was achieved by measurement of trypsin outputs, after 45 min of stimulation. In addition, the pancreatic polypeptide response may be used as a marker of residual pancreatic function in chronic pancreatitis.

Topics: Adult; Aged; Bicarbonates; Celiac Disease; Ceruletide; Chronic Disease; Female; Humans; Islets of Langerhans; Lactoferrin; Male; Middle Aged; Motilin; Pancreas; Pancreatic Polypeptide; Pancreatitis; Secretin; Trypsin

Topics: Adult; Aged; Ceruletide; Cholangiopancreatography, Endoscopic Retrograde; Chronic Disease; Female; Humans; Male; Middle Aged; Pancreas; Pancreatitis; Secretin

Topics: Adult; Antipsychotic Agents; Ceruletide; Chronic Disease; Drug Evaluation; Female; Humans; Male; Middle Aged; Schizophrenia

A quantitative correlation between computer-tomographic (CT) findings and exocrine pancreatic function following secretin-ceruletide stimulation was performed in 48 patients with chronic pancreatitis; thereby a significant correlation between the degree of morphological changes in CT and the stage of functional impairment was found (r = 0,7841, p less than 0,001). Bicarbonate secretion/h showed the strongest correlation to CT findings (r = -0,7193, p less than 0,001) within the single functional parameters. CT showed a limited sensitivity (50%) in detecting chronic pancreatitis in cases with a slight functional impairment (stage 1). Morphological signs as calcifications, pancreatic duct ectasia were constantly coupled with a severe degree of functional impairment, whereas enlargement and cysts were found throughout the different functional stages.

Topics: Adult; Aged; Amylases; Bicarbonates; Ceruletide; Chronic Disease; Chymotrypsin; Exocrine Pancreatic Insufficiency; Female; Humans; Male; Middle Aged; Pancreas; Pancreatitis; Secretin; Tomography, X-Ray Computed; Trypsin

Topics: Animals; Apomorphine; Behavior, Animal; Brain; Bucladesine; Ceruletide; Cholecystokinin; Chronic Disease; Dopamine; Humans; Rats; Rats, Inbred Strains; Schizophrenia; Species Specificity

The reliability of the para-aminobenzoic acid (PABA) test (performed in the conventional manner, i.e. without control day) and of the pancreolauryl test was assayed in respect of the exocrine pancreatic capacity measured by using the secretin-caerulein test in 57 subjects, 22 of which were suffering from chronic pancreatitis. When 50 and 20% urinary excretion of the orally administered Bz-Ty-PABA and pancreolauryl, respectively, were chosen as the lower normal limits, the PABA test showed a specificity quite similar to that of the pancreolauryl test (97 and 95%, respectively) despite the lack of a control day test, but a lower sensitivity (39 vs. 83%). The association of both tests was not advantageous compared with the pancreolauryl test alone.

Topics: 4-Aminobenzoic Acid; Aminobenzoates; Ceruletide; Chronic Disease; Exocrine Pancreatic Insufficiency; Humans; Pancreas; Pancreatic Extracts; Pancreatic Function Tests; Pancreatitis; para-Aminobenzoates; Secretin

Topics: Adult; Ceruletide; Cholelithiasis; Chronic Disease; Female; Gallbladder; Humans; Male; Middle Aged; Pressure; Rest

The diagnostic accuracy of a tubeless pancreatic function test--Pancreolauryl (PLT)--was evaluated on 97 patients and healthy controls: we found a pathological result of PLT in 31 (88.6%) of 35 patients with proven chronic pancreatitis and a normal PLT in 30 (90%) of 33 controls with no pancreatic disease. In 29 patients with a defined gastrointestinal disease other than chronic pancreatitis the test result was pathological in 51%. This result points towards a limited specificity of the PLT in this latter group, but shows its usefulness as an indicator for maldigestion accompanying the primary disease. In comparison to firmly established diagnostic means for chronic pancreatitis the PLT result was in accordance with the Secretin-Ceruletide function test in 81.3% with ERCP in 80.9% and with computertomography in 76.4%.

Topics: Ceruletide; Cholangiopancreatography, Endoscopic Retrograde; Chronic Disease; Female; Fluoresceins; Humans; Indicators and Reagents; Male; Middle Aged; Pancreatic Function Tests; Pancreatitis; Secretin; Tomography, X-Ray Computed

Caerulein, a decapeptide chemically related to CCK-8, was administered intramuscularly to 20 patients with chronic schizophrenia in two different doses of 0.3 and 0.6 microgram/kg. BPRS ratings were made before and 3 weeks after the injection. The neuroleptic therapy was not discontinued, but both drug and dose were not changed at least 3 weeks before the first injection and during the study period. Clinically obvious and statistically significant improvement in psychotic symptoms occurred shortly after the injection of caerulein. The greatest change occurred 1--2 weeks later. There was an evident correlation between the observed changes and the dose injected. Our findings suggest that caerulein has a long-acting, antipsychotic activity in chronic schizophrenia. Furthermore, our findings suggest the involvement of CCK-like peptides in the pathogenesis of schizophrenia.

Topics: Adult; Ceruletide; Chronic Disease; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Topics: Adult; Ceruletide; Chronic Disease; Female; Humans; Male; Middle Aged; Pancreas; Pancreatic Function Tests; Pancreatitis; Secretin

Eleven healthy volunteers (C) and nine patients affected by chronic relapsing pancreatitis (CP) were administered N-Benzoyl-L-Tyrosyl-PABA orally, at a dose of 150 mg combined, on different days, with: 1) water alone (schedule a); 2) Lundh meal (schedule b); 3) Secretin-Caerulein by i.v. infusion (0.5 CU/kg/hr and 75 ng/kg/hr respectively) (schedule c); 4) Caerulein by i.m. injection (300 ng/kg) (schedule d). The mean urinary PABA recovery in CP was lower than in C with all the schedules, but this was statistically significant only with schedules a and c (P less than 0.02 and P less than 0.05 respectively). With respect to b, c, and d, the mean urinary PABA recovery seemed to increase both in C and in CP as compared with schedule a, but only in the CP group with schedule b was the increase statistically significant (P less than 0.05). The present data show that the exocrine pancreatic stimulants do not improve the reliability of the PABA test.

Topics: 4-Aminobenzoic Acid; Aminobenzoates; Ceruletide; Chronic Disease; Humans; Infusions, Parenteral; Injections, Intramuscular; Pancreatitis; para-Aminobenzoates; Secretin; Tyrosine; Water

Series of total bile acid levels in blood plasma of definite time intervals before and after administration of three different stimulants, i.e. caerulein, egg yolk and fatty meal, were investigated in 10 normal subjects as a control group, in three patients in the florid stage of acute viral hepatitis, in 15 patients in the convalescent stage of acute viral hepatitis, in 10 patients with chronic persistent hepatitis, in 15 patients with chronic aggressive hepatitis, in 20 patients with cirrhosis of the liver and in 15 patients with fatty liver. This procedure can be regarded as an endogenous bile acid tolerance test and can be utilized as a differential diagnostic tool for chronic liver diseases.

Topics: Adult; Aged; Bile Acids and Salts; Ceruletide; Chronic Disease; Dietary Fats; Egg Yolk; Enterohepatic Circulation; Fatty Liver; Female; Gallbladder; Hepatitis; Humans; Liver Cirrhosis; Liver Diseases; Male; Middle Aged; Muscle Contraction

Topics: Adult; Alcoholism; Ceruletide; Chronic Disease; Contrast Media; Female; Hepatic Artery; Humans; Male; Mesenteric Arteries; Middle Aged; Pancreatitis; Radiography

The inhibitory effects of intravenous infusions of secretin, glucagon and caerulein on the gastric acid response to bombesin were studied in 8 duodenal ulcer patients. Bombesin was found to be a very potent stimulator of gastric acid secretion in patients with duodenal ulcer. There were no significant differences in acid outputs per 15-min period between bombesin infused in a dose of 0.9 microgram/kg/h and pentagastrin infusion administered in a maximal dose, at a rate of 6.0 microgram/kg/h. Secretin (1 U/kg/h), glucagon (30 microgram/kg/h) and caerulein (0.1 microgram/kg/h) produced significant decreases in gastric acid secretion evoked by bombesin given in a dose of 0.9 microgram/kg/h. Percentages of inhibition were 48.6, 45.2 and 35.5, respectively. It is supposed that secretin and glucagon given in pharmacological doses are capable of interfering with the action of gastrin released from antrum by means of bombesin on the parietal cell by noncompetitive kinetics. Caerulein administered in a pharmacological dosis, however, can inhibit the effect of gastrin released by bombesin on the parietal cells by a competitive kinetic.

Topics: Adult; Bombesin; Ceruletide; Chronic Disease; Duodenal Ulcer; Gastric Juice; Glucagon; Humans; Male; Middle Aged; Pentagastrin; Peptides; Secretin

The literature dealing with the debated and not yet completely settled question of the causal relationship between dyslipidaemia and acute and chronic diseases of the pancreas is reviewed. Four personal cases of chronic pancreatitis associated with dyslipidaemia are presented and their possible pathogenetic relationships are discussed.

Topics: Adult; Amylases; Ceruletide; Chronic Disease; Creatinine; Female; Humans; Hyperlipidemias; Lipase; Lipids; Male; Middle Aged; Pancreas; Pancreatitis; Trypsin

Exocrine pancreatic function was studied by rapid intravenous injection and by prolonged intravenous infusion of a combination of secretin and caerulein in a group of patients with proven pancreatic disease and in controls. The aim was to compare the value of the two procedures of stimulation in the diagnosis of exocrine pancreatic insufficiency. Results showed that the pancreatic response to infusion of the stimulants discriminates normal from abnormal pancreatic function better than responses to rapid injection.

Topics: Adolescent; Adult; Ceruletide; Chronic Disease; Diabetes Mellitus, Type 1; Female; Humans; Infusions, Parenteral; Injections, Intravenous; Male; Middle Aged; Pancreas; Pancreatic Juice; Pancreatitis; Secretin

During infusion of caerulein, the output of gamma-glutamyl transpeptidase and biliary alkaline phosphatase is significantly more increased in chronic pancreatitis patients than in normal subjects. The presence of the gall-bladder is necessary to observe this effect of caerulein. It is not related to the discharge of large amounts of both enzymes by the diseases pancreas.

Topics: Alkaline Phosphatase; Ceruletide; Chronic Disease; Duodenum; gamma-Glutamyltransferase; Humans; Intestinal Secretions; Pancreatitis

The effect of maximal doses of cholecystokinin and caerulein on lipase and chymotropsin concentrations were compared in large groups of patients with almost equal capacities of bicarbonate secretion. The responsiveness of the pancreas is, as a whole, higher with caerulein than with cholecystokinin, this feature being specially evident in patients with chronic calcifying pancreatitis.

Topics: Bicarbonates; Ceruletide; Cholecystokinin; Chronic Disease; Chymotrypsin; Duodenum; Humans; Lipase; Pancreas; Pancreatitis

Comparative studies between activity of serumlipase, lipaseevocationstest and endoscopic retrograde cholangiopancreaticography (ERCP) in 45 patients with chronic pancreatitis, pancreatic cysts or pancreatic carcinoma confirm, that elevated enzyme values after caerulein stimulation indicate an alteration of the pancreatic parenchyma. However, this findings does not give information on the etiology of the damage. On the basis of the presented results it seems that the lipase-evocationstest has only limited value as screening method within the total of clinical methods for the assessment of light and medium severe stages of chronic pancreatitis and accompanying forms of pancreatitis. There is no evidence that this method may be used for screening for carcinoma of the pancreas. A positive result gives a valuable information, but the lack of an increase of lipase activity does not exclude the existence of pancreatic affection. In each case with clinical suspicion for pancreatic disease further diagnostic investigation by the ERCP and additional radiographic methods should be performed.

Topics: Adult; Aged; Amylases; Ceruletide; Cholangiography; Chronic Disease; Clinical Enzyme Tests; Endoscopy; Humans; Lipase; Male; Middle Aged; Pancreatic Cyst; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis

Serum lipase activity, which is a more specific indicator of pancreatic damage than serum amylase activity, was determined in 51 patients before and immediately after endoscopic retrograde cholangio-pancreatography (ERCP) and 24 hours subsequently. An increase in serum lipase activity without clinical signs of acute pancreatitis was observed immediately after pancreatography in 20 cases. Increased serum lipase activity after 24 hours is largely observed in patients with parenchymography or those displaying increased values already in the fasting state before ERCP. This observation emphasizes the need for caution in the assessment of the indication for ERCP in patients with preexisting increased serum lipase activity in view of the very real risk of acute pancreatitis and the need to avoid parenchymography of the pancreas. According to our experience the addition of a broadspectrum antibiotic such as gentamycin to the contrast medium may, to a large extent, avoid the development of acute pancreatitis. Lipase evocation tests carried out 10 days after the ERCP showed negative results in patients with increased enzyme activity and parenchymography after pancreatography. Hence, it is concluded that ERCP causes symptomless reversible biochemical pancreatic changes, as opposed to irreversible pancreatic damage.

Topics: Acute Disease; Ceruletide; Cholangiography; Chronic Disease; Clinical Enzyme Tests; Endoscopy; Humans; Lipase; Pancreatitis; Stimulation, Chemical

Exocrine pancreatic function has been evaluated in 24 controls and 29 patients with confirmed chronic pancreatitis by continuous infusion (90 min) of synthetic caerulein, 100 ng/kg/h, plus GIH secretin, 1 CU/kg/h. Mean secretory values of the controls were comparable to those obtained by others using maximal doses of secretin and CCK. Unlike the controls, patients suffering from chronic pancreatitis demonstrated a progressive reduction in secretion during infusion. Thus, the comparison of responses for the final 30-min period gave much clearer and more complete discrimination between normal and abnormal pancreatic function than the preceding 30-min period.

Topics: Adolescent; Adult; Bicarbonates; Ceruletide; Chronic Disease; Chymotrypsin; Female; Humans; Injections, Intravenous; Lipase; Male; Middle Aged; Pancreas; Pancreatitis; Secretin; Secretory Rate; Trypsin

Angiography of the pancreas was performed in 55 patients after the administration of different drugs stimulating the blood flow in the pancreas and the pancreatographic effect in this group was compared with that in a series of 174 celiac angiographies without drugs. With drugs the pancreatographic effect appeared more frequently (74.5 per cent) than without (18.4 per cent). The small pancreatic arteries and veins were better demonstrated with drugs. The pancreatographic effect seems to be of value for the differential diagnosis of chronic pancreatitis and carcinoma of the pancreas.

Topics: Adult; Angiography; Ceruletide; Chronic Disease; Diagnosis, Differential; Female; Humans; Male; Middle Aged; Pancreatic Neoplasms; Pancreatitis; Secretin; Serotonin; Tolazoline

Topics: Ceruletide; Cholecystokinin; Chronic Disease; Endoplasmic Reticulum; Golgi Apparatus; Humans; Insulin; Insulin Secretion; Microscopy, Electron; Pancreas; Pancreatic Diseases; Pancreatic Juice