Health care enigmas

A study of the exacrinous function of the pancreas made in 205 healthy persons aged from 18 to 90 has evidenced that in ageing there takes place in the duodenal mixture of juices a statistically significant decline in the activity of trypsin and of its inhibitor, lipase, amylase, in the level of bicarbonates and in the volume of the juice along with an increase in the content of chlorides. In ageing more marked changes become apparent following application of the agents stimulating the pancreatic secretion of the secretin and pancreozymin mechanism of action, and then the greatest changes are seen to occur on the level of lipase and trypsin and the least -- on the level of the amylase activity and the bicarbonate alkalinity content. Note has also been taken of an age-specific statistically significant decline in the activity of the studied pancreatic enzymes in the blood (trypsin, its inhibitor, lipase, amylase) and in the urine (lipase, amylase).     

Inhibitory effect of somatostatin analogue, SMS 201-995, on secretin-stimulated exocrine secretion in isolated perfused rat pancreas

In order to clarify the effect of somatostatin of the ductal secretion of the exocrine pancreas, we measured pancreatic juice and protein secretion stimulated with 10 pM secretin and/or 10 pM cholecystokinin (CCK) in the presence or absence of somatostatin analogue, SMS 201-995 (SMS) utilizing the isolated perfused pancreas of rats. SMS significantly inhibited both pancreatic juice flow and protein output elicited by 10 pM secretin without affecting basal secretion. The inhibitory effect of SMS was dose-dependent and maximal inhibition was observed with 1-10 nM. Half-inhibitory dose of SMS for juice secretion was 140 pM. Because CCK is thought to potentiate secretin action on the ductal system, we examined the effect of SMS on pancreatic secretory response to 10 pM secretin in combination with 10 pM CCK. In the experimental system we used, the amounts of pancreatic juice and protein secreted during a 30-min stimulation with secretin and CCK were additive. SMS inhibited both pancreatic juice and protein secretion to the level comparable with that obtained with either stimulus and SMS. SMS had no effect on CCK-stimulated pancreatic juice secretion but significantly inhibited protein output. The present study demonstrated, therefore, that SMS inhibits ductal secretion in response to physiological concentration of secretin.     

Clinical significance of the tests used in the diagnosis of pancreatic diseases

Different methods available for investigating patients for pancreatic disease are discussed. They first include measurement of pancreatic enzymes in biological fluids. Basal amylase and/or lipase in blood are truly diagnostic in acute pancreatitis but their utility is low in chronic pancreatic diseases. Evocative tests have been performed to increase the sensitivity of blood enzyme measurement. The procedure is based on enzyme determination following administration of pancreozymin and secretin, and offers a valuable aid in diagnosis of chronic pancreatitis and cancer of the pancreas. They are capable of discerning pancreatic lesions but are not really discriminatory because similar changes are observed in both diseases. The measurement of urinary enzyme levels in patients with acute pancreatitis is a sensitive indicator of disease. The urinary amylase excretion rises to abnormal levels and persists at significant values for a longer period of time than the serum amylase in acute pancreatitis. The fractional urinary amylase escretion seems to be more sensitive than daily urinary measurement. The pancreatic exocrin function can be assessed by examining the duodenal contents after intravenous administration of pancreozymin and secretin. Different abnormal secretory patterns can be determinated. Total secretory deficiency is observed in patients with obstruction of excretory ducts by tumors of the head of the pancreas and in the end stage of chronic pancreatitis. Low volume with normal bicarbonate and enzyme concentration is another typical pattern seen in neoplastic obstruction of escretory ducts. In chronic pancreatitis the chief defect is the inability of the gland to secrete a juice with a high bicarbonate concentration; but in the advanced stage diminution of enzyme and volume is also evident. Diagnostic procedures for pancreatic diseases include digestion and absorption tests. The microscopic examination and chemical estimation of the fats in stool specimens in different conditions of intake are still important screening tests. Isotopic estimates of steatorrhea and distinction between labeled triolein and oleic acid absorption do not provide greater diagnostic discrimination than traditional procedures. 131I labeled proteins permit a good evaluation of a negative nitrogen balance. Sophisticated procedures to estimate exocrine pancreatic insufficiency are based on the study of endoluminal digestive processes at several times and different level of the small intestine. They permite esclusion of extrapancreatic factors interfering in digestion and absorption functions. The endocrin pancreatic function is evaluated by mean of oral tolerance test an radioimmunoassay of blood insulin. It is generally agreed that "diabetes" caused by insulin deficiency and digestion and absorption defects are the result of diffuse pancreatic destruction. Many methods are now available investigating patients with pancreatic disease but the single use of one of them is never satisfactory...     

Pancreatic function and congenital duodenal anomalies

Six children operated on for congenital anomalies of the duodenum were investigated to find out if pancreatic dysfunction was associated with the duodenal malformation, even in the absence of clinical evidence of pancreatic insufficiency. None of the children had diarrhea and none requested nutritional support. Pancreatic function was assessed by enzyme activities (lipase, trypsin, and chymotrypsin) bicarbonate and calcium measurements in pancreatic juice obtained through a nasoduodenal tube under stimulation by secretin and cerulein. Results showed no significant modification in hydro-electrolytic secretion, but impairment of enzymatic secretion was seen. The physiopathological relationship between duodenal anomalies and pancreatic dysfunction is discussed.     

Pancreatic duct cells in rats: secretory studies in response to secretin, cholecystokinin-pancreozymin, and gastrin in vivo

In rats given a copper-deficient diet plus penicillamine to destroy the acinar tissue selectively, the sensitivity and secretory pattern of pancreatic duct cells to a variety of hormones has been investigated. Resting flow rate of this pancreatic duct model was in the same range as in the intact gland. The duct cells responded to increasing doses of secretin by producing more juice with increasing outputs of bicarbonate, sodium, potassium, and chloride. Bicarbonate concentration increased with the lowest dose of secretin up to values of 64 mEq per liter and did not further increase with higher doses of secretin and increasing secretory rates. The concentration of potassium increased with increasing doses of secretin and flow rates, whereas chloride concentration decreased in a reciprocal fashion to bicarbonate. Gastrin and cholecystokinin-pancreozymin did not significantly stimulate the duct cells. Atropine did not inhibit the action of secretin on the flow rate or on bicarbonate secretion.     

Treatment of angiographically produced cord seizures by intra-arterial diazepam

Motilin and secretin were compared in regard to their effects on pancreatic bicarbonate and protein secretion in conscious dogs provided with chronic pancreatic fistulas. Dose-response analysis showed that maximal bicarbonate response to motilin was about 5% of that to secretin and maximal protein response was about 35% of that to caerulein. The interaction of these two peptides showed that motilin is a potent inhibitor of secretin-induced bicarbonate secretion. Since motilin is released by duodenal alkalinization and inhibits pancreatic bicarbonate secretion, it is possible that this peptide is involved in the feedback mechanism of inhibition of pancreatic secretion by alkaline pancreatic juice present in the duodenum.     

The behavior of mucopolysaccharide in the pancreatic juice in chronic pancreatitis

In order to study whether or not mucosubstance increases occur in the pancreatic juice of patients with chronic pancreatitis, hexosamine was measured in duodenal aspirates during the secretin phase (S-40) following pancreozymin-secretin stimulation in 16 normal subjects, 37 patients with chronic pancreatitis, 6 patients with alcoholism, 13 patients with gallstones, and 11 patients with peptic ulcer. The hexosamine concentrations in the pancreatic secretions showed a negative correlation with the bicarbonate concentrations and volume output. Rises in hexosamine concentration were seen in alcoholism and chronic pancreatitis, especially in alcoholic pancreatitis. This is probably intimately related with the repeated ingestion of large amounts of alcohol over long periods of time. Since high hexosamine values are noted in the relapsing type of chronic alcoholic pancreatitis, increases in viscosity due to mucosubstance increases in the pancreatic juice are probably related with the recurrence of acute attacks accompanying ductal stenosis or obstruction.     

Role of secretin in negative feedback regulation of postprandial pancreatic secretion in dogs

BACKGROUND: A negative feedback regulation of pancreatic exocrine secretion has been observed in fasting rats, pigs, and humans, but this phenomenon could not be found in fasting dogs. The aims of the present study were to investigate whether or not postprandial pancreatic secretion is regulated by a negative feedback mechanism and to determine if the mechanism is mediated by secretion and/or cholecystokinin (CCK) in dogs. METHODS: In eight dogs prepared with gastric and Herrera's pancreatic cannulas, pancreatic juice was collected for 3 hours after feeding a mixed meal to measure volume, bicarbonate, and trypsin output. Peripheral venous blood was obtained to determine plasma immunoreactive secretin and CCK levels. Four groups of experiments were performed while pancreatic juice was diverted from the duodenum: (1) diversion of pancreatic juice alone, (2) intraduodenal infusion of fresh pancreatic juice while pancreatic juice was diverted, (3) intraduodenal infusion of 150 mg/h of trypsin and 300 mg/h of chymotrypsin, and (4) intraduodenal infusion of 0.1 mol/L NaHCO3. RESULTS: Pancreatic secretion during diversion of pancreatic juice was significantly greater than that obtained while pancreatic juice was returned. Diversion-induced pancreatic hypersecretion was significantly suppressed by intraduodenal administration of pancreatic proteases, but it was not influenced significantly by 0.1 mol/L NaHCO3. The suppression by either pancreatic juice or proteases paralleled the decrease in plasma secretin response, whereas the CCK response remained unchanged. The inhibitory effect of pancreatic proteases on pancreatic secretion was blocked by a physiological dose of exogenous secretin, 0.06 clinical U.kg-1.h-1. CONCLUSIONS: In dogs, postprandial pancreatic secretion is controlled by a negative feedback mechanism mediated mainly by the release of secretin, but not by CCK.     

Clinical application of a new mobile integrated orbital implant]

Uraemic pancreatopathy is frequently observed in patients with chronic renal failure. The aim of the study was to assess some parameters of exocrine pancreatic function in uraemic patients maintained on intermittent haemodialyses. Elevated serum amylase activity was found in these patients. The most significant finding was the low bicarbonate output in duodenal content after secretin-cerulein stimuli, comparable with that obtained in patients with chronic pancreatitis. It indicates pancreatic exocrine defect in uraemic patients. A fall in protein output and lower amylase activity in duodenal content was also observed in haemodialyzed patients after stimulation. Low basal acid output (BAO) and enhanced maximal (MAO) and peak (PAO) acid outputs were found in uraemic patients after pentagastrin stimulation. Gastritis and duodenitis were frequently diagnosed in endoscopic and histopathological examinations in these patients. In patients with chronic renal failure even without clinical signs of pancreatic, laboratory findings of exocrine pancreatic abnormalities are reported. It may be the cause of uraemic pancreatopathy.     

Comparison of the effects of natural and synthetic secretin on the exocrine secretion of the human pancreas (author's transl)

In 16 healthy male subjects the effects of natural and synthetic secretin on the function of the exocrine pancreas were compared. Following; stimulation with secretin in all cases pancreozymin was injected to ascertain normal pancreatic secretory capacity. The methods applied corresponded to those used in the multicenter study of the European Pancreatic Club. No significant differences were found between the results concerning volume of secretion, maximal bicarbonate concentration, maximal bicarbonate output and enzyme secretion rates after stimulation with natural and synthetic secretin, respectively. It is concluded that the synthetic peptide can be utilized in the same way as the natural product in the secretin-pancreozymin-test.     

Exocrine pancreatic secretion in man following one week of M1-muscarinic receptor blockade

A double-blind, randomized, placebo-controlled crossover study was performed to assess the influence of one week of selective M1-muscarinic receptor blockade on pancreatic exocrine secretion in man. Ten healthy subjects received telenzepine (3 mg p.o.) and placebo each for 8 days, with a 6-day drug-free washout interval between treatment sequences. On Day 8 of each sequence, pancreatic secretion was stimulated for 2 h by infusion of submaximal secretin (0.2 U.kg/h) followed by maximal stimulation with secretin (1.0 U.kg/h) and ceruletide (120 ng.kg/h). Telenzepine had no significant effect on secretory parameters during submaximal stimulation with secretin. During maximal stimulation, total protein, secretory volume, and output of amylase, trypsin and bicarbonate were unexpectedly increased by telenzepine. These findings might be partially explained by removal of the inhibitory influence of pancreatic polypeptide, which was depressed by telenzepine. Acute studies have shown that M1-receptor antagonists inhibit exocrine secretion. Our results suggest that adaptation of physiological mechanisms governing the exocrine pancreas may occur after one week of receptor blockade by a therapeutic dosage of telenzepine, to the extent that M1-blockade no longer inhibits secretion.     

Protective effect of prostaglandin E2 on cerulein-induced rat pancreatitis]

In order to clarify the effect of prostaglandin E2 (PGE2) on cerulein-induced rat pancreatitis, we investigated the interaction of PGE2 with cerulein or secretin. Intravenous infusion of 10 micrograms/kg.h cerulein inhibited external secretion of the pancreas from one hour and caused macroscopic edema at 3 hours. Administration of PGE2 relieved the inhibitory effect of supramaximal dose of cerulein and decreased the pancreatic edema. The 100 micrograms/kg.hr PGE2 had no significant effect on the pancreatic juice volume and amylase secretion stimulated with 0.2 micrograms/kg.hr of cerulein. Intravenous injection of 100 micrograms/kg PGE2 inhibited both the volume and amylase secretion of pancreatic juice stimulated with 1 U/kg.h of secretin. The protective effect of PGE2 on cerulein-induced pancreatitis was not the stimulation on secretion but caused the cytoprotective effect of PG such as stabilization of cytoplasmic and lysosomal membrane.     

Behavior of exocrine pancreatic function during treatment with antibiotics and antineoplastic agents

The thesis is composed of two parts, the first part is concerned with experiments in rats, the second part confirms the findings in human beings. After administration of oxytetracycline, chloramphenicol and cyclophosphamide, respectively, to rats an approximately dose-dependent decrease in the pancreatic secretion of proteins and enzyme activities was demonstrable in vivo under exogenous stimulation. The exocrine pancreatic function was studied in humans by performing a secretin-pancreocymin test before and after treatment with oxytetracycline or chloramphenicol and before and after massive-dose therapy with cyclophosphamide or combined cytotoxic treatment (as outlined by De Vita). The investigations further included an examination of the exocrine pancreatic function in subjects on maintenance therapy with cyclophosphamide or busulfan and a comparison with the exocrine pancreatic function in a group of controls. In the oxytetracycline-treated humans there was a depression of the amylase and lipase activities in the duodenal secretion. Administration of chloramphenicol produced a decrease in the amylase output only. In the patients on massive-dose or continued therapy with cyclophosphamide the pancreatic function remained essentially unchanged. In contrast, cytotoxic combination treatment resulted in decreased activities of amylase and lipase. After maintenance treatment with busulfan a reduction of the trypsin and amylase activities was detectable. The volume and electrolyte outputs were found to remain essentially unchanged in all investigations. An impairment in enzyme synthesis is suggested as the major cause of the observed changes of pancreatic secretion after antibiotic and cytotoxic treatment.     

Altered pancreatic function after proximal gastric vagotomy in man

The secretion of bicarbonate into the duodenum in response to stepwise increasing doses of secretin (0.078, 0.23, 0.7, and 2.1 U/kg-hr) was investigated in 11 duodenal ulcer patients before and about 1 1/2 years after proximal gastric vagotomy. After the vagotomy the mean output of bicarbonate in response to the two lowest doses of secretin increased from 2.2 to 3.7 mmoles per 30 min im response to 0.078 U/kg-hr and from 6.6 to 9.8 mmoles per 30 min in response to 0.23 U/kg-hr. On the other hand, the output of bicarbonate in response to the highest dose of secretin decreased from 20.3 mmoles per 30 min before to 16.5 mmoles per 30 min after the vagotomy. The dose of secretin required for half-maximal stimulation decreased from 0.7 to 0.3 U/kg-hr. The calculated maximal bicarbonate response decreased from 27.8 to 17.7 mmoles per 30 min. Thus, increased sensitivity of the bicarbonate-producing cells to low doses of secretin and decreased bicarbonate secretory capacity of the pancreas after proximal gastric vagotomy were found.     

Absence of rapid adaptation of the exocrine pancreas of conscious dogs to diets enriched in fat or carbohydrates

Adult mongrel dogs were fed during 8 days on one of two diets, one rich in fat (FR) and the other rich in carbohydrates (CR), in order to compare the exocrine pancreatic secretion in the basal period and in response to food. Under resting conditions, mean pancreatic juice flow and mean values of protein content, amylase and lipase activity and production were similar in both experimental groups, suggesting that the period of adaptation used did not produce any influence on the measured parameters. No significant difference between the two dietary groups was found in postprandial volume of pancreatic juice. The peak of pancreatic juice flow in FR-group was smaller but remained elevated until the end of the 5th h, possibly due to the fact of delayed gastric emptying when animals are fed with a high fat diet. No significant differences were found between the groups in neither postprandial amylase activity and secretion nor lipase activity. On the other hand, lipase output was significantly higher in FR-group but only during the 5 postprandial h. This fact may be related to some intestinal factor stimulated by the hydrolysis products of fat. Finally, our findings show that no rapid adaptation of exocrine pancreatic secretion exist to the diet, at least in our experimental conditions. Of course, this does not exclude that the phenomenon of adaptation may appear in the dog under long-term adaptation to the diet.     

Chemoprevention of head and neck cancer

The role of pituitary adenylate cyclase-activating polypeptide (PACAP) in the regulation of exocrine and endocrine pancreas was investigated in conscious sheep. Intravenous infusions of PACAP-27 and PACAP-38 (1, 3, and 10 pmol/kg/min) for 10 min during phase II of the duodenal migrating myoelectric complex accelerated pancreatic protein and amylase outputs dose-dependently. The responses in enzyme secretion to both PACAPs at the highest doses were inhibited significantly by atropine infusion (14.4 nmol/kg/min). Vasoactive intestinal polypeptide (VIP) at 3 pmol/kg/min significantly accelerated protein but not amylase outputs, although the response to the highest dose was not significantly influenced by atropine. PACAP-27 and VIP increased pancreatic juice flow and bicarbonate output dose-dependently; however, the responses to the highest dose were not altered significantly by atropine. On the other hand, intravenous injection of PACAP-38 (100 pmol/kg) did not influence basal plasma concentration of insulin, glucagon, and glucose. Moreover, PACAP-38 (1-100 pmol/kg) altered neither pancreatic endocrine response to intravenous infusion of glucose (20 mumol/kg/min) not that to n-butyric acid (33 mumol/kg/min). These results suggest that PACAP contributes to the regulation of exocrine secretion of the ovine pancreas but not to endocrine secretion. PACAP appears to accelerate pancreatic enzyme secretion mostly via the cholinergic nerves.     

Kinetics of pancreatic juice secretion in relation to duodenal migrating myoelectric complex in preruminant and ruminant calves fed twice daily

Daily secretion of pancreatic juice, including postprandial responses to food, was investigated in two groups of calves: preruminant (fed with liquid food) and ruminant (fed with solid food). Male Friesian calves (1 week old and 6 weeks old) were surgically fitted with a pancreatic duct catheter, duodenal cannula and two duodenal electrodes. Continuous 24 h collections of pancreatic juice and myoelectrical recordings were performed with minimal restraint and disturbance of animals. In both groups of calves clear periodic fluctuations in pancreatic juice secretion (volume, protein output and trypsin activity) coinciding with duodenal migrating myoelectric complexes (MMC) were recorded. Secretion of juice per cycle and per day was greater in ruminant calves, but the frequency and amplitude of cycles were lower in this group. There were no differences between day and night-time preprandial pancreatic cycles and duodenal MMC in preruminant calves, whilst in ruminant calves, evening MMC were longer than morning MMC. The pancreatic cephalic phase (increase of volume flow, protein output and trypsin activity during and just after food intake) was significant only in preruminant calves following morning feeding. Postprandial pancreatic cycles did not differ from preprandial cycles, except the pancreatic cycle (juice volume and trypsin activity) in which food was offered in preruminant calves. No gastric or intestinal phase was observed in either group of calves. In conclusion, biological cycles of the gastrointestinal tract are present in both preruminant and ruminant calves, and these cycles evolve along with the change from liquid to solid food.     

Telomerase activity detected in pancreatic juice 19 months before a tumor is detected in a patient with pancreatic cancer

We report a patient with pancreatic cancer in whom telomerase activity had been detected in the pancreatic juice 19 months before he was diagnosed as having pancreatic cancer. A 61-yr-old alcoholic man complaining of epigastric and back pain was diagnosed as having groove pancreatitis based on the presence of inflammation in the pancreatic head and its extension to the duodenal mucosa with an associated elevated serum amylase level. All imaging modalities showed no sign of a tumor. However, high telomerase activity was detected in the pancreatic juice collected during endoscopic retrograde pancreatography. His symptoms subsided due to abstinence from alcohol. A tumor, however, was recognized on computed tomography 19 months later, at which time the patient immediately underwent a pylorus-preserving pancreaticoduodenectomy. The carcinoma was located mainly in the Santorini duct region. High telomerase activity in the pancreatic juice may precede clinical detection of pancreatic cancer and thus could be a useful early diagnostic marker for pancreatic cancer.     

Treatment of childhood acute lymphoblastic leukaemia with the BFM regimen

This study was undertaken to further characterize the secretory response of the rat pancreas after reserpine treatment. Rats were given reserpine (1 mg kg-1 day-1 i.p.) or vehicle for 7 days. To distinguish between specific effects of reserpine and those related to secondary malnutrition caused by the drug, the secretory response of a group of pair-fed (PF) animals to reserpine was also investigated. Amylase release from dispersed pancreatic acini, prepared from control (C), PF and reserpine-treated (R) rats were used to evaluate functional secretory capacity. Reserpine and pair-feeding caused reduced responses of pancreatic acini to secretin. The pair-feeding-altered secretin response was greatly improved by increasing extracellular Ca2+ concentration, whereas a slight improvement was noticed in the R group. Reserpine significantly reduced the secretory response to the ionophore A23187 at concentrations above 5 x 10(-7) M in 1.25 mM Ca2+; in 2.5 mM Ca2+, the response to the ionophore was significantly higher in the R group than in C at all ionophore concentrations. Furthermore, at 2 x 10(-7) M ionophore, the secretory response to secretin in the R group became significantly higher than that in the C group but comparable to that of the control+ionophore. In conclusion, reserpine affects the secretory response to secretin as did pre-exposure of pancreatic acini to a high concentration of carbamylcholine. The modified secretory response to the ionophore following reserpine treatment indicates that reserpine may act as a 'Ca2+ entry mechanism' antagonist which may explain the partial reduction in the secretin response.     

Effect of somatostatin immunoneutralization on gastric acid and pancreatic enzyme secretion in anesthetized rats

The involvement of somatostatin in urethane-anesthesia-evoked suppression of gastric acid secretion has been described. The present study has examined the role of endogenous somatostatin in diminished pancreatic enzyme secretion during anesthesia, while monitoring acid secretion concurrently. Rats were anesthetized with either urethane or sodium pentobarbital. An indwelling catheter was placed into the right jugular vein. The esophagus and the pylorus were ligated, and the stomach was perfused with saline. The common bile duct was ligated at the hepatic hilum, and cannulated at the duodenal end of the duct for collecting pure pancreatic juice. Purified somatostatin monoclonal antibody (CURE.S6) or control antibody (keyhole limpet hemacyanin, KLH) was injected iv in increasing doses (0.05; 0.15; 0.5; and 1.5 mg) every 30 min (n = 6). Gastric acid and pancreatic amylase secretions were measured. The effect of the antibodies on CCK-8-stimulated (0.25-2.50 nmol/kg/h) pancreatic amylase secretion was also tested. During urethane anesthesia somatostatin antibody induced a dose-dependent increase in acid output, while control antibody did not change it. Basal pancreatic amylase secretion was not affected by either somatostatin or by control antibody. Pancreatic secretory responses to high but not to low doses CCK-8 were found to be significantly increased following immunoneutralization of somatostatin. In sodium pentobarbital-anesthetized rats somatostatin antibody stimulated basal acid secretion but did not affect basal pancreatic amylase secretion. Our data indicate that in anesthetized rats endogenous somatostatin mediates suppression of basal gastric acid secretion but not that of basal pancreatic amylase secretion, and this action does not depend on the type of anesthesia. Furthermore, endogenous somatostatin may play a physiological role in modulating stimulated pancreatic enzyme secretion in this species.