B. Lembcke

Effect of the Somatostatin Analogue Sandostatin (SMS 201–995) on Gastrointestinal, Pancreatic and Biliary Function and Hormone Release in Normal Men

The effect of the long-acting somatostatin analogue Sandostatin (SMS 201-995) on intestinal absorption and propagation (mouth-to-caecum transit time; MCTT), on pancreatic secretion and on gall bladder contraction after direct (secretin-pancreozymin test) and indirect stimulation (Lundh meal), and on meal-induced responses of seven gastrointestinal regulatory peptides has been investigated. In a double-blind cross-over study, 9 healthy volunteers completed two 7-day periods with subcutaneous injections of either placebo or 25 micrograms SMS 201-995 twice daily. Mean faecal fat excretion was increased to 19.2 g/day and MCTT was three times longer during the SMS period. After duodenal infusion of a mixture containing D-galactose, D-xylose and triglycerides, SMS 201-995 significantly reduced the serum concentrations of D-galactose but increased serum levels of D-xylose. After 6 days of pretreatment, SMS 201-995 completely suppressed duodenal trypsin, lipase and bilirubin increases in response to endogenous stimulation by a Lundh meal. Concomitantly, cholecystokinin (CCK) release and gall bladder contraction were almost abolished. Compared with placebo, SMS 201-995 significantly diminished pancreatic amylase, trypsin and lipase output after stimulation with CCK, while the secretion of fluid and bicarbonate in response to secretin was unchanged. This inhibition of enzyme response was significantly more marked after a single injection of the analogue than after pretreatment for 7 days and did not reach the level of exocrine pancreatic insufficiency. CCK-induced gall bladder contraction was significantly inhibited by a single dose of 25 micrograms SMS 201-995 but not after 7 days of pretreatment with the somatostatin analogue.

Functional Reserve Capacity of the Exocrine Pancreas

The functional reserve capacity of the pancreas, as reflected by the absence of steatorrhea, was correlated with the results of a secretin-pancreozymin test (SPT) in 47 patients with exocrine pancreatic insufficiency due to chronic pancreatitis. The results indicate that a severe reduction in enzyme output (but not in bicarbonate concentration and output) is usually associated with steatorrhea. However, there were a number of patients with steatorrhea despite only moderate enzyme output impairment, while others had normal fat excretion but severely reduced enzyme secretion. Thus, the degree of impaired pancreatic function, as measured by the SPT, cannot be predicted by the presence of steatorrhea; vice versa, a moderately abnormal SPT does not exclude the presence of pancreatic steatorrhea. Therefore, for a sophisticated evaluation of the functional reserve capacity of the exocrine pancreas, both the SPT and fecal fat analysis are considered necessary. The correlation between impaired glucose tolerance and exocrine pancreatic function was poor.

Effect of somatostatin analogue (SMS 201-995, Sandostatin) on pancreatic secretion in humans.

The effect of the long-acting somatostatin analogue SMS 201-995 on exocrine pancreatic function and hormone release was investigated in a double-blind, placebo-controlled study in healthy subjects. SMS 201-995 was administered subcutaneously at a dose of 25 micrograms twice daily, and all tests were performed 30 minutes after the morning injection. Pancreatic enzyme secretion, gall bladder contraction, and cholecystokinin response after a Lundh meal were completely inhibited by SMS, while pancreatic enzyme secretion elicited by intravenous injection of secretin and pancreozymin was suppressed by 80 percent. The inhibitory effect of SMS on endogenous cholecystokinin release was fully operative on the sixth day of injection treatment, whereas the inhibitory effect on exogenous cholecystokinin injection significantly decreased after SMS administration for seven days, indicating desensitization of the end organ by somatostatin. The release of pancreatic polypeptide by a solid test meal is abolished by administration of 25 micrograms of SMS, the release of gastric inhibitory polypeptide is nearly completely suppressed, the response of insulin and C-peptide are significantly lowered, and the gastrin response is only slightly reduced.

Pancreatic Calcifications: No Indicator of Severe Exocrine Pancreatic Insufficiency

Pancreatic calcifications are believed to occur only in advanced stages of exocrine pancreatic insufficiency. This belief has been reevaluated by correlating the results of the secretin-pancreozymin test, fecal fat analysis, and the presence of pancreatic calcifications on plain abdominal x-rays in 79 patients with chronic pancreatitis. Exocrine pancreatic insufficiency was classified as slight, moderate, or severe according to the results of the function tests, and pancreatic calcifications were assessed semi-quantitatively (grades 1-3) by an independent examiner. The results showed that severe exocrine pancreatic insufficiency did occur even in the absence of calcifications. Calcifications were more frequently detected with increasing severity of exocrine pancreatic insufficiency. The qualitative demonstration of pancreatic calcification was, however, not an indicator of severe, decompensated exocrine pancreatic insufficiency (50% false-positive results). It is concluded that pancreatic calcification is not necessarily an indicator of severe exocrine pancreatic insufficiency, and vice versa. Comparison between the results of tests for endocrine pancreatic function and plain abdominal x-ray showed such similarity that it can also be concluded that pancreatic calcifications are no indication of abnormal endocrine function, and vice versa.

Effect of 1-desoxynojirimycin derivatives on small intestinal disaccharidase activities and on active transport in vitro.

The influence of two new 1-desoxynojirimycin derivatives, BAY m 1099 and BAY o 1248, on rat small intestinal disaccharidases (sucrase, maltase, isomaltase, glucoamylase, lactase, trehalase) and alkaline phosphatase activity has been investigated in vitro. Both compounds are very potent alpha-glucosidase inhibitors. Tested in the range of 0.1-5.0 micrograms/ml, inhibition is strongest on sucrase (up to 97.1%) and glucoamylase (up to 96.7%). BAY m 1099 also reduced (up to 56.4%) beta-galactosidase (lactase) activity. For both inhibitors a competitive type of sucrase inhibition was demonstrated (Lineweaver-Burk plot). Affinity versus sucrase was unusually tight. The Ki of BAY m 1099 versus sucrase amounted to 1.14 x 10(-7) M and of BAY o 1248 to 6.92 X 10(-8) M (Dixon plot). Both inhibitors did not impair active transport of L-leucine or methyl-alpha-D-glucoside into everted rings of rat jejunum in vitro.

Postprandial Glycemic Control, Hormonal Effects and Carbohydrate Malabsorption during Long-Term Administration of the Alpha-Glucosidase Inhibitor Miglitol

This double-blind study was performed to evaluate the relation of the glycemic and hormonal (insulin, gastric inhibitory polypeptide) responses to standardized starch and sucrose meals to signs (H2 exhalation) and subjective symptoms of carbohydrate malabsorption during administration of 100 mg BAYm 1099 (miglitol) t.i.d. over a period of 8 weeks. Two groups of 8 male healthy volunteers received either placebo or verum. Oral sucrose loading tests (50 g) with and without miglitol were performed at day -5, 1, 25 and 53 of the study, starch loading tests (50 g) with and without the inhibitor were carried out at day -2, 4, 28 and 56. Miglitol significantly flattened the glycemic responses to sucrose and starch without evidence of diminished efficacy over the 8-week period. Also the blunting effect of miglitol on serum insulin and gastric inhibitory polypeptide responses and the stimulation of breath hydrogen exhalation proving carbohydrate malabsorption with starch and sucrose remained unchanged over time. Comparing breath hydrogen exhalation, responses were more pronounced after sucrose than after the starch loading tests. Symptoms (bloating, flatulence, diarrhea, cramps) were merely noticeable with starch as the substrate, but clearly present after sucrose. These symptoms were substantially curtailed during continuous drug intake. It is concluded that - irrespective of the substrate (starch/sucrose) - there is no escape of the desired effects of alpha-glucosidase inhibition by miglitol over 8 weeks, but symptoms of gaseousness due to carbohydrate malabsorption may undergo habituation.

Detection of pancreatic steatorrhea by oral pancreatic function tests.

Pancreolauryl and NBT-PABA tests were performed in urine of 54 patients with exocrine pancreatic insufficiency and, additionally, in serum of 29 of these patients. All patients underwent a secretin-pancreozymin test and a 72-hr fecal fat analysis. Pancreatic steatorrhea occurred (with only three exceptions) when the pancreolauryl test revealed a T/C ratio [recovery of the fluorescein of the test (T) and the control (C) day] of <10, or when serum fluorescein concentrations were below 0.5 Μg/ml. The NBT-PABA test also showed a negative correlation between urinary PABA excretion or serum PABA concentration and fecal fat excretion, but there was no diagnostically useful cutoff limit indicating decompensation of exocrine pancreatic insufficiency. These findings indicate that the pancreolauryl test may facilitate clinical evaluation of patients with chronic pancreatitis by simultaneously assessing exocrine pancreatic insufficiency as a cause and predicting pancreatic steatorrhea as a sequel of maldigestion. In clinical practice, the pancreolauryl test can be used as a parameter for deciding whether to initiate pancreatic enzyme substitution if direct pancreatic function tests and fecal fat analysis are not available.

Polycations. A new class of inhibitors for in vitro small intestinal transport of sugars and amino acids in the rat

Polycationic compounds like polylysine, protamine or polyethylenimine may interfere with a cation-related membrane transport system depending on superficially accessible binding sites for particular cations. In vitro experiments were performed using either everted segments of rat small intestine to measure tissue accumulation or everted sacs to determine mucosal-to-serosal transport. The effect of polycations was also tested using brush-border membrane vesicles of rat jejunum. Polycations inhibited the tissue accumulation of methyl alpha-D-glucoside as well as binding of phlorizin. Inhibition of accumulation was increased by raising the polycation concentration and by preincubation of the tissue with the polycations. Kinetic experiments revealed a competitive type of inhibition for the uptake of neutral amino acids and actively transported sugars. Using everted sacs to compare the monomeric cations with their corresponding polymeric forms for their inhibitory effect, it was found that only polymers applied to the mucosal compartment impaired active transport. The passive diffusion of solutes, e.g. 2-deoxy-D-glucose or mannitol, was slightly increased by polycations. With some intermediate oligomers of lysine it could be shown that more than 20 cationic groups are required for approximate complete inhibition. That membrane-related events are responsible for the observed inhibition is suggested by the reduced uptake of D-glucose by brush-border membrane vesicles in the presence of polycations. Therefore an interaction with transport-related cation binding sites, i.e. anionic residues, at the mucosal surface may be assumed.

In vitro inhibition of rat small intestinal absorption by lipophilic organic cations

Cationic, lipid-soluble organic compounds may interfere with cation-mediated membrane transport processes. Thus, small intestinal absorption may be influenced by lipophilic organic cations. Therefore a series of arylalkylamines was studied in the concentration range from 0.5 to 20 mmol/l for their effect on the transport of various monosaccharides and leucine in the rat small intestine in vitro by means of the tissue accumulation technique. Whereas the monophenyl substituted monoamines (e.g. benzylamine, 2-phenylethylamine, 3-phenylpropylamine) did not show a significant effect on the active transport, the corresponding omega,omega-diphenyl derivatives exhibited a strong inhibition of the active transport of the sugars and the amino acid. These monoamines and drugs of similar structure (e.g. benzoctamine, diphenydramine) exhibited a mixed or non-competitive type of inhibition which correlated quite well with their octanol-water partition coefficients. In contrast, di- or triamines (e.g. harmaline, imipramine, pyrilamine) revealed a rather pure competitive type of inhibition. These findings tentatively suggest a different mode of action on the active transport by lipid-soluble organic amines according to the molecular charge distribution. In addition, membrane vesicles were used to examine the effect of the different amines on the sucrase activity. Regarding the cation-dependent hydrolysis of sucrose, however, no distinct pattern developed.

Biliary lithotripsy with a new electromagnetic shock wave source : a 2-year clinical experience

During a two-year study period 170 consecutive patients with gallbladder stones, suitable for lithotripsy, were treated with a new electromagnetic lithotriptor (Modulith) and oral bile acids; 142 patients were treated as outpatients. Sufficient fragmentation were obtained in 94% when 2112±137 shocks in 211 sessions with an energy setting of 17.8±0.8 kV were administered. Only 4/170 patients needed transient analgesia. Overall, side effects were transient and mild, but three patients developed biliary pancreatitis, which was treated by endoscopic sphincterotomy in two of them. A total of 67/100 patients were free of stones after one year. Subgroup analysis showed that 80% of the patients (stone diameter 5–20 mm), 64% (20–30 mm) and 65% (multiple stones), respectively, can expected to be free of stones after 12 months. In addition, 25 patients with large, endoscopically not extractable common bile duct stones were treated by lithotripsy with the Modulith. After endoscopic placement of a nasobiliary tube, stone targeting was possible by ultrasonography in 14 patients and by fluoroscopy in another 11 cases. In 23 of the 25 patients (92%) stone clearance by endoscopy was achieved after application of 2516±565 shocks with an energy preset of 18 kV. One patient refused further endoscopic procedures after successful fragmentation and another required local stone dissolution therapy. Side effects occurred more frequently (P<0.05) after lithotripsy of bile duct stones than of gallbladder stones, but they were without major clinical relevance. The new lithotriptor Modulith thus enables safe and highly effective lithotripsy of gallbladder calculi on an outpatient basis. Moreover, the device also allows successful lithotripsy of bile duct stones.