Somatostatin analogue (SMS 201-995) in patients with gastrinomas

We have examined the effects of the somatostatin analogue (SMS 201-995) in 10 patients with gastrinoma syndrome. Four had hepatic metastases, one had a tumor in a peripancreatic lymph node, two had resectable intrahepatic and intraduodenal gastrinomas, and in three the primary tumor was not found. Acutely, SMS 201-995 decreased acid secretion and restored the BAO/MAO ratio to normal in eight of eight patients. Basal and secretin-stimulated gastrin responses were suppressed but not normalized in eight of eight patients. Suppression of endogenous gastrin restored responsiveness to exogenous gastrin. Treatment for up to 12 months with SMS 201-995 controlled symptoms in six of eight patients, suppressed serum gastrin in three of five, and suppressed acid secretion in three of three patients. Treatment with SMS 201-995 in three patients for 5 months decreased tumor secretion of gastrin and diminished basal acid secretion, an effect that persisted in two of three patients 48 hours after withdrawal of SMS. In patients with metastatic disease who had high levels of gastrin, SMS treatment for 5 to 12 months did not inhibit tumor growth or decrease gastrin levels. SMS treatment arrested progression of tumor growth only in patients who had a reduction in gastrin and gastric acid secretion. We conclude that SMS may be useful in the management of gastrinoma patients by decreasing hypersecretion of gastrin and gastric acid and, over a longer term, may even change tumor capacity to release gastrin and gastric acid secretion. SMS may thus be useful as a palliative agent and as an adjunct to conventional treatment of the gastrinoma syndrome. SMS does not appear to shrink tumor mass in patients with very high basal gastrin levels.     

Treatment of the dumping syndrome with the somatostatin analogue SMS 201-995.

In six patients suffering from severe early dumping and six patients with late dumping after peptic ulcer surgery, the effect of the somatostatin analogue SMS 201-995 was compared with placebo. In early dumpers subcutaneous administration of 50 micrograms SMS 201-995 prior to meal ingestion induced a strong improvement of dumping symptoms as reflected by a decrease of the Sigstad dumping score from 12 +/- 2 during placebo to 5 +/- 2 (p less than 0.05). Furthermore, the postprandial increase of pulse rate was abolished; maximum pulse rate decreased from 85 +/- 7 beats/min to 67 +/- 7 beats/min (p less than 0.05). SMS 201-995 did not significantly affect postprandial changes in packed cell volume. In late dumpers 50 micrograms SMS 201-995 reduced peak plasma insulin after oral glucose from 173 +/- 16 mU/L during placebo to 35 +/- 9 mU/L during SMS 201-995 (p less than 0.05) and increased individual plasma glucose nadirs from 1.9 +/- 0.3 mmol/L to 7.5 +/- 3.3 mmol/L (p less than 0.01). Both in early and late dumpers SMS 201-995 improved postprandial expiratory breath hydrogen excretion indicating slowing of gastrointestinal hurry. SMS 201-995 is a powerful therapeutic agent for the management of patients suffering from the dumping syndrome after gastric surgery.     

Therapeutic efficacy of a somatostatin analogue (SMS 201-995) in active acromegaly

Twelve patients with active acromegaly, six of whom had not responded to previous combined surgery, radiotherapy, and bromocriptine administration, were treated with an octapeptide long-acting somatostatin analogue, SMS 201-995, given subcutaneously for up to 1 year. Growth hormone (GH) levels decreased by 50% to 90% after a single 25-micrograms SMS 201-995 injection in all patients, including two who were resistant to bromocriptine therapy. After GH values reached a nadir, they returned to preinjection values over a 12-hour period and no rebound was seen. Assessment of the GH-lowering effect of the drug at weekly intervals for the first 6 weeks and monthly thereafter disclosed no tachyphylaxis. Gradual increase of the dose from 50 to 150 micrograms daily led to a significant increase in clinical improvement. Shrinkage of the size of the pituitary tumor was documented in three of nine evaluated cases. Abdominal cramps of a transient nature not associated with diarrhea were noted in two patients but there were no other side effects. Hematological and biochemical blood and urine tests, including serum thyroxine and cortisol levels, did not reveal any abnormality during chronic treatment. This study demonstrates the safety and efficacy of SMS 201-995 in the short-term treatment of acromegaly.     

The effect of somatostatin analogue (SMS 201-995) on pancreatic blood flow

The effect of somatostatin analogue SMS 201-995 on pancreatic blood flow was studied. In 24 dogs all vessels to the pancreas, except for the pancreaticoduodenal artery and vein, were divided. A flow probe was placed around the pancreaticoduodenal artery. The animals were divided into four groups. Control animals received a subcutaneous injection of 0.5 ml of normal saline solution. Treated animals received 0.002, 0.02, and 0.2 mg/kg of SMS 201-995 at the outset of the experiment. Mean systemic arterial blood pressure, cardiac output, and serum amylase values were monitored, in addition to pancreaticoduodenal blood flow. SMS 201-995 produced a prompt and sustained decrease in pancreatic blood flow in all treated groups compared with control animals without alteration of systemic hemodynamics. This suggests that SMS 201-995 decreases local vascular resistance, which results in decreased pancreatic blood flow.     

Effect of somatostatin analogue (SMS 201-995) on molecular species of gastrin in gastrinoma

Somatostatin analogue (SMS 201-995) has been shown to decrease total serum gastrin in patients with gastrinoma; however, the gastrin level rarely returns to normal, despite the near-complete inhibition of acid secretion. This implies that SMS may have an inhibitory action on the biologically active molecular species of gastrin and have little effect on biologically inactive species. To test this hypothesis, we determined the effect of SMS on the molecular species of gastrin in eight patients with the Zollinger-Ellison syndrome. Serum obtained before treatment and 6 hours and 18 hours after treatment (SMS 1 microgram/kg, subcutaneously) was sampled and assayed for molecular species of gastrin by means of gel filtration chromatography and fractional quantitation of gastrin species by radioimmunoassay. There was a significant decrease in the amount of G-34 and G-17 species. BBG and G-14 decreased, a change not significant at 6 hours but significant 18 hours after SMS. The distribution of the various molecular species as a percent of total immunoreactive gastrin was analyzed before and after SMS. There was a shift in the distribution of the molecular species, so that 6 hours after SMS treatment nearly 50% of total gastrin activity was accounted for by BBG and component I. SMS seems to have a different potency to inhibit release of the various gastrin molecular species. This observation may explain the failure of total gastrin levels to return to normal after SMS treatment in patients with the Zollinger-Ellison syndrome.     

Effects of a somatostatin analogue (SMS 201-995) on hepatic and splenic reticulo-endothelial function in the rat

The effects of a long acting somatostatin analogue, SMS 201-995, on reticulo-endothelial system (RES) activity were studied in rats. Administration of 2 micrograms SMS 201-995 subcutaneously twice a day for 7 days significantly increased the splenic and hepatic uptake of 99mTc-sulphur colloid and damaged 51mCr-red blood cells. Furthermore, SMS 201-995 administration significantly increased the plasma clearance of colloidal carbon as indicated by a lower area under the curve and an increased elimination constant. SMS 201-995 administration also significantly improved survival after intraperitoneal injection of Escherichia coli endotoxin. These results suggest that SMS 201-995 stimulates RES activity in rats. It is suggested that SMS 201-995 may be of value in stimulating RES activity in patients with cirrhosis and portal hypertension.     

The effects of a somatostatin analogue SMS 201-995 on hepatic haemodynamics in the cirrhotic rat

The effects of a somatostatin analogue, SMS 201-995 on hepatic haemodynamics were studied in rats with dimethylnitrosamine-induced cirrhosis. An intravenous infusion of 1, 2 or 4 micrograms kg-1 body wt h-1 SMS 201-995 produced a rapid and sustained decrease in portal pressure, portal venous flow and liver blood flow without significantly altering arterial blood pressure or pulse. The reductions in portal pressure, portal venous flow and liver blood were accompanied by an increase in splanchnic vascular resistance. Portal venous resistance was not affected. Subcutaneous injection of 2 micrograms kg-1 body wt SMS 201-995 produced a gradual decrease in portal pressure, the maximum reduction occurring 18 min after administration. This reduction in portal pressure was sustained for a further 20 min. The results suggest that SMS 201-995 may be of value in the control of bleeding oesophageal varices. Furthermore, the prolonged duration of action of SMS 201-995 following its subcutaneous administration suggests that the analogue may be useful in the long-term management of portal hypertension in patients with cirrhosis.     

Successful closure of intestinal fistulae in an infant using the somatostatin analogue SMS 201-995

Enterocutaneous and other gastrointestinal fistulae create tough challenges with respect to wound care, nutrition, and strategy for closure. SMS 201-995 is a long-acting somatostatin analogue that has been effective in the treatment of adult enteric fistulae. The use of SMS 201-995 as an adjunct in the successful closure of intestinal fistulae in an infant is reported. This newborn infant developed a high-output enterocutaneous fistula and multiple enteroenteric fistulae after an intestinal resection for necrotizing enterocolitis. Copious fistulae output led to extensive wound breakdown, dehydration, and failure to thrive. Despite traditional management with bowel rest, total parenteral nutrition, antibiotics, and wound care, the high-output fistulae persisted unabated. On postoperative day 12, SMS 201-995 was started at 0.7 microgram/kg subcutaneously twice daily and gradually increased to 2.5 micrograms/kg. Within 2 days of SMS 201-995 therapy, the fistulae drainage had decreased from 62 mL/kg/d to 36 mL/kg/d, a 42% decrease from pretreatment levels. By day 8 of treatment, all fistulae had closed. After 14 days of treatment, the wound had healed and the infant was gaining weight. An upper gastrointestinal examination showed a patent ileostomy and no fistulae. Feeding was initiated, SMS 201-995 was discontinued without significant ileostomy output increase, and successful ileostomy closure took place 4 weeks posttreatment. Furthermore, the infant had no demonstrable side effects from the drug. Use of this drug should be considered in the treatment of other infants with complex, recalcitrant gastrointestinal fistulae.     

Treatment of 27 postoperative enterocutaneous fistulas with the long half-life somatostatin analogue SMS 201-995.

Twenty-seven patients with postoperative enterocutaneous fistulas were treated with parenteral nutrition and SMS 201-995 (100 micrograms/8 hours, subcutaneously), a long half-life somatostatin analogue. At the time SMS 201-995 was started, 11 patients had low output fistulas (less than 1000 ml/48 hours), 11 patients had high output fistulas (above 1000 ml/48 hours), and 5 patients had fistulas sitting in large abdominal wall defects. Within 24 hours of treatment, a mean reduction of 55% of the fistula output was observed. Fistula site or output before treatment had no influence on the magnitude of output reduction. Spontaneous closure was achieved in 77% of the patients after a mean of 5.8 +/- 2.7 days of treatment with this drug. Two patients died (7.4%). Pain at the injection site was referred by 15% of the patients but no other side effects were observed. Glucose intolerance was not observed. SMS 201-995 has been shown to be very useful in the conservative treatment of enterocutaneous fistulas because of its ability to rapidly reduce fistula output and accelerate spontaneous closure.     

Effects of a somatostatin analogue SMS 201-995 on hepatic haemodynamics in the pig and on intravariceal pressure in man

The effects of a somatostatin analogue, SMS 201-995, on hepatic haemodynamics in the pig and on intravariceal pressure in man were studied. An infusion of 250 micrograms/h SMS 201-995 significantly reduced portal pressure, portal venous flow and hepatic artery flow in the pig. These changes in hepatic haemodynamics were accompanied by a reduction in cardiac output, a reflex slowing of the heart and an increase in arterial blood pressure. Splanchnic vascular resistance was increased following SMS 201-995 administration but hepatic vascular resistance remained unchanged. Administration of 50 micrograms SMS 201-995 reduced the intravariceal pressure from 27.4 +/- 2.5 to 15.8 +/- 2.1 mmHg in 9 patients with cirrhosis and portal hypertension. Administration of 50 micrograms SMS 201-995 also reduced portal pressure from 29 to 22 mmHg in a patient undergoing an elective portacaval shunt. These results suggest that SMS 201-995 may be of value in the control of bleeding oesophageal varices. Furthermore, because of its prolonged duration of action SMS 201-995 may be useful in the long term management of portal hypertension in patients with cirrhosis.     

Effect of long-term treatment with somatostatin analogue (SMS 201-995) on pituitary tumor shrinkage in acromegaly--report of two cases.

The effect of long-term somatostatin analogue (SMS 201-995) treatment in two acromegalic patients is reported. Continuous tumor shrinkage was observed even after 129 and 139 weeks of treatment with 600 micrograms of SMS 201-995 daily. A huge and firm adenoma underwent shrinkage during treatment with SMS 201-995. No serious side effect appeared during 160 weeks of treatment. SMS 201-995 has a longterm tumor shrinkage effect and improves endocrinopathies.     

Effects of SMS 201-995, a somatostatin analogue, on the exocrine pancreatic secretion and gut hormone release in dogs

The effect of SMS 201-995, an analogue of somatostatin, on pancreatic exocrine secretion was investigated in both interdigestive and digestive states in dogs. In four dogs with gastric and Thomas duodenal cannulas, the pancreatic juice was collected by direct cannulation of the main pancreatic duct. SMS 201-995 was infused intravenously at doses of 0, 15, 30, 60, and 120 ng/kg/hr for 2 to 3 hours in the following experimental conditions: (1) interdigestive pancreatic secretion, (2) pancreatic secretion stimulated by the intravenous infusion of both secretin, 0.06 CU/kg/hr, and cholecystokinin octapeptide (CCK8), 0.03 microgram/kg/hr, and (3) pancreatic secretion after ingestion of a test meal. Pancreatic juice was analyzed for volume and outputs of bicarbonate and protein. Plasma levels of motilin, pancreatic polypeptide (PP), CCK, and secretin were determined by radioimmunoassay. SMS 201-995 inhibited significantly the pancreatic secretion and release of hormones, including secretin, CCK, PP, and motilin, in all three experimental conditions. The inhibitory action of SMS 201-995 on pancreatic secretion and hormone releases was dose dependent.     

Effect of SMS201-995 (a long-acting somatostatin analog) on bile-induced acute hemorrhagic pancreatitis in the dog

Recent reports claim a beneficial role for SMS201-995 (SMS) in pancreatitis. To study the effects of SMS in a canine pancreatitis model, four groups of eight dogs each were subjected to laparotomy; and after cannulation of the dorsal pancreatic duct, a mixture of bile and trypsin was infused to induce pancreatitis. Group I constituted the control group and received no SMS. Group II received SMS intravenously at 5 micrograms/hr beginning 1 hour before the induction of pancreatitis. Group III and Group IV received SMS at the same dose starting at 2 hours and 6 hours, respectively, after the induction of pancreatitis. Infusions were maintained until 24 hours after the induction of pancreatitis. Leukocyte counts, serum lipase and amylase levels were obtained preoperatively and at 24 hours. All dogs were killed at 24 hours and autopsies performed. At autopsy, severity of pancreatitis was graded, based on survival, the presence or absence of pancreatic edema, hemorrhage, and necrosis, as well as the presence and severity of bloody ascites. Only on a dog (Group III) died before the 24-hour period. When SMS was used before the induction of pancreatitis, the pancreatitis seen was less severe (Group I vs Group II, P = .022). No effects were found when using SMS after the induction of pancreatitis (Group III or Group IV vs Group I). The serum lipase, amylase, and leukocyte counts changed significantly in all the dogs (P less than .001) with the onset of pancreatitis, but this difference was not significant between groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of a somatostatin analogue (SMS 201-995) on the growth and development of hepatic tumour derived by intraportal injection of Walker cells in the rat

Administration of a long active analogue of somatostatin, SMS 201-995 (2 micrograms subcutaneously twice a day) for 3 weeks after intraportal administration of Walker cells significantly inhibited their growth and development in the liver. This was not due to a direct cytotoxic effect of the analogue on Walker cells whose growth was stimulated in vitro. Furthermore, SMS 201-995 had no effect on the growth of Walker cells implanted into the thigh of rats suggesting that the inhibitory action of the analogue could be confined to tumour cells growing in the liver. Further studies suggested that the inhibitory effect of SMS 201-995 on the growth of Walker cells in the liver could be related to a marked stimulation of the hepatic reticuloendothelial system, by a reduction in portal venous flow in the early stages of treatment or by a combination of these effects. Further studies are required to delineate more precisely the mechanism whereby SMS 201-995 inhibits the growth of hepatic tumour derived from intraportal administration of Walker cells.     

Effects of octreotide (somatostatin analog SMS 201-995) on superior mesenteric artery blood flow in swine. An experimental study using Doppler color ultrasonography

The effect of octreotide on splanchnic haemodynamics was investigated in 25 domestic pigs by mean of US-colordoppler. In a blind-operator design the superior mesenteric artery (SMA) blood flow was evaluated before and after i.m. injection of 5, 10, 20, 25 micrograms/kg or of an equivalent volume of saline solution. Seven serial measurements were taken every 10 min in each pig excluding the higher and the lower values. The administration of 5 and 10 micrograms/kg determined a rapid and stable (3 hours) decrease of the SMA blood flow (6 and 8.5% respectively) (p < 0.05). The blood flow decreased by 27-29% (p < 0.001) in response to the administration of 20 and 25 micrograms/kg respectively. The reduction started 30 min after injection and the blood flow remained lower than basal for up to 5 hours. Because of the mean standard error of US blood flow assessment is 10% due to the interobserver and intraobserver variations, we considered statistically significant only the reduction occurred after the administration of 20 or 25 micrograms/kg. Authors findings suggest that high dose of octreotide is effective in reducing the splanchnic haemodynamics in the pig. Such animal can be used in experimental setting planed to assess the effect of splanchnic blood flow reduction.