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 long-acting somatostatin analogue in patients with severe ileostomy diarrhoea

Proctocolectomy (PC) with small bowel resection may lead to profuse ileostomy diarrhoea which can be difficult to treat. The effect of a recently developed long acting somatostatin analogue (SMS 201-995) on ileostomy output was investigated in 5 patients who had undergone PC and ileal resection (median 120 cm) and who suffered severe diarrhoea (4-7 litres/24 h). Gastric emptying, transit of a standard meal through the small bowel and the amounts of nutrients excreted were simultaneously determined during double blind infusion of SMS (25 micrograms/h) and placebo (isotonic saline 125 ml/h). SMS 201-995 significantly reduced ileostomy output (P less than 0.05) and water excretion (P less than 0.05) and prolonged small bowel transit time (P less than 0.05). Whilst having little effect on gastric emptying, or on the excretion of glucose or nitrogen, fat excretion was significantly increased (P less than 0.05). In two patients subcutaneous administration of SMS 201-995 (50 micrograms b.d.) has maintained a reduced ileostomy output for 4 and 6 months respectively.     

Observations on the effect of a somatostatin analog in the Zollinger-Ellison syndrome: implications for the treatment of apudomas

Somatostatin is known to inhibit hormone release and gastrointestinal secretion and hence may be useful in the treatment of amine precursor uptake, decarboxylase tumors. Clinical application has been limited by the short half-life, potency, and specificity of the natural hormone. Our study evaluated the effect of a synthetic analog of somatostatin, SMS 201-995 (Sandoz, Inc., E. Hanover, N.J.) on basal and stimulated gastrin release and gastric acid secretion in 10 patients with the Zollinger-Ellison syndrome. In experiment 1, H2-receptor antagonists were discontinued for 48 hours; SMS 201-995, 1 microgram/kg, was given subcutaneously; gastrin and SMS levels in plasma were determined by radioimmunoassay; and gastric secretion was measured and titrated at 0, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, and 18 hours. The mean +/- SEM baseline gastrin level (1526 +/- 733 pg/ml) was significantly inhibited for 16 hours (p less than 0.05, paired t test). Gastric secretion was neutralized for as long as 18 hours (p 0.05). In experiment 2, three patients received either a secretin (2 U/kg) or a calcium stimulation test (2 mg/kg) with or without pretreatment with SMS 201-995, 1 microgram/kg, subcutaneously. The mean +/- SEM interpreted change in gastrin (ng X 60 min/ml) without SMS 201-995, 36.8 +/- 11 (secretin), and 129 +/- 30 (calcium) were reduced with SMS 201-995 to -1.1 +/- 0.76 (secretin) and -29 +/- 28 (calcium) (p less than 0.05). In the Zollinger-Ellison syndrome, SMS 201-995 caused significant and long-lasting inhibition of both tumor gastrin release and gastric acid secretion, probably by direct action on both the gastrinoma and the stomach. SMS 201-995 blocks acid secretion and secretin- and calcium-stimulated gastrin release, indicating that SMS 201-995 inhibits peptide secretion by postreceptor mechanisms. SMS 201-995 will be useful in the palliative treatment of apudomas.     

Treatment of pancreatic cutaneous fistulas with a somatostatin analog

Five pancreatic cutaneous fistulas were treated by subcutaneous administration of a long-acting synthetic analog of somatostatin, SMS 201-995. Patients included four men and one woman who ranged in age from 52 to 77 years. The fistulas developed after drainage of a pancreatic abscess, biopsy of a pancreatic mass, splenectomies for idiopathic thrombocytopenic purpura and Felty's syndrome, and operative trauma, respectively. Fistula output consisted of 1,000 ml/day of amylase- and lipase-rich fluid in the patient with a pancreatic biopsy. The other four patients had low-output fistulas (100 to 250 ml/day) that had been draining for 1 to 12 months. Direct communication with the pancreatic duct was demonstrated by endoscopic retrograde cholangiopancreatography, sinography, or both in four of the five patients. Fistula output decreased from 340 +/- 376 ml/day to 63 +/- 36 ml/day on the first day of therapy with two daily doses of 0.05 mg SMS 201-995 (p less than 0.03) and to 13 +/- 19 ml/day on the seventh day of therapy (p less than 0.03). Two patients had prompt closure of their fistulas and one closed in 3 months. One patient with chronic pancreatitis and a duct stricture and one patient with recurring infection did not achieve permanent fistula closure with SMS 201-995. Because of its safety, ease of administration, and efficacy in decreasing fistula output, we believe somatostatin analog therapy is beneficial in hastening closure of pancreatic fistulas.     

Early ileostomy closure in necrotizing enterocolitis

The nutritional and metabolic complications following intestinal resection and ileostomy for necrotizing enterocolitis (NEC) in low birth weight preterm infants often necessitate repeated prolonged hospitalization for salt and water imbalance and reliance on total parentaral nutrition (TPN). The traditional concerns about anesthetic and anastomotic complications delays the restoration of intestinal continuity until the infant has attained a weight of about 5 kg, but recent nutritional balance studies in our unit have shown a combination of nutrient and mineral malabsorption in neonates with ileostomies. Beginning 4 years ago, a prospective study of early closure of the ileostomy was undertaken in infants weighing as low as 2 kg to examine the effect on surgical morbidity, infant growth, and gastrointestinal function using the preclosure infant as his/her own control. Ten infants with birthweights ranging from 670 to 2,000 g developed NEC requiring ileostomy at age three days to 11 weeks. In addition to partial ileal resection, the cecum was resected in 10 patients, ascending colin in 7, transverse in 4, descending colon in 1 patient. Postoperative treatment, including short-term TPN and elemental diet, preceded closure of ileostomy at a mean age of 18 weeks (range 5 to 36 weeks). Mean weight at time of closure was 3,052 +/- 994 g. There were no short-term complications of early closure in this series, nor was there any incidence of anastomotic dysfunction, colon stricture, or recurrent NEC.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of SMS 201-995 on meal and CCK-stimulated peptide YY release

Somatostatin is known to inhibit the postprandial release of most gastrointestinal hormones. The aim of the present study was to evaluate the effect of an analog of somatostatin, SMS 201-995 (120 ng/kg/hr), on both meal-induced and cholecystokinin octapeptide (CCK-8, 500 ng/kg/hr)-induced peptide YY (PYY) release. Six mongrel dogs with distal ileal Thiry-Vella loops were used in this study. PYY was measured in both plasma and ileal luminal effluent. SMS 201-995 did not affect interdigestive plasma or ileal luminal PYY concentrations. CCK-8 and a fat meal both stimulated PYY release into the circulation. SMS 201-995 completely inhibited the CCK-8 and fat-stimulated circulatory release of PYY. Both CCK-8 and a mixed meal increased ileal luminal PYY recovery. SMS 201-995 inhibited CCK-8-induced, but not meal-induced, ileal luminal PYY recovery. These findings support previous studies that describe independent circulatory and ileal luminal PYY release. We conclude that both somatostatin and CCK may have a regulatory role in postprandial circulatory release of PYY.     

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.     

Effects of SMS 201-995 on the pharmacokinetic profile and cellular immune and toxic effects of cyclosporine in male Wistar rats

The immunosuppressant cyclosporine and the long-acting somatostatin analog SMS 201-995 (octreotide acetate) may have to be given simultaneously in diseases such as pancreatic transplantation. The aim of the study was to evaluate the effects of SMS 201-995 on the pharmacokinetics of cyclosporine, and to assess whether the addition of SMS 201-995 altered some of the cellular immune and toxic (renal, hepatic, glucose tolerance) effects of cyclosporine. Male Wistar rats were treated with cyclosporine 10 mg/kg/day, SMS 201-995 100 micrograms/kg b.i.d., a combination of the two drugs, or the vehicle alone. The addition of SMS 201-995 delayed the peak plasma levels of cyclosporine without affecting the through levels, and did not alter the effects of cyclosporine on the mononuclear cell subsets. This combination caused significant increases in plasma creatinine and hepatic enzymes, suggesting renal and hepatic toxicity, and severe glucose intolerance. If present in humans, the appearance of severe glucose intolerance with combined administration of SMS 201-995 and cyclosporine for pancreatic transplantation could be misinterpreted as rejection and lead to inappropriate interventions.     

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.     

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.     

SMS 201-995 and provocation tests in preparation of patients with carcinoids for surgery or hepatic arterial embolization

Patients with midgut carcinoids undergoing surgical resection or ischemic treatment of hepatic metastases by embolization are at risk for development of carcinoid crises due to release of hormonally active tumor products. Eight such patients were treated on nine separate occasions with increasing subcutaneous doses of a synthetic somatostatin analogue (SMS 201-995) 4 days prior to surgery or hepatic arterial embolization. The patients were tested by pentagastrin provocation and simultaneous measurement of serotonin (5-HT) levels in peripheral blood before and after prophylactic treatment, to evaluate the efficacy of SMS 201-995. The provoked release of 5-HT was markedly diminished, and the basal levels of 5-HT were markedly reduced in patients with high initial levels. During surgery or embolization both SMS 201-995, as well as ketanserin, a 5-HT2 receptor blocker, were given. With this combined treatment all patients were hemodynamically stable during surgery or embolization. During embolization the arterial levels of 5-HT increased only moderately, while urinary excretion of 5-hydroxyindoleacetic acid remained unchanged despite a proven adequate embolization. Two patients were operated on without previous treatment with SMS 201-995; both developed severe crises at induction of anesthesia, but IV SMS 201-995 rapidly reversed the bronchoconstriction and facial flush and gradually restored arterial blood pressure, even though cardiac output remained depressed for a prolonged period. The crisis reaction correlated well with high circulating levels of 5-HT, but after treatment with SMS 201-995 these levels were still high.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Somatostatin analogue SMS 201-995 (octreotide) as a possible solution to the dumping syndrome after gastrectomy or vagotomy

The dumping syndrome, which may follow partial gastrectomy or truncal vagotomy and drainage, may be refractory to treatment. The aim of this study was to determine the effect of the somatostatin analogue, SMS 201-995 (octreotide), on dumping provoked by hypertonic glucose. Ten patients with symptoms and signs of dumping were studied. After a dumping provocation test with placebo, all patients developed severe symptoms: seven patients had early dumping, two had both early and late dumping and one had late dumping alone. With either 50 or 100 micrograms SMS 201-995, the symptoms of early dumping were much reduced in all patients, and those of late dumping were completely abolished. The packed cell volume, pulse and systolic blood pressure changes of early dumping were significantly reduced by SMS 201-995 and the fall in blood glucose in patients with late dumping was abolished. SMS 201-995 may be a useful treatment for early and late dumping.     

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.     

High-output external fistulae of the small bowel: management with continuous enteral nutrition

Three hundred and thirty-five patients with high-output enterocutaneous fistulae arising from the small intestine are reported. Median fistula output was 1350 ml/24 h. Eighty-two per cent of patients were referred from other institutions. The fistula opening was associated with evisceration in 165 cases (49 per cent). One or more severity factors were present in 75.5 per cent of the patients. Patients were divided into three groups according to their initial therapy: 21 patients (6 per cent) referred in a moribund state were not operated on (non-intervention); 80 patients (24 per cent) were operated on as an emergency, and the fistula was either exteriorized or defunctioned; 234 patients (70 per cent) were initially managed conservatively. Appropriate local care and nutrition were provided in all cases. Enteral nutrition was the exclusive nutritional support in 285 patients (85 per cent). In 92 cases with proximal fistulae, methods limiting the fistula output or allowing reinfusion of chyme were required. The overall mortality rate was 34 per cent: 100 per cent in the non-intervention group, 55 per cent after emergency surgery, and 19 per cent after conservative treatment. In the latter group, spontaneous closure was obtained in 88 patients (38 per cent). Overall mortality rate was reduced to 19 per cent in patients treated since 1980. Enteral nutrition with appropriate local care may be used in the majority of high-output enterocutaneous fistulae, with an acceptable rate of spontaneous closure. Conservative management is the treatment of choice in the initial period. Emergency surgery should be restricted to the treatment of haemorrhage or intra-abdominal abscesses associated with uncontrolled systemic sepsis.     

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.     

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 somatostatin and a long-acting somatostatin analogue on the prevention and treatment of experimentally induced acute pancreatitis in the rat

The effects of somatostatin (SRIF) and its long-acting analogue, SMS 201-995 on the prevention and treatment of acute pancreatitis were studied in rats. Acute pancreatitis was established by ligating the bile duct at the point of entry into the duodenum, thereby allowing reflux of bile into the pancreas. Administration of SRIF (4 micrograms kg-1 body wt IV followed by a 12 h infusion of 4 micrograms kg-1 body wt h-1) or SMS 201-995 (2 micrograms kg-1 body wt SC) at the time of bile duct ligation prevented the increase in the serum concentrations of amylase and lipase observed in control rats 12 h after bile duct ligation. Moreover, SRIF and SMS 201-995 administration prevented development of the histological changes consistent with acute pancreatitis observed in control animals. These results suggest that SRIF or SMS 201-995 may be of value in preventing acute pancreatitis following ERCP or after surgery on the pancreas. In rats with established pancreatitis, SRIF (IV bolus of 4 micrograms kg-1 body wt followed by a 24 h continuous infusion of 4 micrograms kg-1 body wt h-1) or SMS 201-995 (2 micrograms kg-1 body wt SC followed by a similar dose 12 h later): (1) significantly improved survival; (2) produced histological changes in the pancreas consistent with organization and healing; (3) prevented the accumulation of ascitic fluid; (4) reduced the serum levels of amylase and lipase. These results suggest that SRIF and SMS 201-995 may prove valuable in the treatment of established acute pancreatitis in man.     

A Comparison of Sms 201-995 and Oesophageal Tamponade in the Control of Acute Variceal Haemorrhage

Forty endoscopically proven active variceal bleeds were entered in a prospective trial comparing oesophageal tamponade with SMS 201-995 infusion.Oesophageal tamponade controlled 19 of 20 bleeds over the first four hours and 14 of 18 bleeds over 48 hours. SMS 201-995 infusion controlled 18 of 20 bleeds over the first four hours and 10 of 20 bleeds over 48 hours (p = 0.15). No significant differences between the groups were seen in time to control of bleeding, amount of blood transfused or number of patients crossed over to the opposite treatment. Complications in the oesophageal tamponade group were discomfort due to the tube (17 patients) and chest infection (10 patients), while in the SMS 201-995 group 7 chest infections and one episode of hyperglycaemia occurred, with no symptomatic complaints. The patient survived the admission in 15 of the oesophageal tamponade bleeds and all of the SMS 201-995 bleeds (p = 0.047).An intravenous infusion of SMS 201-995 appears to have comparable efficacy to oesophageal tamponade in variceal bleeding.