Treatment of metastatic islet cell carcinoma with a somatostatin analogue (SMS 201-995)

We used an octapeptide analogue of somatostatin, SMS 201-995, in dosages ranging from 150 to 450 micrograms/d administered subcutaneously in three daily doses for 1 to 16 months, to treat 22 patients with advanced malignant islet cell carcinomas. Of the 22 patients, there were 9 with gastrinomas; 3 with glucagonomas; 4 with insulinomas; 1 with ectopic production of parathyroid hormone; and 3 with mixed syndromes. The only biochemical marker in 1 patient was pancreatic polypeptide, and 1 patient had no demonstrable peptide production from the tumor. In 14 patients, dramatic decreases in the levels of circulating peptides (insulin, vasoactive intestinal polypeptide, gastrin, and glucagon) have been accompanied by major alleviations of symptoms. Steatorrhea appears to be the most significant toxicity. This analogue of somatostatin may be appropriate for use as early therapy in patients who have symptoms from syndromes related to islet cell carcinomas but in whom there is no immediate threat from tumor progression.     

Reduction of the effluent volume in high-output ileostomy patients by a somatostatin analogue,SMS 201-995

Twelve ileostomy patients were given subcutaneous SMS 201-995 therapy (100 g t.d.s. for 5 days) in a randomized placebo-controlled trial. All patients had ileostomies constructed 60 cm proximal to the terminal ileum (proximal ileostomy) following restorative proctocolectomy. SMS 201-995 reduced the daily ileostomy output from 997±52 g to 736±28 g, P<0.05, along with a decrease in daily sodium and chloride excretion (sodium: 92.60±8.51 to 75.22±8.64 mEq, chloride: 143.46±8.54 to 113.60±15.84 mEq; both P<0.05). There were no significant changes in the plasma levels of glucagon, C peptide, insulin, renin or aldosterone with SMS 201-995 therapy. Patients developed no severe side effects and reported easier management of the ileostomy and a reduction in thirst. Our results suggest a possible clinical role for SMS 201-995 in the management of proximal ileostomy.

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Résumé 12 patients avec iléostomie ont reçu une injection sous cutanée de SMS 201-995 (100 g t.d.s. pour 5 jours) au cours d'une étude randomisée contre placebo. Tous ces patients avaient une iléostomie réalisée à 60 centimètres de la fin de l'iléon (iléostomie proximale) après proctocolectomie restaurative. Le SMS 201-995 diminuait le débit journalier de l'iléostomie de 997±52 g à 736±28 g, P<0.05 allant de pair avec une diminution de l'excrétion de sodium et de chlore (sodium: 92.60±8.51 à 75.22±8.64 mEq, chlore: 143.46±8.54 à 113.60±15.84 mEq, tous les deux P<0.05). Il n'y avait pas de variations significatives des taux plasmatiques de glucagon, peptide-C, insuline, renine, et aldostérone au cours du traitement par SMS 201-995. Les malades n'ont pas developpé d'autres effets sévères et rapportaient un entretien plus facile de leur iléostomie et une réduction de la soif. Nos résultats suggèrent un possible rôle clinique pour SMS 201-995 dans le management d'une iléostomie proximale.

     

Long term treatment with the somatostatin analog SMS 201-995 in a patient with a thyrotropin- and growth hormone-secreting pituitary adenoma

A patient with a mixed pituitary tumor secreting TSH and GH was treated, starting 3 months after partial adenomectomy, with the somatostatin analog SMS 201-995 for 8 months. Somatostatin itself inhibited TSH, GH, and alpha-subunit release by the tumor both in vivo and in vitro. Long term treatment with twice daily sc injections of SMS 201-995 resulted in decreased TSH secretion and lower serum thyroid hormone levels. However, euthyroidism was achieved only when the patient was treated with three daily 200-micrograms injections of SMS 201-995. After 30 weeks of SMS 201-995 therapy, TSH secretion increased, while GH secretion remained suppressed. After withdrawal for 6 months, SMS 201-995 (100 micrograms, sc, twice daily) again completely inhibited TSH secretion. SMS 201-995 did not alter the volume of the residual adenomatous tissue. We conclude that SMS 201-995 may be a valuable therapeutic agent for the management of patients with a thyrotroph adenoma. However, desensitization may occur during long term treatment.     

Use of long-acting somatostatin analog SMS 201-995 in patients with pancreatic islet cell tumors

Natural somatostatin reduces plasma concentrations of many peptides, and is of short term benefit in patients with islet cell tumors, but has to be given as a continuous intravenous infusion. We review the published experience with the long acting synthetic somatostatin analogue SMS 201-995 in patients with islet cell tumors. Fifteen of 18 patients with vasoactive intestinal peptide-producing tumors, 8 of 8 patients with glucagonomas, 7 of 7 patients with unresectable insulinomas, and 3 of 3 patients with growth hormone releasing factor-producing tumors had a good sustained symptomatic response to SMS 201-995. Patients with benign insulinomas responded variably and are best treated by surgery. Patients with gastrinomas are best treated by oral gastric antisecretory agents. In all these syndromes, the clinical response to SMS 201-995 did not necessarily parallel the change in plasma concentration of marker peptide, suggesting that SMS 201-995 may have actions at various sites. The effect of SMS 201-995 on tumor size has been assessed in 46 patients, less than 20% of whom showed a reduction in tumor size. Side effects have been mild, but include steatorrhea and gastrointestinal disturbances. More studies will be required to fully assess the effects of longterm administration of SMS 201-995.     

Placebo-controlled trial with the somatostatin analogue SMS 201-995 in peptic ulcer bleeding

A 5-day, double-blind, placebo-controlled, multicenter trial in 23 centers with a total of 273 patients [241 evaluable patients; 126 on placebo and 115 on a long-acting somatostatin analogue (SMS 201-995, octreotide, Sandostatin)] resulted in no difference in stopping bleeding and preventing rebleeding between placebo (70.6%) and SMS 201-995 (69.6%). Surgery rates, blood transfusion requirements, and time required before bleeding stopped were also not significantly different between the two groups. A retrospective subgroup analysis according to age, sex, localization of the ulcers, severity of the bleeding, and arterial spurting vs. oozing showed homogeneity and did not allow identification of a subgroup that might benefit from treatment with SMS 201-995. The tolerability of SMS 201-995 was very good. No difference was found between placebo and SMS 201-995 with regard to the side-effect profile.     

Shrinkage of a primary thyrotropin-secreting pituitary adenoma treated with the long-acting somatostatin analogue octreotide (SMS 201-995)

The long-acting somatostatin agonist octreotide can control TSH hypersecretion from most thyrotropic adenomas. Octreotide therapy has even been shown to improve chiasmal dysfunction. We report another patient in whom octreotide therapy was associated with gradual suppression of TSH hypersecretion, which escaped partially, dramatic and very rapid and sustained improvement of chiasm compression, and dramatic and sustained shrinkage of an unresectable TSH-secreting pituitary tumour. Unusual and prolonged gastrointestinal adverse reactions eventually disappeared except for steatorrhea. In conclusion, octreotide may be considered as first line treatment in patients with unresectable thyrotropic adenomas.     

Treatment of resistant acromegaly with a long-acting somatostatin analogue (SMS 201-995)

Six patients with resistant acromegaly were given a long-acting somatostatin analogue (SMS 201-995) for 5 to 12 months. The clinical response was dramatic; relief of headache occurred within minutes of the injection. The mean 24-hour growth hormone levels fell acutely after the administration of 50 or 100 micrograms every 12 hours, especially in four patients with small tumors (p less than 0.001). Dosages of up to 1500 micrograms/d were necessary to produce maximum lowering of growth hormone secretion in some patients. On long-term treatment, plasma somatomedin-C levels fell in all patients and became normal in four. Plasma immunoreactive levels of SMS 201-995 related inversely to growth hormone concentration: A reproducible threshold for growth hormone inhibition in five of the patients, ranging from 70 to 1200 pg/mL, was maintained for 6 to 8 hours after the injections. This somatostatin analogue is effective in the treatment of acromegaly, has no major side effects, and causes only transient changes in carbohydrate metabolism.     

Treatment of severe reactive hypoglycemia with a somatostatin analogue (SMS 201-995)

Reactive (or postprandial) hypoglycemia can sometimes represent a severe disorder refractory to conventional therapeutic measures. We present in this first individual trial, to our knowledge, that the administration of a somatostatin analogue (SMS 201-995) may alleviate the severity of complaints and does not appear to be diabetogenic. The effects of the somatostatin analogue were documented in a 5-hour oral glucose tolerance test, where not only the glucose-induced and C-peptide rise was clearly attenuated, but also the blood glucose concentration did not fall low enough to induce hypoglycemic symptoms.     

Treatment of diabetic diarrhea and orthostatic hypotension with somatostatin analogue SMS 201-995

A diabetic patient was treated with a somatostatin analogue, SMS 201-995, to control chronic diarrhea and orthostatic hypotension. The patient was injected with 50 micrograms, 100 micrograms, and 150 micrograms of SMS 201-995 subcutaneously twice daily for three days at each dose. Stool weight decreased from a basal mean value of 906 g per 24 hours to 628 g, 445 g, and 408 g per 24 hours, respectively. Diarrhea remained suppressed for 18 months when the patient was last seen. When SMS 201-995 was then given at 5 micrograms to 10 micrograms per hour by continuous subcutaneous infusion, stool weight decreased to a mean of 321 g per 24 hours. Basal blood pressure, which averaged 99/71 mm Hg, rose to 133/91 mm Hg five minutes after 75 micrograms of SMS 201-995 was injected subcutaneously; it remained elevated for six hours after injection. Serum motilin levels decreased significantly from 126 pg/ml before injection of SMS 201-995 to 52 pg/ml after injection. Serum norepinephrine levels rose from 50 pg/ml supine (normal range, 150 to 550 pg/ml) and 52 pg/ml erect before injection of SMS 201-995 to 72 pg/ml supine and 110 pg/ml erect after injection. SMS 201-995 may raise blood pressure, in part by increasing the release of circulating norepinephrine.     

Inhibition of meal stimulated gastric acid secretion by an octapeptide somatostatin analogue SMS 201-995.

A dose response study of the effect of an octapeptide somatostatin analogue, SMS 201-995, on meal stimulated gastric acid secretion was carried out in 12 healthy volunteers. Infusion of SMS 201-995 in a dose of 50 pmol/kg/h almost completely abolished the acid response to the meal. Pl-gastrin was significantly decreased during infusion of 10 pmol/kg/h of SMS 201-995 and insulin was significantly inhibited during infusion of 50 pmol/kg/h. SMS 201-995 in a dose of 50 pmol/kg/h inhibited basal and submaximal pentagastrin stimulated acid secretion by 77% and 84% respectively (p less than 0.01). On a molar basis SMS 201-995 is substantially more potent than natural somatostatin in inhibiting gastric acid secretion.     

Treatment of relapsing bleeding peptic ulcers with the somatostatin analogue SMS 201 995 in a patient with Zollinger-Ellison syndrome

SMS 201-995 is an octapeptide analogue of natural somatostatin characterized by pharmacological properties similar to those of somatostatin itself. In addition, its serum half-life of about 60 minutes after i.v. injection is significantly longer than that of the natural compound. A patient with active bleeding from a peptic ulcer jejuni due to a Zollinger-Ellison syndrome was successfully treated with SMS 201-995. Bleeding stopped after continuous infusion (25 micrograms/h) within the first 24 hours of infusion. The serum gastrin concentration dropped from 3,300 pg/ml to 170 pg/ ml (normal range 40-100 pg/ml). Continuation of the treatment by subcutaneous injections of SMS 201-995 (100 micrograms twice daily) maintained serum gastrin concentrations between 300 to 400 pg/ml over a period of 8 months. Side effects have not been observed. Four subsequent endoscopic examinations have revealed no ulcer relapse.     

Successful treatment of idiopathic secretory diarrhea of infancy with the somatostatin analogue SMS 201-995

The somatostatin analogue SMS 201-995 has been reported to be effective in treating adult secretory diarrhea due to vasoactive intestinal polypeptidoma. We report the effectiveness of this drug in treating severe refractory secretory diarrhea of uncertain etiology in an infant. The patient developed diarrhea within the first few days of life, with mean stool output of 250 ml/kg.day (expected 10 ml/kg.day). Small bowel biopsy showed mild focal enteritis. Serum levels of known gastrointestinal secretagogues were normal. No tumor was detected. Diarrhea was not adequately controlled by various drug treatments. Addition of subcutaneous SMS 201-995 produced a significant sustained decrease in stool output to 80-100 ml/kg.day. During SMS 201-995 treatment, no metabolic, hormonal, or growth abnormalities were noted. SMS 201-995 was discontinued after 9 mo because of patient irritability. Stool output rose immediately to 173 ml/kg.day, and remained stable for 6 mo. It is concluded that SMS 201-995 was a safe and effective treatment in this single childhood case of severe idiopathic secretory diarrhea.     

Treatment of malignant endocrine pancreatic tumors with a new long-acting somatostatin analogue, SMS 201-995

Ten patients with malignant endocrine pancreatic tumors were treated with SMS 201-995 at doses of 50 micrograms twice daily, administered subcutaneously. Four out of 10 patients (40%)-1 patient with the Zollinger-Ellison syndrome and 3 of 6 with the watery diarrhea syndrome--responded objectively with more than 50% reduction of peptide levels, with a median duration of 15.5 months. All four patients improved symptomatically, with decreasing dyspeptic symptoms and decreasing diarrhoea. Three additional patients had a clear relief of symptoms without an effect on tumor-secreted peptides. The disease progressed in three patients during treatment. No reduction of tumor mass was seen in any of the patients. The main side effect noted was a slight but maintained increase in fasting blood glucose in four patients. In conclusion, SMS 201-995 had a beneficial effect in more than half of the patients and seems to be a valuable adjunct to other causal therapy in this patient category, especially in acute situations and weak patients because of its very few side effects.     

The response of serum growth hormone levels to the long-acting somatostatin analog SMS 201-995 in acromegaly

SMS 201-995 (SMS) is a long-acting analog of somatostatin. We studied the effect of SMS (50-100 micrograms, sc, every 8 h) on serum GH in five patients with acromegaly. Serum GH decreased significantly in four of the five patients 4 h after SMS treatment. In two of the four patients, this reduction was not sustained for 7 h, but sustained reduction to normal GH concentrations did occur in the two patients who had basal serum GH levels below 15 ng/ml. In the two patients whose responses were not sustained for 7 h, a higher dose of SMS did not cause sustained reduction in GH. SMS was well tolerated, except for one episode of elevated serum aminotransferase levels. These results indicate that SMS-induced reductions in serum GH in patients with acromegaly are often not sustained despite SMS administration every 8 h and indicate that the insufficient duration of effect may limit its therapeutic efficacy.     

Inhibition of omeprazole induced hypergastrinaemia by SMS 201-995, a long acting somatostatin analogue in man.

Whether the long acting somatostatin analogue SMS 201-995 (octreotide, Sandostatin) could inhibit the basal and meal stimulated hypergastrinaemia and hyperpepsinogenaemia induced by omeprazole was investigated. Eight healthy subjects were randomised to receive five day courses of SMS 201-995 (25 micrograms subcutaneously three times daily), omeprazole (40 mg once a day), a combination of both drugs, or placebo. Basal and meal stimulated serum gastrin and basal serum pepsinogen A and C values were measured the day before treatment, on day five of treatment, and the day after each course of treatment. Omeprazole caused significant increases in basal and meal stimulated peak and integrated serum gastrin values and pepsinogen A and C levels, which were still significantly raised the day after stopping omeprazole treatment. Giving SMS 201-995 with omeprazole significantly reduced any omeprazole induced increases in basal and meal stimulated peak and integrated serum gastrin levels; serum pepsinogen A and C values were significantly inhibited too. Serum gastrin values during combined therapy were not significantly different from those during placebo treatment, whereas pepsinogen A and C levels were still significantly raised. On the day after stopping combined therapy, basal and meal stimulated peak and integrated serum gastrin and serum pepsinogen C (but not pepsinogen A) levels were not significantly different from values obtained on the day after stopping omeprazole alone. SMS 201-995 without omeprazole significantly inhibited basal and meal stimulated peak and integrated serum gastrin levels. Pepsinogen A was also significantly inhibited by SMS 210-995, but the reduction in pepsinogen C failed to reach statistical significance. In conclusion, SMS 201-995 prevents basal and meal stimulated increases in serum gastrin during omeprazole therapy. This finding may have clinical importance in the few patients who have pronounced hypergastrinaemia because of profound long acting acid inhibition.