Effect of a new long-acting somatostatin analogue (SMS 201-995) on glycemic and hormonal response to a mixed meal in acromegalic patients

We investigated in 6 acromegalic patients the acute effects on glucose tolerance and insulin secretion of a single sc injection of the somatostatin analogue SMS 201-995, performed 4 h before a mixed meal with xylose administration. Growth hormone levels decreased from 34.0 +/- 20.3 (mean +/- SE) to a minimum of 9.3 +/- 3.0 ng/ml, 3 1/2 h after the injection. A significant inhibition of insulin secretion was also noticed, with a fall from 25.3 +/- 6.4 to 6.3 +/- 2.3 microU/ml at 1 h, and a lower and delayed peak level after the mixed meal. However, the postprandial plasma glucose increase was not different from a control day, while plasma xylose levels were lower. Mean glucagon level after SMS 201-995 was lower than control value in 3 out of the 4 patients in whom it was determined. The decrease of serum growth hormone levels, together with partial glucagon inhibition and, more important, a slowing of intestinal absorptive processes, counterbalanced the inhibitory action of SMS 201-995 on insulin secretion, and no deterioration in carbohydrate tolerance could be demonstrated. However, before SMS 201-995 is employed in the management of acromegalic patients refractory to surgery and bromocriptine therapy, we need further observations of postprandial glycemic profiles during long-term therapy with multiple daily injections of the compound.     

The long-acting somatostatin analogue SMS 201-995 causes malabsorption

Somatostatin and its long-acting analogue SMS 201-995 (Sandostatin) have been suspected of causing steatorrhoea. The aim of this study was to examine the effect of SMS 201-995 on fat assimilation in healthy subjects, using 14C-triolein and 3H-oleic acid as tracers of dietary triglycerides and free fatty acids, respectively, and 51CrCl3 as non-absorbable marker. Six healthy male volunteers participated in the double-blinded, randomized, crossover study. In each test period either 1 ml of SMS 201-995, containing 200 micrograms, or 1 ml of isotone saline was given subcutaneously three times within 16 h. Faeces were collected for 3 days, every stool separately. The faecal 14C-triolein and 3H-oleic acid excretion was calculated from two aliquots of faeces. In addition, the mean daily faecal fat excretion was estimated. When placebo was given, the median 14C-triolein excretion was 1% (range, 0.9-1.6%), the median 3H-oleic acid excretion was 5% (range, 3-10%), and the daily faecal fat excretion was 4 g/day (range, 1-6 g/day), all within normal limits. When SMS 201-995 was given, the faecal 14C-triolein excretion increased to a median of 75% (range, 43-119%), the 3H-oleic acid excretion increased to a median of 82% (range, 46-126%), and the faecal fat excretion increased to a median of 22 g/day (range, 4-34 g/day), all clearly above normal. The faecal 14C-triolein/3H-oleic acid test showed triglycerides and free fatty acids to be equally malassimilated, which indicates malabsorption.     

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 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.     

Effect of the long-acting somatostatin analogue SMS 201-995 on small-intestinal interdigestive motility in the dog

The long-acting somatostatin analogue SMS 201-995, also called Sandostatin, is used in the treatment of acromegaly and peptide-secreting tumors. Little is known about its effect on gut motility, although such an effect might be expected considering the spectrum of activities of its parent molecule, somatostatin. We have studied the effect on the interdigestive motility of intravenous boluses of 0, 0.1, 0.5, 1.5, and 5.0 micrograms/kg of this analogue in 10 dogs with bipolar electrodes implanted along the entire small bowel. All doses induced, within 5 min of administration, premature phase-3 activity that was isolated to one segment, normally progressive, or simultaneous (stationary) in all channels. Only low doses induced isolated phase 3, whereas the frequency of the induction of stationary phase 3 increased with higher doses. In the next cycle of the migrating motor complex the duration of phase 1 was increased, although the duration of the whole cycle was not changed. This cycle ended with mostly ectopic phase-3 activity. During phase 2 of the following cycle ultra-rapid rushes of spiking activity progressing at a speed of 25 +/- 3 cm/sec in the upper jejunum were regularly observed. Although this pattern occurs very rarely under control conditions, it was present in 20%, 80%, and 100% of the experiments after doses of 0.5, 1.5, and 5.0 micrograms/kg, respectively. We conclude that gastrointestinal side effects observed during administration of SMS 201-995 might be related to these motility effects, which warrant further investigation. SMS 201-995 may be a tool to study the mechanism of the induction of ultra-rapid rushes and of stationary phase 3.     

Hyperthyroidism due to non-tumoural inappropriate TSH secretion. Effect of a long-acting somatostatin analogue (SMS 201-995)

Inappropriate hypersecretion of TSH was investigated in a 25 year old man whose hyperthyroidism had relapsed 4 years after subtotal thyroidectomy. Serum TSH levels were further increased by both TRH and metoclopramide and were partially suppressed by triiodothyronine (120 micrograms/day). The serum alpha-subunit: TSH molar ratio was less than 1.0, and computerised axial tomography showed no evidence of a pituitary tumour. These features are characteristic of inappropriate TSH secretion due to thyrotroph resistance to thyroid hormones. A long-acting somatostatin analogue (SMS 201-995), 50 micrograms injected sc twice-daily for three days, suppressed TSH levels and nearly normalised thyroid hormone levels. Somatostatin analogues may be therapeutically useful in thyrotoxicosis due to non-tumoural inappropriate TSH hypersecretion.     

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.     

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 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.     

Resistance to a long-acting somatostatin analog (SMS 201-995) reversed by surgery in acromegaly

A 42-year-old woman had acromegaly and a large macroadenoma with supra- and parasellar extension. Her GH levels (median 85 ng/ml, range 63-170 ng/ml) were not responsive to TRH (200 micrograms iv), GHRH (100 micrograms iv) and bromocriptine (Br 2.5 mg po) acute tests; Sm-C level was 8 U/ml. She was treated with octreotide (SMS) (up to 1500 micrograms daily) for 3 months. No changes of clinical, biochemical and radiological findings were seen, therefore she underwent transsphenoidal surgery. After surgery, hypopituitarism and diabetes insipidus appeared: GH levels remained high (median 45 ng/ml; range 37-56 ng/ml), but became responsive to Br acute test. The patient was given SMS again, and this resulted in clinical improvement, marked reduction of GH and Sm-C levels and slight shrinkage of the residual tumor. Speculative hypotheses about this previously unreported phenomenon might be either an excess of both GHRH and somatostatin, caused by a primary increase of dopaminergic tone, or a primary excess only of GHRH; in both cases the surgical lesion of the hypothalamic-pituitary region might have impaired the neurohormones inflow to the residual pituitary and so let SMS and Br exert their inhibitory actions on GH secretion.     

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.     

Effect of a long-acting somatostatin analogue (SMS 201-995) on postprandial gastric emptying of 99mTc-tin colloid and mouth-to-caecum transit time in man

The effect on gut motility of a single subcutaneous injection of 50 micrograms of the long-acting somatostatin analogue, SMS 201-995, was investigated in 8 normal volunteers who took a drink containing 99mTc and lactulose with a mixed meal. The rate of gastric emptying was assessed by disappearance of the isotope from the stomach area as measured by a gamma camera, and mouth-to-caecum transit time (MCTT) was measured by the appearance of hydrogen in the breath. Gastric emptying was accelerated, with a significant reduction of the time taken to 50% isotope disappearance (37.2 +/- 3.3 min during control study vs 23.3 +/- 3.4 min after SMS injection; p less than 0.01). In contrast, MCTT was prolonged from 57.3 +/- 9.4 min (control) to 203.6 +/- 14.7 min after SMS (p less than 0.001).     

Treatment of acromegaly with the long-acting somatostatin analog SMS 201-995

Current treatment of acromegaly (surgery, radiation, and bromocriptine) is often unsatisfactory, and a sizeable proportion of patients with this disease continue to have GH hypersecretion after all therapeutic modalities have been exhausted. Fifteen patients with active acromegaly (8 previously treated and 7 newly diagnosed) were treated with the long-acting somatostatin analog SMS 201-995 (Sandoz; 50-250 micrograms, sc, every 6-8 h for up to 21 months). The mean daily plasma GH concentration was significantly suppressed in 13 patients, and it became normal in 10. Two patients, however, did not have GH suppression by SMS 201-995 treatment alone; in 1, a significant decline in mean daily GH was achieved after the addition of bromocriptine. As expected, suppression of GH secretion was associated with normalization of plasma somatomedin-C values and significant clinical improvement. Plasma GH responses to synthetic GHRH-(1-44) and TRH were either abolished or blunted by SMS 201-995. Thyroid function remained normal, and glucose tolerance did not change. Significant shrinkage of pituitary tumors occurred in 7 previously untreated and 2 previously treated patients. Side-effects were minimal. SMS 201-995 is an effective agent for the treatment of acromegaly. Further studies are necessary to establish guidelines for identification of non-responders and to examine the effect of preoperative tumor shrinkage on subsequent surgical outcome.     

The effect of the long-acting somatostatin analogue SMS 201-995 on ACTH secretion in Nelson's syndrome and Cushing's disease

Chronic therapy of a patient with Nelson's syndrome for 2 years with 300 micrograms SMS 201-995 per day resulted in a significant decrease in circulating ACTH levels, normalization of the visual field defect and of loss of visual acuity of one eye, and stabilization of tumour growth, without radiological evidence of shrinkage of the pituitary tumour. In two other patients with Nelson's syndrome, SMS 201-995 acutely inhibited circulating ACTH levels. This effect could be shown best if cortisol replacement was temporarily withheld. SMS 201-995 did not affect plasma ACTH and cortisol levels in three patients with untreated Cushing's disease.     

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.     

In vitro effects of the long-acting somatostatin analogue SMS 201-995 on electrolyte transport by the rabbit ileum

We have investigated the in vitro properties of SMS 201-995, a long-acting somatostatin analogue, on electrolyte transport in rabbit ileum. Similar to native somatostatin, serosal addition of this compound inhibits electrogenic anion secretion and stimulates neutral sodium and chloride absorption. Both compounds have similar maximal effects on ion transport; however, the ED50 of SMS 201-995 (2.4 X 10(-10) M) was 60 times less than that for somatostatin. In addition, unlike somatostatin, no inherent tachyphylaxis was observed in response to SMS 201-995. The antisecretory profile of SMS 201-995 was also compared with that of epinephrine. Unlike treatment with epinephrine, pretreatment of tissues with SMS 201-995 did not directly inhibit electrogenic anion secretion stimulated by vasoactive intestinal polypeptide, calcium ionophore A23187, and bethanechol. In contrast, this agent blocked vasoactive intestinal polypeptide and bethanechol inhibition of net sodium absorption. We conclude that SMS 201-995 has several unique in vitro properties that may explain its greater biologic activity compared with that of somatostatin. Its effects on secretagogue-stimulated electrogenic anion secretion and electroneutral NaCl absorption appear to differ.