Medical treatment of acromegaly with SMS 201-995, a somatostatin analog: a comparison with bromocriptine

We studied the effects of acute and chronic sc administration of SMS 201-995 (SMS), a long-acting somatostatin analog, in acromegalic patients. The results were compared with those obtained in the same patients treated with oral bromocriptine (Brc). A single dose of 50 micrograms SMS administered to 28 patients induced a more rapid, greater, and more prolonged reduction in plasma GH levels than did 2.5 mg Brc. Chronic treatment [60-330 days; mean 208 +/- 23 (+/- SEM)] with SMS (100-300 micrograms/day) induced in 16 patients a significantly greater decrease in mean plasma GH and somatomedin-C levels than did 20 mg Brc. Combined treatment with the 2 agents had an additional effect. The clinical and metabolic parameters of acromegaly dramatically improved in all patients whose plasma GH and somatomedin-C levels decreased even if they were not normalized by SMS. Reduction in tumor size occurred in 3 of the 10 patients examined by computed tomography before and during SMS treatment. We conclude that SMS is more effective than Brc and that the 2 drugs may be complementary in the medical treatment of acromegaly.     

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 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.     

A randomized study of SMS 201-995 versus bromocriptine treatment in acromegaly: clinical and biochemical effects

Twenty-six acromegalic patients were randomized to treatment with either SMS 201-995 or bromocriptine in increasing doses and were investigated before treatment, after 2, 4, and 8 weeks of treatment, and 2 weeks after discontinuation of treatment. There were two dropouts from the bromocriptine group and one from the SMS 201-995 group. Amelioration of clinical signs and symptoms was seen in both groups during treatment. After 8 weeks mean 12-h GH concentrations had declined from 13.8 +/- 5.2 to 2.9 +/- 4.4 (mean +/- SEM) in SMS 201-995-treated and from 18.8 +/- 7.5 to 5.4 +/- 1.2 micrograms/L in bromocriptine-treated patients. Somatomedin-C concentrations fell from 3.04 +/- 0.36 to 1.43 +/- 0.36 in SMS 201-995-treated and from 2.93 +/- 0.40 to 2.13 +/- 0.27 U/mL in bromocriptine-treated patients. Size reduction of the pituitary tumor was seen in one patient receiving bromocriptine. Gastrointestinal glucose absorption was delayed, and insulin secretion suppressed during treatment with SMS 201-995. Hemoglobin-A1 concentrations remained unchanged in SMS 201-995-treated patients, but declined in the bromocriptine group. Side-effects were common, but usually tolerable, with both treatments. It is concluded that both drugs are of benefit in the treatment of acromegaly.     

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.     

Effects of somatostatin analog SMS 201-995 on enterotoxigenic diarrhea

Somatostatin analog SMS 201-995 causes a dose-related suppression of the release and/or action of several gastrointestinal hormones and impairs several anterior pituitary functions. Some patients with illness involving abnormal hormonal activity have responded to treatment with SMS 201-995, including resolution of severe secretory diarrhea. This study examined SMS 201-995 inhibition ofEscherichia coli heat-stable enterotoxin STa (STa) effects and effects of the analog in the rabbit RITARD model with enterotoxigenicEscherichia coli. SMS 201-995 did not alter STa binding to its receptor on piglet brush border membranes. The analog, at concentrations of 0.1 g/ml (0.1 M) and 1 g/ml (1 M) did not significantly alter STa activation of intestinal epithelial cell particulate guanylate cyclase. At maximal dosing the analog significantly reduced intestinal fluid secretion in suckling mice that was induced by either 8-bromo cyclic GMP or STa. In piglets, the analog reduced by 37–44% the amount of diarrhea induced by STa. However, even with maximal dosing, the piglets still had significant diarrhea, although of a lesser amount. In the rabbit RITARD model the drug failed to alter the severe diarrheal response seen when dosing the animals with enterotoxigenicEscherichia coli. Overall, SMS 201-995 had a significant but incomplete effect in reducing the STa effects seen in the various assays. Additionally, in the RITARD model the analog did not alter the clinical responses to various enterotoxigenic bacteria. SMS 201-995 should be useful as a probe into the mechanisms involved in intestinal fluid secretion, but a clinical role in enterotoxigenic gastrointestinal disease was not supported by this study.This work was supported by the Ralston Purina Co., St. Louis, Missouri, by Sandoz Inc., East Hanover, New Jersey, and by the Department of Veterans Affairs.The work was presented in part at the Sixth International Symposium on Gastrointestinal Hormones, July 1986, Vancouver, British Columbia, Canada.     

Postprandial gallbladder motility during long term treatment with the long-acting somatostatin analog SMS 201-995 in acromegaly

The effects on gallbladder motility of long term treatment with the somatostatin analog SMS 201-995 (SMS) were studied in five patients with acromegaly treated for 6-32 months with 200-300 micrograms SMS daily. SMS (100 micrograms) or placebo was injected sc 45 min before a standard breakfast. Gallbladder volume (ultrasonography), plasma cholecystokinin (CCK), and pancreatic polypeptide (PP) were measured until 120 min after the meal. SMS completely suppressed the postprandial gallbladder contraction, despite a blunted, though still statistically significant, increase in plasma CCK from 1.6 +/- 0.2 pmol/L to an average of 3.7 +/- 1.7 pmol/L (P less than 0.01). The postprandial plasma PP peak after placebo was replaced by a slight but statistically significant decrease after SMS (P less than 0.05). A statistically significant correlation between the plasma CCK values and corresponding gallbladder volumes was seen only after placebo injection, not in the SMS study. We conclude that during long term treatment of acromegalics with SMS, an injection of 100 micrograms, sc, completely abolishes gallbladder contraction for at least 2 h after a standard breakfast, despite blunted, but still significant, CCK release. The data suggest a decreased sensitivity of the gallbladder to endogenous CCK during long term treatment with SMS. Careful control of patients with respect to the formation of gallstones is recommended.     

Antiproliferative effects of somatostatin and the somatostatin analog SMS 201-995 on three human breast cancer cell lines

Summary The antiproliferative effect of somatostatin and the somatostatin analog SMS 201-995 on three human breast cancer cell lines (CG5, T 47 D, and ZR 75-1 is reported. Both peptides markedly inhibited CG5 cell growth with a maximal inhibition of about 40% as compared with control cells. The antiproliferative effect of somatostatin on T 47 D and ZE 75-1 cells was much less evident. These results suggest that somatostatin is a peptide inhibitory factor for human breast cancer cells. Possible therapeutic implications of these findings are still to be investigated.     

The effect of the somatostatin analog SMS 201-995 on normal growth hormone secretion in the rat. A comparison with the effect of bromocriptine on normal prolactin secretion

The somatostatin analog SMS 201-995 was recently shown to be effective in suppressing GH secretion and in causing tumour shrinkage in patients with GH-secreting pituitary tumours. In this respect, the action of SMS 201-995 seems similar to that of the dopamine-agonist bromocriptine in patients with PRL-secreting pituitary tumours. In the present study we compared the respective effects of SMS 201-995 and bromocriptine on normal rat GH and PRL release in vivo and in vitro. Both in vitro and in vivo, repeated administration of SMS for up till 6 days suppressed circulating GH concentrations, and the ability of the pituitary glands to release GH in vitro. A dose-dependent diminution occurred of the total pituitary GH content in rats treated in vivo with SMS 201-995 for 4-6 days. During short-term in vitro incubation for only 4 h, the total amount of GH measured in the medium + gland was also diminished. Chronic administration with SMS 201-995 (2 micrograms/kg twice daily for 15 days), however, resulted in a complete desensitization of its inhibitory effect on GH synthesis and release. In similar experiments it was shown that the dopamine agonist bromocriptine affects normal PRL secretion in a different manner. Both in vitro (10 nmol/l) and in vivo administration for 6 days (0.2 mg/kg twice daily) greatly inhibited circulating PRL levels and the ability of the pituitary glands to release PRL in vitro. This is, however, in all instances accompanied by an accumulation of PRL within the pituitary gland.(ABSTRACT TRUNCATED AT 250 WORDS)     

A long-term dose-response study of somatostatin analogue (SMS 201-995, octreotide) in resistant acromegaly

Ten acromegalic subjects were studied in a trial designed to ascertain the optimum dosage of the somatostatin analogue SMS 201-995 (octreotide) in active acromegaly. Twenty-four-hour growth hormone (GH) profiles were assessed monthly for 6 months and again after 1 year of continuous therapy. After basal assessment octreotide was administered subcutaneously at a dose of 100 micrograms three times a day throughout the first month. The dose was increased by 300 micrograms/day at monthly intervals to a maximum of 1500 micrograms/day, unless serum GH fell to within set criteria. Eight patients completed the trial. One patient withdrew because of intractable diarrhoea while another died of causes related to his acromegaly and we have no evidence that octreotide played any part in his death. Mean 24-h GH fell from a basal level of 34.3 +/- SEM 7.6 mU/l to 8.0 +/- 1.3 mU/l (P less than 0.05) after 6 months. At 1 month (300 micrograms/day) mean GH was 13.6 +/- 2.2 mU/l and at 2 months (600 micrograms/day) 10.8 +/- 2.2 mU/l (P less than 0.05 vs 300 micrograms/day dose), and at 5 months (1500 micrograms/day) 11.3 +/- 2.0 mU/l (all P less than 0.05 vs basal). Analysis of group means revealed no significant difference between any dose schedules above 600 micrograms/day. After 1 year the mean GH of the group (n = 8) was 7.5 +/- 1.3 mU/l (P less than 0.05 vs basal). Three patients developed a deterioration and one an improvement in their glucose tolerance and three developed asymptomatic gallstones during the year of therapy. In conclusion, octreotide lowered GH levels in acromegaly over a 1-year period. We found no evidence that routinely increasing the dose beyond 600 micrograms/day was helpful.     

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 chronic non-secretory diarrhea in ileostomy with the long-acting somatostatin analog SMS 201-995

A patient with chronic refractory non-secretory diarrhea following ileostomy was treated with the long acting somatostatin analogue SMS 201-995. Under treatment with somatostatin stool weights were drastically reduced and electrolyte dysbalance was normalized within a few days. This case report shows that somatostatin is also therapeutically effective in non-secretory diarrhea.     

Therapeutic efficacy of the somatostatin analog SMS 201-995 (octreotide) in acromegaly. Effects of dose and frequency and long-term safety

STUDY OBJECTIVE: To determine the efficacy of stepwise incremental doses, to compare twice- with thrice-daily administration of the same total daily dosage of the long-acting somatostatin analog SMS 201-995 (octreotide, Sandoz Australia, Sydney, Australia), and to evaluate the risk for cholelithiasis after long-term therapy for acromegaly. DESIGN: Nonrandomized, controlled trial. SETTING: Tertiary care center at a medical research institute. PATIENTS: Sequential sample of 19 patients with active acromegaly. Twenty-five age-matched normal subjects were also studied to establish the normal range for growth hormone (GH) and insulin-like growth factor 1 (IGF-1). INTERVENTIONS: Eight patients (group 1) were treated with 100, 250, and 500 micrograms twice daily of octreotide, then switched to 333 micrograms three times daily, whereas 11 patients (group 2) were treated with 100, 200, 300, and 500 micrograms three times daily. Each treatment stage lasted 6 to 12 weeks. MEASUREMENTS AND MAIN RESULTS: Octreotide, 100 micrograms administered twice or thrice daily, significantly reduced mean 12-hour and nadir GH (P less than 0.01), IGF-1 (P less than 0.05), and hand volume (P less than 0.05). Dose increment to 500 micrograms in both groups did not further reduce mean 12-hour GH, nadir GH, or hand volume. Switching from 500 micrograms twice daily to 333 micrograms thrice daily resulted in significant (P less than 0.05) reduction of mean 12-hour GH, IGF-1, and hand volume. Normalization of mean 12-hour GH and IGF-1 occurred in 8 of 19 patients; 7 of the 8 patients had pretherapy mean 12-hour GH below 20 mIU/L. The pretherapy mean blood glucose was a significant negative predictor (r = -0.89) of the change in mean blood glucose during therapy. Gallstones were present in 9 of 18 patients after therapy. CONCLUSION: Thrice-daily was more effective than twice-daily administration of octreotide, and dose increments above 100 micrograms thrice daily did not confer additional benefit. Biochemical remission was achieved in 40% of patients and was dependent on the GH concentration at initiation of treatment. Cholelithiasis is a risk of octreotide therapy. Octreotide is effective and can be considered as a first-line therapy in patients with acromegaly with mean pretherapy GH concentrations below 20 mIU/L. In patients with mean GH over 20 mIU/L, octreotide may be used as an adjuvant to surgery or radiotherapy.     

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.     

Preoperative treatment of acromegaly with long-acting somatostatin analog SMS 201-995: shrinkage of invasive pituitary macroadenomas and improved surgical remission rate

Ten patients with previously untreated acromegaly and invasive pituitary macroadenomas were treated with the long-acting somatostatin analog SMS 201-995 (Sandoz) for 3-30 weeks before transsphenoidal or subfrontal pituitary adenomectomy. Preoperatively, treatment with SMS 201-995 reduced mean 24-h plasma GH concentrations from 8.5-66.7 to below 4.6 micrograms/L in eight patients and by 60-80% in the remaining two patients. Pituitary tumor size decreased 20-54%. Morphologically, the tumors showed decreased total cell, cytoplasmic, and nuclear areas; varying degrees of perivascular fibrosis; and dense granularity. Postoperatively, plasma GH and insulin-like growth factor I concentrations fell into the normal range, and GH dynamics became normal in eight patients. In the remaining two patients mild GH hypersecretion persisted after surgery (mean fasting and random plasma GH, 6.1 and 7.9 micrograms/L), and in one of them GH secretion became normal 1 yr after pituitary irradiation. Thus, preoperative administration of SMS 201-995 consistently induced shrinkage of GH-producing pituitary tumors, and the apparent remission rate was high in the treated patients.     

Long term effect of incremental doses of the somatostatin analog SMS 201-995 in 58 acromegalic patients. French SMS 201-995 approximately equal to Acromegaly Study Group

Fifty-eight acromegalic patients were included in a multicenter prospective study of increasing doses (300-1500 micrograms) of SMS 201-995 (octreotide, Sandostatin) administered 3 times daily, sc, during 6 months to determine its effect on signs and symptoms of GH hypersecretion. Subsequently, 34 of the patients were maintained for 12-26 months on the minimal efficacious dose, determined from the previous dose-response study. Some adverse effects were frequently encountered, mostly at the initiation of treatment, and disappeared with time. Asymptomatic gallstones occurred in 5 patients. Minimal changes in carbohydrate tolerance, consisting of a rise in blood glucose and a transient decrease in plasma insulin level after meals, were noted. GH normalized in 22% of the patients, improved in 56%, and remained unchanged in 22% regardless of the dose. The optimal daily dose was 300 micrograms in 50% of the patients and 1500 micrograms in 20%. Pituitary tumor size reduction occurred in 47% of the patients harboring large tumors or tumor remnants. No additional improvement or escape from being controlled occurred with time. These data indicate that SMS 201-995 is an effective treatment for refractory acromegaly and for some de novo patients for whom surgical therapy is not advisable.     

Treatment of hyperthyroidism due to inappropriate secretion of thyrotropin with the somatostatin analog SMS 201-995

The management of hyperthyroidism due to inappropriate secretion of TSH (IST) includes agents that selectively suppress TSH hypersecretion both in patients with TSH-secreting tumor [neoplastic IST (nIST)] in whom pituitary surgery was unsuccessful and in those with selective pituitary resistance to thyroid hormone action [nonneoplastic IST (nnIST)]. Among such agents, somatostatin administration has proven to be effective in blocking TSH hypersecretion, but its short plasma half-life prevented its use in long term therapeutic trials. The recent availability of a potent and long-acting analog of somatostatin (SMS 201-995, Sandostatin) prompted us to study its effects on serum TSH, alpha-subunit, and free thyroid hormone (FT4 and FT3) concentrations in five patients with nIST and three patients with nnIST. During short term SMS 201-995 administration (100 micrograms, sc, three times daily for 5 days) both serum TSH and alpha-subunit levels decreased in all patients with nIST (mean decrements, -86% and -85%, respectively), with concomitant normalization of serum FT4 and FT3 concentrations. In the three patients with nnIST, this treatment lowered serum TSH levels less well (mean decrement, -47%), although serum FT4 and FT3 levels normalized in one patient. Chronic SMS 201-995 (100 micrograms, sc, every 12 h for 1-7 months) treatment in four hyperthyroid patients (two with nIST and two with nnIST) resulted in a steady euthyroid state in both patients with nIST, with restoration of normal visual fields in one patient. In contrast, in both patients with nnIST, escape occurred after 2 weeks of therapy. We conclude that SMS 201-995 administration is effective treatment for patients with nIST, able to suppress TSH hypersecretion from the adenomatous thyrotrophs and, consequently, to restore clinical and biochemical euthyroidism in such patients. On the contrary, the inhibitory effects of SMS 201-995 on TSH secretion in patients with nnIST are weaker and transient.     

The somatostatin analog SMS 201-995 induces long-acting inhibition of growth hormone secretion without rebound hypersecretion in acromegalic patients

The acute effect of the somatostatin analog SMS 201-995 (SMS) was investigated in eight acromegalic patients. This substance is an octapeptide [DPhe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-(ol)] that inhibits GH release in experimental animals and man. After a control day, 50 micrograms SMS were injected sc, and plasma GH and insulin and blood glucose levels were measured at multiple intervals for 24 h. GH significantly (P less than 0.001) decreased in seven of eight acromegalic patients from 30 +/- 5 (+/- SE) to an average of 10.7 +/- 4 micrograms/l from 1-10 h after drug administration. No rebound effect occurred. Postprandial blood glucose levels were significantly (P less than 0.01) higher between 2 and 4 h after SMS treatment compared with control day values, and there was a substantial reduction in insulin secretion, as estimated by the area under the curve (P less than 0.01), during the first 3 h after SMS administration. Circulating GH was not altered by SMS or the dopamine agonist mesulergine in one patient, but the combination of both substances (50 micrograms SMS, sc, and 0.5 mg mesulergine, orally) reduced GH to below 50% of basal. In vitro studies showed that 1 PM, 0.1 nM, and 10 nM SMS or natural somatostatin exerted a similar inhibitory effect (12-39% reduction; P less than 0.01 for all three strengths) on GH release by cultured human pituitary tumor cells. In conclusion, the somatostatin derivative SMS exerts a potent and prolonged inhibitory action on GH secretion and a shorter lasting suppression of insulin in acromegalic patients. Therefore, it may represent a useful tool in the chronic management of this condition.