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.     

Successful treatment with SMS 201-995 of Cushing's syndrome caused by ectopic adrenocorticotropin secretion from a metastatic gastrin-secreting pancreatic islet cell carcinoma

Signs and symptoms of Cushing's syndrome developed rapidly after total gastrectomy in a 37-yr-old man with a metastatic gastrin-secreting islet cell carcinoma. Argyrophilic tumor cells in a lymph node removed during operation immunostained for gastrin and ACTH. Treatment for more than 6 months with the somatostatin analog SMS 201-995 (300 micrograms/day) greatly reduced serum gastrin levels and normalized plasma ACTH and cortisol levels and urinary cortisol excretion, and the signs and symptoms of Cushing's syndrome disappeared. The size of the primary tumor in the head of the pancreas, which had grown rapidly before SMS 201-995 therapy, stabilized after 6 months of treatment with the analog. We conclude that SMS 201-995 can reduce ACTH as well as gastrin secretion from islet cell carcinomas as well as control tumor growth.     

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.     

Medical management of acromegaly due to ectopic production of growth hormone-releasing hormone by a carcinoid tumor

A 59-yr-old woman with a disseminated carcinoid tumor was evaluated for acromegaly. She had previously undergone a hypophysectomy for acromegaly and an enlarged pituitary, with a reduction in her serum GH levels from 100 to 4 micrograms/L. Recurrence of acromegalic symptoms 2 yr later was accompanied by elevated serum GH (16 micrograms/L) and insulin-like growth factor I (IGF-I; 528 micrograms/L) and plasma GHRH levels (12 micrograms/L; normal, less than 30 ng/L). Computed tomographic scan did not reveal pituitary enlargement. Metastatic carcinoid tissue in bone removed at biopsy contained GHRH (100 pg/mg tissue). High performance liquid chromatography of plasma GHRH revealed predominantly GHRH-(3-40)-OH, a biologically inactive GHRH metabolite, along with mature GHRH forms, while carcinoid tissue contained both GHRH-(1-40)-OH and GHRH-(1-44)-NH2. Treatment with pergolide initially resulted in reduction in serum GH and IGF-I levels and amelioration of symptoms of acromegaly. However, after 14 months of pergolide therapy, serum GH levels increased despite administration of up to 1000 micrograms pergolide/day. Plasma GHRH levels remained elevated throughout the treatment period. Subsequent treatment with SMS 201-995, a long-acting somatostatin analog, for over 1 yr resulted in sustained reductions of ectopic GHRH secretion, GH hypersecretion, and IGF-I levels. Plasma GHRH levels correlated with simultaneously measured serum GH levels in response to acute SMS 201-995 administration. SMS 201-995 was an effective medical treatment for acromegaly caused by ectopic GHRH production in this patient.     

INTERACTION BETWEEN GROWTH HORMONE RELEASING FACTOR (GRF) AND SOMATOSTATIN ANALOGUE (SMS 201–995) IN NORMAL SUBJECTS

Continuous infusion or pulsatile administration of growth hormone releasing factor leads to decreasing GH levels and GH responses in normal subjects. We have given 50 micrograms GRF 1-44 i.v. four times in 2-hourly intervals to five normal subjects. After 1 week the same protocol was repeated after s.c. administration of 50 micrograms of the synthetic octapeptide somatostatin (SMS 201-995). The GH response to the same GRF doses was higher after the initial GRF pulse and blunted to the following GRF pulses (pulse I: 37:0 +/- 11.2 ng/ml; Pulse II: 5.3 +/- 1.2 ng/ml; pulse III: 5.9 +/- 2.5 ng/ml; pulse IV: 5.9 +/- 3.2 ng/ml; mean +/- SE). When SMS 201-995 was given 60 min before pulsatile GRF administration, the GH secretion pattern was reversed (pulse I: 2.4 +/- 0.7 ng/ml; pulse II: 2.0 +/- 0.9 ng/ml; pulse III: 4.4 +/- 2.1 ng/ml; pulse IV: 11.4 +/- 3.6 ng/ml). Radioimmunoassayable GRF levels were not different before and after administration of SMS 201-995. The half time of disappearance was 8.6 +/- 0.4 min before and 8.0 +/- 0.5 min after SMS 201-995. Basal thyrotrophin and insulin levels, which remained constant over the 8 h period with GRF only, decreased significantly after SMS 201-995 administration. These findings are compatible with a limited releasable GH pool which is exhausted by chronic GRF stimulation but can be conserved by prior administration of the somatostatin analogue. Thus, when somatostatin bioactivity tapers off, there is recovery of GRF-stimulated GH secretion.     

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.     

Effect of a new long-acting somatostatin analogue (SMS 201-995) on glycemic and hormonal profiles in insulin-treated type II diabetic patients

Five type II diabetic patients were studied after secondary failure of oral agents, with and without the addition of the new long-acting somatostatin analogue SMS 201-995 to an intermediate-acting insulin regimen. SMS 201-995 was administered twice daily, before breakfast and dinner, as 100 micrograms sc injections, and resulted in a lowering of plasma glucose, as well as of plasma glucagon and serum C-peptide levels. SMS 201-995 abolished postprandial glycemic and xylosemic peaks related to meals and to oral d-xylose when they were taken shortly after the administration of the analogue, while it had no effect on glycemic and xylosemic increments that followed the midday meal. The new somatostatin analogue improves glucose tolerance in type II diabetic patients, both by inhibiting counterregulatory hormones and by delaying and reducing intestinal absorption of nutrients. Its administration could lead to a reduction of daily insulin requirements. Our findings indicate that SMS 201-995 may have a role as an adjunct to insulin in the management of type II diabetic patients after secondary failure of oral agents.     

Effects of atropine, proglumide, and somatostatin analogue (SMS 201-995) on bombesin-induced gallbladder contraction and CCK secretion in humans

The effects of atropine, proglumide, and somatostatin analogue (SMS 201-995) on bombesin-induced gallbladder contraction and plasma cholecystokinin (CCK) secretion were investigated in healthy volunteers. The gallbladder size was measured by real-time ultrasonography and the plasma CCK levels by radioimmunoassay. Bombesin (5 micrograms/30 min infusion) induced gallbladder contractions that reduced the gallbladder area to 36.6 +/- 2.1% of the original area 45 min after bombesin infusion, and caused a significant increase of plasma CCK from a basal level of 10.3 +/- 1.8 pg/ml to a peak level of 42.9 +/- 8.9 pg/ml (p less than 0.01) at 20 min. Atropine (500 micrograms, im) inhibited significantly (p less than 0.01) the gallbladder contraction (maximum contractile rate, 78.7 +/- 6.4%) in response to bombesin without any change of plasma CCK secretion, whereas proglumide (800 mg/day for 3 days, per os) decreased slightly but not significantly the gallbladder contraction, and had no effect on plasma CCK secretion. On the other hand, SMS 201-995 (50 micrograms, sc) almost completely inhibited both bombesin-induced CCK secretion and gallbladder contraction (maximum contractile rate, 93.6 +/- 6.2%). These findings suggest that atropine inhibits bombesin-induced gallbladder contraction, not via suppression of CCK release, but probably by inhibiting cholinergic mechanisms, whereas somatostatin inhibits gallbladder contraction, at least in part, by the suppression of bombesin-stimulated CCK secretion.     

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.     

Gastrin-producing ovarian cystadenocarcinoma: sensitivity to secretin and SMS 201-995

We report a patient with severe peptic ulcer disease and a right ovarian mass that was found to be a gastrin-producing cystadenocarcinoma. Gastrin production by the tumor was stimulated by secretin and inhibited by the long-acting somatostatin analogue SMS 201-995. Following resection of the tumor, serum gastrin levels and the gastrin response to secretin returned to normal. Histologic examination, including Alcian blue staining for mucin and immunoperoxidase staining for gastrin, revealed gastrin at the base and mucin at the apex of the tumor cells. This report demonstrates secretin stimulation and somatostatin inhibition of gastrin secretion from a cell that is apparently not of endocrine origin.     

Effects of a somatostatin derivative (SMS 201-995) on postprandial hyperglycemia in insulin-dependent diabetics studied by means of a closed-loop device

We studied the effects of a premeal sc injection of an analog of somatostatin (SMS 201-995, Sandoz) on the postprandial glycemic excursions, insulin requirement and hormone profiles (GH, glucagon and C-peptide) in 8 IDDM patients (diabetes duration 14.0 +/- 6.5 yr, daily insulin requirement 36 +/- 6.4 U) maintained normoglycemic by connecting them to a closed-loop insulin infusion system (Betalike, Genoa). The morning of the test the patients were connected to the Betalike and their glucose levels stabilized for at least 4 h. At 13:00 h the study was begun with a sc injection of 50 micrograms of SMS 201-995 or placebo (randomly) and a standardized mixed meal (800 Kcal) was given. Blood samples were obtained 0, 15, 30, 60, 120 and 180 min after the injection. Each patient was tested both with SMS 201-995 and placebo. Postmeal glycemic peaks were decreased after SMS 201-995 (119.6 +/- 5.4 mg/dl vs 149.1 +/- 4.2; p less than 0.05) as well as insulin requirements (3.2 +/- 0.8 U vs 13.3 +/- 1.9; p less than 0.01) for the 180 min postprandial period. Similarly, glucagon level was reduced 30 min postprandially (24 +/- 6 pg/ml vs 59 +/- 24; p less than 0.05) and so GH level only 180 min after lunch (p less than 0.05). The premeal injection of SMS decreases postprandial glycemic excursions and the corresponding insulin requirement. The action of SMS 201-995 may be mainly mediated by the suppression of postprandial glucagon peak.     

Does SMS 201-995 normalize growth hormone secretion in acromegaly? GH day profiles and GH concentrations after oral glucose loading

GH secretion in acromegaly was studied in 8 patients before and during treatment with SMS 201-995, a somatostatin analogue, 100 micrograms twice daily, by evaluating GH day profiles and GH suppressibility after oral glucose tolerance tests (OGTT). Normalization of GH secretion, estimated by OGTT, was only observed in the three patients who had a decrease in plasma GH to less than 2 micrograms/l after SMS 201-995 injection, and who had the lowest mean plasma GH levels during the day and the largest percent decline of mean plasma GH levels. We conclude that real normalization of GH secretion during SMS 201-995 therapy only occurs in a subset of patients. The data illustrate that the applicability of the generally held cut-off value of 5 micrograms/l, between normal and abnormal plasma GH, has to be reconsidered in the case of chronic intermittent subcutaneous therapy with SMS 201-995.     

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.     

Development of resistance to a long-acting somatostatin analogue during treatment of two patients with metastatic endocrine pancreatic tumours

Two patients with metastatic endocrine pancreatic tumours initially responded well to therapy with the long-acting somatostatin analogue SMS 201-995. In the first patient with an insulinoma both the number of hypoglycemic attacks and the increased insulin levels decreased initially, but returned to pretreatment intensity and concentrations within 9 days after the start of therapy with 200-300 micrograms SMS 201-995 daily. After a short interruption, no effect was observed of re-institution of therapy at a dose of 400 micrograms SMS 201-995 daily. In the other patient with a metastatic vipoma both diarrhea, hypokalemia and plasma VIP levels reacted initially well to SMS 201-995 treatment with 300 micrograms per day, but resistance to therapy developed after 2 weeks. An increase in the dose of the analogue to maximally 600 micrograms/day was followed by a transient improvement, but finally both the volume of diarrhea and the levels of vasoactive intestinal polypeptide were higher than those before the start of therapy. Conclusions: Development of resistance to SMS 201-995 both with regard to the clinical effect and to the inhibitory effect on tumour hormone secretion can be expected in some patients with metastatic endocrine pancreatic tumours. On the basis of our clinical observations down-regulation of somatostatin receptors is suggested to be one of the mechanisms of this development.     

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.     

Studies on the mechanism of action of the inhibitory effect of the somatostatin analog SMS 201-995 on the growth of the prolactin/adrenocorticotropin-secreting pituitary tumor 7315a

The somatostatin analog SMS 201-995 (2 X 6 or 2 X 20 micrograms daily for 30 days) inhibited the growth of the PRL/ACTH-secreting pituitary tumor 7315a by 36% and 48%, respectively. A biphasic curve of the inhibitory effect of the SMS analog on tumor growth was recognized: the actual tumor growth inhibitory effect occurred during the first 15 days, after which the tumors grew in parallel with the control tumors despite SMS 201-995 treatment. At the end of the 30-day SMS 201-995 treatment, plasma GH and plasma somatomedin-C levels were similar to those in the control tumor-bearing rats. Separate experiments in normal rats showed that tachyphylaxis of the GH-secretion inhibitory effects of three different doses of SMS 201-995 occurred within 6-10 days. No specific somatostatin-14 or SMS 201-995 receptors were present on well grown, untreated 7315a pituitary tumors. However, PRL and ACTH secretion by cultured cells prepared from the 7315a tumor was inhibited by SMS 201-995. Pretreatment of the cultured cells with dexamethasone made PRL secretion by these tumor cells insensitive to SMS 201-995. These studies suggest that several factors played a role in the mechanism of action of the tumor growth-inhibitory actions of SMS 201-995. Twice daily administration of the somatostatin analog rapidly (within 6-10 days) induces tachyphylaxis of the GH-inhibitory effect. From 10 days after implantation the PRL/ACTH-secreting pituitary tumor causes adrenal hyperplasia and increased plasma corticosterone concentrations. Exposure of the 7315a tumor to high glucocorticosteroid levels probably decreases the number of somatostatin receptors, diminishing the possible direct antitumor effect of SMS 201-995.     

THE SENSITIVITY OF GROWTH HORMONE AND PROLACTIN SECRETION TO THE SOMATOSTATIN ANALOGUE SMS 201–995 IN PATIENTS WITH PROLACTINOMAS AND ACROMEGALY

The somatostatin analogue SMS 201-995 has recently been shown to be effective in suppressing GH secretion in most acromegalic patients. In the present study it was investigated whether PRL release in prolactinoma and acromegalic patients might also be sensitive to SMS 201-995 and whether co-secretion of PRL in acromegaly plays a role in determining the sensitivity of GH secretion to SMS 201-995. The s.c. administration of 50 micrograms SMS 201-995 did not affect high plasma PRL levels in four microprolactinoma patients. Therapy of one of these patients for 3 d with 50 micrograms three times a day also did not affect PRL levels. The single administration of 50 micrograms SMS 201-995 in 22 acromegalic patients lowered plasma GH levels for 2-6 h to less than 5 micrograms/l in 14 patients and to less than 50% of control values in 16 patients. In 18 of these 22 patients the immunohistochemical picture of the pituitary tumour was known. Eleven patients had pure GH-containing tumours and in seven patients there were mixed GH/PRL-containing tumours. In two of these latter patients there was evidence for GH and PRL being secreted by the same tumour cells. The sensitivity of GH secretion to SMS 201-995 did not differ between the patients with pure GH or mixed GH/PRL-containing adenomas. Plasma PRL levels were not affected by SMS 201-995 in the patients with pure GH-secreting tumours, but were significantly suppressed in four of the seven patients with mixed GH/PRL containing tumours. Chronic treatment for 16 weeks of one patient with a mixed GH/PRL-containing tumour with SMS 201-995 (100 micrograms three times a day) resulted in normalization of both the increased GH and PRL levels. It is concluded that SMS 201-995 does not affect tumorous PRL secretion in patients with pure prolactinomas. In acromegalic patients with mixed GH/PRL-containing tumours PRL secretion in some patients is sensitive to SMS 201-995, making these patients good candidates for chronic treatment with the analogue. The simultaneous presence of PRL in the GH-secreting pituitary tumour or the presence of hyperprolactinaemia in acromegalics does not play a role in the sensitivity of GH secretion to the somatostatin analogue.     

The effects of the somatostatin analogue SMS 201-995 on carbohydrate homeostasis of insulin-dependent diabetics as assessed by the artificial endocrine pancreas

On the basis of the inhibitory actions of the somatostatin analogue SMS 201-995 on growth hormone (GH) and glucagon (IRG) secretion we investigated its effects on carbohydrate metabolism of insulin-dependent diabetics. Six patients with no residual insulin secretion were connected to the artificial endocrine pancreas (AEP) and after the establishment of a steady state overnight they were injected either normal saline or 50 micrograms of SMS 201-995 s.c., t.i.d., or 100 micrograms of the same compound b.i.d. Insulin requirements were assessed by the AEP and compared during the 24 h and after the main meals. The inhibition of GH and IRG secretion was evaluated as well. 50 micrograms of SMS analogue t.i.d. induced a significant reduction of insulin requirement (mean +/- SEM) while no significant difference was observed between control and 100 micrograms s.c., b.i.d., nor between 50 micrograms and 100 micrograms. The curve of glucose fluctuations was smoother after 50 micrograms than after 100 micrograms and control. Postprandial IRG secretion was inhibited by both regimens of SMS after lunch and dinner. GH secretion was significantly inhibited after all meals during the days of analogue administration. SMS 201-995 analogue appears to have a remarkable antidiabetic activity as shown by the sparing of administered amount of insulin, suppression of counter-insulin hormones and smoothing of blood glucose curve. It may constitute a safe and effective adjunctive measure in the management of insulin-dependent diabetics.     

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.     

Comparison of the effectiveness of 2-hourly versus 8-hourly subcutaneous injections of a somatostatin analog (SMS 201-995) in the treatment of acromegaly

To determine whether sc injections of a somatostatin analog (SMS 201-995) every 2 h (q2h) is more effective than sc injections every 8 h (q8h) in achieving a constant suppression of GH levels and a more satisfactory clinical response, we studied 10 patients with acromegaly (4 newly diagnosed and 6 previously treated with bromocriptine/pituitary irradiation/transfrontal hypophysectomy). The dose of SMS 201-995 was increased from 300 micrograms/day to a maximum of 600 micrograms/day when the mean serum GH (hourly samples for 12 h) failed to be suppressed to undetectable levels in over 75% of the samples. Five patients received a 200-micrograms sc injection q8h (600 micrograms/day), and the other 5 received sc injections q2h [418 +/- 46 micrograms/day (mean +/- SE); range, 288-504 micrograms/day]. In the group receiving q2h sc SMS 201-995 there was a marked suppression of mean GH from a basal level of 77.3 +/- 24.7 mU/L to less than 5 mU/L in all five subjects. In the group receiving q8h sc SMS 201-995, mean GH was suppressed from a basal level of 82.2 +/- 21.7 to 15.4 +/- 3.3 mU/L after 6 months of therapy, and none of the patients had a mean GH level consistently less than 5 mU/L. Despite the difference in the level of GH suppression, mean serum somatomedin-C levels were decreased promptly in both groups of subjects. Associated with the decrease in somatomedin-C levels there was a marked clinical response in both groups, but improvement in clinical features and decreases in hand volumes and ring size occurred earlier in the group receiving SMS 201-995 q2h. Significant tumor shrinkage (25% to greater than 50% reduction) was observed in two patients receiving q2h injections, while a 25-50% reduction in tumor size was noted in another patient receiving q8h injections. Because of the small doses of SMS 201-995 used side-effects of abdominal discomfort and flatulence were mild and rapidly disappeared. Our results show that increasing the frequency of sc administration of the somatostatin analog from q8h to q2h leads to more marked and consistent suppression of GH levels and more rapid improvement of clinical signs. Increasing the frequency of delivery of SMS 201-995 may be an alternative to increasing the dose in some patients with acromegaly.