SMS 201-995 induces a continuous decline in circulating growth hormone and somatomedin-C levels during therapy of acromegalic patients for over two years

Ten acromegalic patients, four previously untreated, were studied before and at regular intervals during treatment with the long-acting somatostatin analog SMS 201-995 (200-300 micrograms daily for 2 or 3 sc injections for 16-108 weeks). All patients had rapid clinical improvement, with disappearance of excessive perspiration, paresthesias, and headache within the first 6 weeks of therapy. The mean 24-h serum GH concentrations fell from 44.0 +/- 7.8 (+/-SE) micrograms/L before to 5.9 +/- 1.0 microgram/L at the end of therapy. The GH levels from 2-6 h after the acute administration of 50 micrograms SMS 201-995 before the start of therapy correlated significantly with the mean 24-h GH concentrations after 16-108 weeks of treatment (P less than 0.05). The initially increased serum somatomedin-C (Sm-C) levels normalized in 5 of these 10 patients; the mean values were 7.3 +/- 0.9 U/mL before and 2.9 +/- 0.7 U/mL at the end of therapy. The Sm-C and mean GH levels continuously decreased during long term therapy; the concentrations after 1.5-2 yr of therapy were significantly lower than those after 6-12 months of therapy (P less than 0.01 and P less than 0.01, respectively). A slight decrease in the size of the pituitary tumor was noted by computed tomography in three of six patients. Transient clinically detectable steatorrhea occurred in two patients. Postprandial hyperglycemia occurred during therapy in eight patients, while in two patients with type 2 diabetes mellitus carbohydrate tolerance improved in one and deteriorated in the other. SMS 201-995 is a highly effective medical treatment for acromegaly. Clinically improvement occurs rapidly, and the inhibition of serum GH and Sm-C levels persisted even after more than 1 yr of therapy. No important subjective side-effects were noted. SMS 201-995 is an excellent drug in patients in whom acromegaly persists after surgery and for interim treatment to shorten the period of clinical activity after irradiation.     

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.     

EFFECTS OF SOMATOSTATIN ANALOGUE SMS 201–995 IN NON-INSULIN-DEPENDENT DIABETES

The 24-h hormonal and metabolic profiles obtained in five non-insulin-dependent diabetics receiving twice daily s.c. injections of the long-acting somatostatin analogue SMS 201-995 (50 micrograms) have been compared with those obtained following placebo injection. Injections were given 30 min before breakfast and the evening meal. GH secretion was not suppressed by the analogue administered in this manner. Despite suppression of serum insulin levels following breakfast and the evening meal, blood glucose levels were similar during the two study periods with no evidence of worsening in diabetic control. Prolonged suppression of plasma glucagon levels was observed and the nocturnal elevation in serum TSH levels was abolished. Free T4 levels fell significantly following the analogue but total T3 levels were unaffected. Blood alanine levels were elevated throughout the study period following SMS 201-995 but changes in lactate, pyruvate, glycerol and 3-hydroxybutyrate were minor. All five subjects suffered gastrointestinal side-effects. SMS 201-995 (50 micrograms) given twice daily before meals does not cause a deterioration in metabolic control, does not suppress 24-h GH secretion and causes significant side-effects in patients with non-insulin-dependent diabetes mellitus.     

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.     

Plasma insulin-like growth factor-I/somatomedin-C in acromegaly: correlation with the degree of growth hormone hypersecretion

We measured plasma insulin-like growth factor I/somatomedin-C (IGF-I/SmC) concentrations and mean 24-h GH secretion serially before and during therapy with the long-acting somatostatin analog SMS 201-995 in 21 patients with acromegaly. When mean plasma GH was elevated above 12.0 +/- 0.6 (+/- SE) micrograms/L, plasma IGF-I/SmC concentrations were uniformly high, but a decline of mean plasma GH below this value was accompanied by a linear decrease in IGF-I/SmC concentrations (r = 0.89; P less than 0.001). Even mildly abnormal mean GH concentrations (greater than 4.6 but less than 10 micrograms/L) were accompanied by high plasma IGF-I/SmC values. The log dose-response interrelation between mean 24-h plasma GH and IGF-I/SmC concentrations was linear (r = 0.86; P less than 0.001). We conclude that 1) an excellent log dose-response correlation between mean 24-h plasma GH and IGF-I/SmC concentrations is present in patients with acromegaly; 2) normalization of plasma IGF-I/SmC occurs only in patients with mean daily GH output within the normal range; and 3) determination of plasma IGF-I/SmC is an accurate indicator of normalcy of GH secretion and should be used in the diagnosis of active acromegaly as well as in monitoring the progress of therapy.     

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.     

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.     

Somatostatin analog SMS 201-995 and insulin needs in insulin-dependent diabetic patients studied by means of an artificial pancreas

SMS 201-995 is a new somatostatin analog which is 10-60 times more potent and specific than somatostatin as an inhibitor of GH and insulin release. The aim of this study was to assess its value as an adjunct to insulin therapy in insulin-dependent diabetic- (IDD) patients. Six IDD patients were studied. Their average insulin doses ranged from 22-46 U/day, and hemoglobin A1c levels varied between 6.5-11.5%. Two patients had background retinopathy and mild sensorimotor neuropathy. After 12 h of glucemic stabilization, the patients were kept normoglycemic by connecting them to the Biostator-GCIIS. The study entailed two parts in random order, in which standardised mixed meals were administered at 0800, 1400, and 2000 h with or without sc bolus injections of 50 micrograms SMS 201-995 immediately before meal ingestion. Plasma free insulin, C-peptide, GH, and glucagon were measured by RIA. Postprandial hyperglycemia was significantly diminished by SMS 201-995 after breakfast, lunch, and dinner. Insulin requirements, both total and 2-h postprandially, decreased significantly with a parallel reduction in free insulin levels. Postprandial glucagon levels also significantly decreased, but GH profiles were similar. In conclusion, the somatostatin analog SMS 201-995 has a potential value as an adjunct to insulin in the management of IDD patients.     

A CLOSE CORRELATION BETWEEN THE INHIBITORY EFFECTS OF INSULIN-LIKE GROWTH FACTOR-I AND SMS 201-995 ON GROWTH HORMONE RELEASE BY ACROMEGALIC PITUITARY TUMOURS IN VITRO AND IN VIVO

In the present study we compared the in-vitro effects of IGF-I and SMS 201-995 on GH release by cultured tumour cells obtained from seven acromegalic patients with the preoperative in-vivo GH dynamics, including the acute response to 50 micrograms SMS 201-995 subcutaneously. IGF-I and SMS 201-995 inhibited GH release during a 24 h incubation in four and five of the seven tumour cell preparations, respectively. The inhibitory effect of SMS 201-995 was greater than that exerted by IGF-I (P less than 0.01). There was a close correlation between the in-vitro inhibitory effects of IGF-I and SMS 201-995 (P less than 0.01). In addition, the acute inhibitory effect of 50 micrograms SMS 201-995 on circulating GH levels in vivo correlated with the inhibitory effects in vitro of both SMS 201-995 (P less than 0.01) and IGF-I (P less than 0.05). The inhibitory effects of IGF-I and SMS 201-995 on GH release in vitro were shown to be additive in two of four tumours. There was no relation between the in-vitro effects of IGF-I and/or SMS 201-995 and several in-vivo parameters, including fluctuations in GH levels, sleep-induced GH release, a paradoxical increase of GH in response to TRH, and the circulating IGF-I and PRL levels. In conclusion: (1) there is a close correlation between the sensitivity of GH release by cultured human adenoma cells to IGF-I and SMS 201-995. (2) There is also a close correlation between the in-vivo inhibitory effect on GH release of SMS 201-995 and the in-vitro inhibitory effects of both SMS 201-995 and IGF-I. (3) A subgroup of acromegalic patients harbour pituitary tumours in which the qualitative regulation of hormone secretion is similar to that of normal GH secretion.     

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.     

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.     

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.     

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.     

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.     

EFFECT OF OCTAPEPTIDE SOMATOSTATIN ANALOGUE (SMS 201-995) ON PLASMA 7B2 (A NEUROENDOCRINE POLYPEPTIDE) LEVELS IN PATIENTS WITH ACROMEGALY

We studied the sequential changes of plasma levels of immunoreactive '7B2' (IR-7B2), a neuroendocrine polypeptide, after a subcutaneous injection of 50 micrograms of synthetic octapeptide somatostatin analogue (SMS 201-995) in seven patients with acromegaly due to GH-producing pituitary adenoma. Compared to the basal levels, mean plasma IR-7B2 and GH levels significantly decreased, until 5 and 10 h respectively after the administration of SMS 201-995. The mean (+/- SEM) nadir levels of plasma IR-7B2 and GH were 68.1 +/- 10.1 and 13.1 +/- 6.9%, respectively, compared to mean plasma levels before treatment (100%). Plasma IR-7B2 as well as GH levels did not change significantly when saline was administered subcutaneously to three acromegalic patients. In addition, plasma IR-7B2 levels did not change significantly after the administration of SMS 201-995 in normal subjects or in patients with primary hypothyroidism in whom SMS 201-995 induced a decrease of plasma TSH levels. These results strongly suggest that SMS 201-995 has an unequivocal suppressive effect on the synthesis and/or the secretion of 7B2 in human somatotroph adenoma cells.     

Cholinergic muscarinic receptor blockade suppresses arginine- and exercise-induced growth hormone secretion in type I diabetic subjects

Stimulatory cholinergic pathways participate in the regulation of GH release, and cholinergic receptor antagonists inhibit GH secretion in normal man. Whether similar mechanisms are active in subjects with insulin-dependent diabetes is not known, yet this is of potential importance since GH hypersecretion has been implicated in both the acute and chronic complications of diabetes mellitus. To address this question we studied the effects of cholinergic receptor blockade on stimulated GH release in 18 type I diabetic men. Paired tests were performed using 1 of 2 different stimuli (30 g arginine, iv, or physical exercise for 30 min) with or without prior administration of the selective cholinergic muscarinic receptor antagonist pirenzepine (30 mg, iv). Arginine elicited a mean peak serum GH level of 9.0 +/- 1.9 (+/- SEM) micrograms/L, which was completely suppressed by pirenzepine (1.5 +/- 0.4 micrograms/L; n = 8; P less than 0.01). Blood glucose rose after arginine infusion and was not affected by pirenzepine. Serum GH levels rose during physical exercise to a mean peak of 7.3 +/- 1.6 micrograms/L, which was abolished by pirenzepine (1.2 +/- 0.3 micrograms/L; n = 10; P less than 0.01). Blood glucose was not influenced by pirenzepine. Two subjects had no serum GH response to exercise. We conclude that GH secretion in subjects with insulin-dependent diabetes, as in normal subjects, is modulated by cholinergic pathways and is responsive to pharmacological suppression by muscarinic receptor blockade. This may have implications for therapeutic trials designed to lower elevated GH levels in subjects with diabetes mellitus.     

EFFECTIVE LONG-TERM TREATMENT OF ACROMEGALY WITH A LONG-ACTING SOMATOSTATIN ANALOGUE (SMS 201–995)

Nine acromegalic patients, six previously untreated, were studied before and after 3-15 months of treatment with a long-acting somatostatin analogue (SMS 201-995; 100 micrograms injected s.c. three times daily). During treatment, the mean (+/- SEM) 24-h GH concentration fell from 82 +/- 22 mIU/l to 33 +/- 7 mIU/l (P less than 0.001), and eight of the 9 patients showed a reduction of at least 50% in GH levels in the fasting state and/or during a glucose tolerance test. There was a significant 30% fall in serum concentrations of insulin-like growth factor (IGF-1) with SMS. All patients showed rapid clinical improvement, with diminished sweating and headaches, and reduction in skinfold thickness, hand volumes and finger size. Computer tomographic scanning of the pituitary in eight patients showed no change in the size of the pituitary tumour during treatment. The only side-effects of SMS noted were transient abdominal discomfort and loose stools in two patients on initiating therapy. Although fasting plasma glucose concentration did not change during treatment (5.4 +/- 0.3 vs 5.5 +/- 0.3 mmol/l), mean 24-h plasma glucose concentration was higher with SMS (6.6 +/- 0.5 mmol/l vs 6.0 +/- 0.4 mmol/l; P less than 0.02). Mean 24-h plasma insulin concentration fell from 87 +/- 11 mIU/l before treatment to 39 +/- 6 mIU/l during treatment (P less than 0.005). No change in other anterior pituitary hormones was observed. SMS appears to be a safe, rapidly effective, long-term treatment for certain patients with acromegaly.     

Endocrine profile of a long-acting somatostatin derivative SMS 201-995. Study in normal volunteers following subcutaneous administration

The pharmacokinetics and the endocrine profile of a new low molecular somatostatin derivative, SMS 201-995, were investigated in a group of 35 normal subjects. Clearance studies (n = 6) for this peptide showed a prolonged half-life in plasma, 113 min, following single sc injections of 50 or 100 micrograms. Arginine stimulation tests (n = 6) were conducted immediately and 180 min after sc injection of 50 micrograms of SMS 201-995. The stimulatory effect of arginine on GH and insulin was counteracted by the peptide at the P less than 0.001 and P less than 0.02 significance level, respectively. Delayed arginine stimulation revealed a persistent blockade of the GH release (P less than 0.02), whereas a recovery of the insulin response was observed. Plasma glucagon increments following a standard protein meal (n = 10) were significantly (P less than 0.001) inhibited by previous sc injection of 50 micrograms of SMS 202-995. Pretreatment with 50 and 100 micrograms of SMS 202-995 sc (n = 9) inhibited (P less than 0.001) the stimulatory effect of TRH (200 micrograms iv) on TSH without modifying basal levels. The injection of 100 micrograms/h during sleep completely abolished the nocturnal GH peak in 4 volunteers. No rebound rise after decline of the suppressive action on GH was recorded in any of the trials. Safety chemistries and blood coagulation studies remained normal and no side-effects or untoward reactions were recorded throughout the investigation.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Differential effects of somatostatin (SRIH) and a SRIH analog, SMS 201-995, on the secretion of growth hormone and thyroid-stimulating hormone in man

We compared the ability of SRIH and SRIH analog, SMS 201-995 (SMS), to inhibit stimulated GH and TSH secretion in men who received 120-min iv infusions of saline, SRIH (5, 50, and 500 micrograms/h), and SMS (3, 30, and 300 ng/kg.h) together with a bolus iv injection of GHRH (1 microgram/kg) and TRH (500 micrograms). Integrated GH secretion during the 60 min after GHRH plus TRH injection was decreased compared to that after saline by (mean +/- SE) 32 +/- 14% (P = 0.059), 78 +/- 5% (P less than 0.001), and 88 +/- 3% (P less than 0.001) during the 5, 50, and 500 micrograms/h SRIH infusions, and by 13 +/- 7% (P = NS), 50 +/- 15% (P less than 0.05), and 80 +/- 6% (P less than 0.001) during the 3, 30, and 300 ng/kg.h SMS infusions. In contrast, integrated TSH secretion was unaltered during the 5 micrograms/h SRIH and 3 ng/kg.h SMS infusions; it decreased by only 43 +/- 5% (P less than 0.001) and 66 +/- 4% (P less than 0.001) during the 50 and 500 micrograms/h SRIH infusions and by 33 +/- 8% (P less than 0.05) and 50 +/- 3% (P less than 0.001) during the 30 and 300 ng/kg.h SMS infusions. Analysis of the dose-response curves indicated approximately 10- and 5-fold greater potencies of SRIH and SMS, respectively, in inhibiting GH as compared to TSH secretion. These results quantify the effect of SRIH as an inhibitor of GH secretion and suggest that if SRIH has a physiological role in the inhibition of TSH secretion in man, it is limited to conditions associated with marked suppression of GH.