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.     

A COMPARISON BETWEEN THE EFFECTS OF SMS 201–995, BROMOCRIPTINE AND A COMBINATION OF BOTH DRUGS ON HORMONE RELEASE BY THE CULTURED PITUITARY TUMOUR CELLS OF ACROMEGALIC PATIENTS

The in-vivo reaction of the plasma GH concentration to the administration of the somatostatin analogue SMS 201-995, bromocriptine and their combination were compared with the in-vitro effects of both compounds and their combination on GH release and the GH tumour cell content of 9 acromegalic patients. Exposure of cultured GH-secreting pituitary tumour cells for 4-96 h to SMS 201-995 showed a variable, but in all instances during longer incubations statistically significant inhibition of GH release, which paralleled the sensitivity of GH secretion to the drug in vivo. This inhibitory effect on GH release was in two of the eight tumours accompanied by a decrease in the GH tumour cell content after 24-72 h of culture. These changes either reflect an inhibition of GH synthesis and/or an increase in intracellular breakdown (crinophagy) of GH and might be the basis for the tumour shrinkage which has been observed in about half of the acromegalic patients during long-term SMS 201-995 therapy. The inhibitory effects of bromocriptine on GH secretion were antagonized by haloperidol, while the inhibitory effect of SMS 201-995 was not affected by the dopamine receptor antagonist. This suggests that the effects of SMS 201-995 and bromocriptine are mediated via separate mechanisms involving different receptors. Additive but no potentiating inhibitory effects of both drugs on GH release were observed in a group of six patients in vivo and in three of six tumours in vitro.     

GROWTH HORMONE-RELEASING FACTOR INCREASES SERUM PROLACTIN CONCENTRATIONS IN NORMAL SUBJECTS AND IN PATIENTS WITH PITUITARY ADENOMAS

We have examined the serum growth hormone (GH) and prolactin (PRL) response to growth hormone releasing factor (hGRF-(1-44)NH2 (GRF) 1 microgram/kg i.v. bolus) in 16 acromegalic patients (eight of whom were hyperprolactinaemic), 13 patients with microprolactinoma, and 14 healthy subjects. The GH responses to TRH and to the somatostatin analogue SMS 201-995 were also studied in acromegalic patients. In these, and in patients with microprolactinoma, GH responses after GRF (P less than 0.001 vs saline) were variable. The absolute GH increase (calculated as area under the curve) in acromegalic patients (2489 +/- 920 micrograms/l min), or in patients with microprolactinoma (1322 +/- 279 micrograms/l min) was not different from that in controls (2238 +/- 633 micrograms/l min). In addition, a significant increase in PRL release was observed after GRF in comparison to saline in acromegalic patients (P less than 0.01), in patients with microprolactinoma and in normal subjects (P less than 0.001). The PRL increase was significantly correlated with basal PRL levels in acromegalic patients (r = 0.99, P less than 0.001) and in patients with microprolactinomas (r = 0.61, P less than 0.05). Furthermore, a significant correlation was found between GH rise after GRF and basal GH, and between GH rise after GRF and GH decrement after SMS in patients with acromegaly. These results suggest that GRF can stimulate PRL release by actions on the normal pituitary and on pituitary adenomas, including microprolactinomas. Moreover, the data suggest that in acromegaly there is a relative functional deficiency of hypothalamic somatostatin.     

A comparison among the growth hormone-lowering effects in acromegaly of the somatostatin analog SMS 201-995, bromocriptine, and the combination of both drugs

The acute GH inhibitory effects of 50 micrograms SMS 201-995, a somatostatin analog, and 2.5 mg bromocriptine were compared in 17 acromegalic patients. SMS 201-995 suppressed plasma GH levels after 2-6 h to 5 micrograms/liter or less in 10 of these 17 patients, while bromocriptine did the same in only 5 of them. There was much variation in the responsiveness to both drugs in these patients, but the GH-lowering effect of 50 micrograms SMS 201-995 was significantly greater than that of 2.5 mg bromocriptine. SMS 201-995 and bromocriptine together significantly suppressed plasma GH levels in 2 of 3 acromegalic patients who were insensitive to both compounds when tested separately. We conclude that most acromegalic patients respond better to SMS 201-995, while a few patients are more sensitive to the GH-lowering effect of bromocriptine. In addition, the combination of SMS 201-995 and bromocriptine can be of value in a few acromegalic patients who do not respond to either drug alone.     

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.     

GLYCOPROTEIN HORMONE ALPHA-SUBUNIT AND PROLACTIN RELEASE BY CULTURED PITUITARY ADENOMA CELLS FROM ACROMEGALIC PATIENTS: CORRELATION WITH GH RELEASE

In-vitro data of pituitary adenoma cells from 28 acromegalic patients were evaluated. In addition to GH, PRL was produced by 16 adenomas (57%) and alpha-subunit by 15 adenomas (54%) while there was a significantly higher incidence of tumours producing PRL and alpha-subunit simultaneously. From 26 pituitary adenomas enough cells were obtained in order to perform secretion studies. Percentage basal hormone release (medium: (medium + intracellular hormone)) x 100% of GH and alpha-subunit by 11 adenomas showed a close correlation while such a correlation for GH and PRL was present only in a subgroup of 10 of 13 adenomas. The responses of GH and alpha-subunit release to 10nM SMS201-995, 10nM bromocriptine, 100 nM TRH and 10nM GHRH were closely related in that a response or an absent response of GH release to the four secretagogues was virtually always attended with a response or an absent response respectively of alpha-subunit release. Such a relationship was less evident with respect to the effects of SMS201-995, bromocriptine. TRH and GHRH on GH and PRL release. We conclude that basal and secretagogue-induced alpha-subunit release by cultured pituitary adenoma cells from acromegalic patients closely follows the pattern of GH release while such a relationship for GH and PRL is present only in a subgroup of the adenomas secreting GH and PRL simultaneously.     

The effect of subcutaneous infusion versus subcutaneous injections of a somatostatin analogue (SMS 201-995) on the diurnal GH profile in acromegaly

Multiple sc injections of a long-acting somatostatin analogue (SMS 201-995) are currently used in the treatment of acromegaly. However, plasma GH concentration often reaches a pathological level (less than 5 micrograms/l) between two injections. In seven patients with active acromegaly we compared, in a short-term trial, the effect of SMS 201-995 administered by continuous sc infusion (50 micrograms and 100 micrograms a day) and by three sc injections (100 micrograms each). In six patients, plasma GH levels were significantly reduced regardless of the mode and dose of treatment (P less than 0.05). However, comparing diurnal profiles, 100 micrograms continuous sc infusion was more effective than discontinuous administration in reducing the number of GH levels above 5 micrograms/l (P less than 0.01). In two patients, continuous infusion was the only way to decrease all plasma GH values below 5 micrograms/l during the diurnal profile determination. Moreover, even when, in a long-term study, the dose of multiple injections was progressively increased to 500 micrograms three times a day, GH levels remained consistently elevated in one of these patients. Thus, in some acromegalic patients continuous sc injection seems currently the most efficient way of treatment with SMS 201-995.     

EFFECT OF SMS 201–995, A LONG-ACTING SOMATOSTATIN ANALOGUE, ON THE SECRETION AND MORPHOLOGY OF A PITUITARY GROWTH HORMONE CELL ADENOMA

The present study reports the effects of SMS 201-995, a long-acting somatostatin analogue, on blood GH levels, glucose tolerance and tumour morphology in a 36-year-old, previously untreated acromegalic woman. Treatment (50 micrograms s.c., 8-hourly) resulted in marked suppression of GH concentration and an improvement in glucose tolerance. After 10 d of treatment, the tumour was removed by transsphenoidal surgery and studied by histology, immunohistochemistry, transmission electron microscopy and morphometry. Histologically, the tumour was an acidophilic adenoma which contained immunoreactive GH in many adenoma cells. By electron microscopy, the tumour was composed of densely granulated somatotrophs containing numerous large secretory granules and many lysosomes showing crinophagy. No cell necrosis or vascular impairment were evident. Using morphometry, the tumour was compared with 10 densely granulated somatotroph adenomas, removed from acromegalic patients not treated with somatostatin. The nuclear and cytoplasmic areas of the adenoma subjected to SMS 201-995 treatment were smaller, and the lysosomes occupied more of the cytoplasmic volume than those of controls. The nuclear/cytoplasmic ratio, cytoplasmic volume densities of endoplasmic reticulum, Golgi apparatus, mitochondria, secretory granules and secretory granule diameters were within the range of control adenomas. In vitro, treated adenoma cells secreted GH and retained responsiveness to both GRH stimulation and somatostatin suppression. The morphologic findings after SMS 201-995 treatment, are consistent with suppression of GH release. There is no evidence that somatostatin has any direct cytotoxic or vasotoxic effects. It appears that SMS 201-995 represents a potent and promising drug in the medical treatment of acromegaly, however, more work is needed to elucidate the mechanism of somatostatin suppression and to provide evidence for adenoma shrinkage.     

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.     

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 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)     

Serum type III procollagen propeptide levels in acromegalic patients

Serum type III procollagen propeptide (PIIIP) is a reliable index of tissue collagen synthesis. Since in acromegaly there is increased collagen production, we measured serum PIIIP in acromegalic patients before any treatment (basal), during medical treatment with the somatostatin analog SMS 201-995, and after pituitary adenomectomy. In all patients, serum GH and plasma somatomedin-C (SmC) levels were also measured. Basal serum PIIIP levels were significantly (P less than 0.01) higher in acromegalic patients (mean +/- SEM, 22.7 +/- 2.1 ng/ml) than in normal subjects (n = 30; 9.7 +/- 0.5 ng/ml), and they were significantly correlated with plasma SmC values (r = 0.31; P less than 0.05). A significant (P less than 0.01) reduction in PIIIP levels occurred in patients treated with SMS 201-995 or surgery (from 24.3 +/- 2.7 to 12.4 +/- 1 ng/ml) as well as in GH and SmC levels. The maximum percent decrease in serum PIIIP was significantly correlated with those in GH (r = 0.65; P less than 0.01) and SmC (r = 0.60; P less than 0.01). Serum PIIIP levels did not change in those patients in whom neither GH nor SmC were decreased by treatment. In conclusion, serum PIIIP levels are elevated in acromegalic patients, and they decline in parallel with GH and SmC during medical or surgical treatment. Serum PIIIP measurements may be useful in the evaluation of acromegalic patients to gain information on the biological activity of GH and in monitoring the course of the disease.     

A somatostatin analogue inhibits chondrosarcoma and insulinoma tumour growth

The in vivo effects on tumour growth of a potent somatostatin analogue, SMS 201-995 [H-(D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-Thr-(ol)], were measured in two characterised transplantable tumours: a) the Swarm rat chondrosarcoma, known to be insulin-, growth hormone (GH)-, somatomedin- and corticosteroid-dependent, b) a hamster insulinoma, bearing specific high affinity somatostatin receptors. SMS 201-995 (1.25 mg/kg/day) given for 25 days to rats bearing freshly transplanted chondrosarcomas inhibited tumour volume by 48%. A significant tumour growth inhibition was measured also in well developed tumours treated with high doses of SMS 201-995 (1.25mg/kg/day) for 7 days. In the treated animals, GH was significantly inhibited. In hamsters bearing a freshly transplanted insulinoma, the daily application of SMS 201-995 (200 micrograms/kg/day, sc) for 33 days could significantly inhibit the growth (as measured by tumour volume) of the tumour. A moderate inhibitory effect of SMS 201-995 on the growth of well grown insulinomas could also be observed. This study shows that SMS 201-995 under the present experimental conditions has a moderate but significant growth inhibitory effect in two different transplantable tumour models. In the rat chondrosarcoma, the effect of SMS 201-995 is probably indirect, due to inhibition of GH, somatomedin and insulin. In the hamster insulinoma, the effect is possibly due to a more direct action of SMS 201-995 on specific somatostatin receptors present in this tumour.     

SOM230: a new somatostatin peptidomimetic with potent inhibitory effects on the growth hormone/insulin-like growth factor-I axis in rats,primates, and dogs

The goal of this project was to find a somatostatin (SRIF) analog with superior therapeutic potential. Receptor binding studies of new SRIF analogs were used to reveal SRIF substructures that interact with individual human SRIF receptor subtypes (sst1-sst5). Incorporation of these substructures into a stable cyclohexapeptide template led to SOM230, which binds with nanomolar affinity to sst1, sst2, sst3, and sst5. In rats, the inhibitory effect of SOM230 on GH was similar to SMS 201-995 (octreotide) at 1 h, but was 4-fold more potent at 6 h post injection, indicating increased metabolic stability. Treatment of rats with SOM230, at 1 and 10 micro g/kg.h, decreased IGF-I plasma levels, on d 2, by 68% and 90% (P < 0.01); whereas, under SMS 201-995 treatment, plasma IGF-I levels decreased by 28% and 49%, respectively. After a 2-wk infusion of rats, the suppression of IGF-I levels by SOM230 was still pronounced, whereas the response to SMS 201-995 was largely lost. This enhanced effect of SOM230 on IGF-I plasma levels was confirmed in an 8-wk study where both analogs were infused at 50 micro g/kg/h in rats. In rhesus monkey, SOM230 and SMS 201-995 treatment resulted in GH inhibition, with half-maximal inhibitory dose values of 0.5 and 0.4 micro g/kg, respectively, but plasma IGF-I levels were only lowered by SOM230 (-53%). In cynomolgus monkeys, a 2-wk infusion of SOM230, but to a much lesser extent of SMS 201-995, lowered plasma GH levels significantly (from 16.3 to 1.8 ng/ml, P = 0.007). Both in cynomolgus monkeys and beagle dogs, infusion of SOM230, but not SMS 201-995, lowered IGF-I levels significantly. In conclusion, SOM230 has a unique structure, binds almost universally to human ssts, and inhibits potently the GH/IGF-I axis cross-species. SOM230 is a candidate drug for clinical use.     

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)     

SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile

OBJECTIVE: The aim of the present study was to identify a small, metabolically stable somatotropin release inhibiting factor (SRIF) analog with a more universal binding profile similar to that of natural somatostatin, resulting in improved pharmacological properties and hence new therapeutic uses. DESIGN: A rational drug design approach was followed by synthesizing alanine-substituted SRIF-14 analogs to determine the importance of single amino acids in SRIF-14 for SRIF receptor subtype binding. The incorporation of structural elements of SRIF-14 in a stable cyclohexapeptide template in the form of modified unnatural amino acids resulted in the identification of the novel cyclohexapeptide SOM230. RESULTS: SOM230 binds with high affinity to SRIF receptor subtypes sst1, sst2, sst3 and sst5 and displays a 30- to 40-fold higher affinity for sst1 and sst5 than Sandostatin (octreotide; SMS 201-995) or Somatuline (BIM 23014). In vitro, SOM230 effectively inhibited the growth hormone releasing hormone (GHRH)-induced growth hormone (GH) release in primary cultures of rat pituitary cells with an IC(50) of 0.4+/-0.1 nmol/l (n=5). In vivo, SOM230 also potently suppressed GH secretion in rats. The ED(50) values determined at 1 h and 6 h post injection of SOM230 indicated its very long duration of action in vivo. This property was also reflected in pharmacokinetic studies comparing plasma levels of SMS 201-995 and SOM230 after subcutaneous application. Whereas SMS 201-995 had a terminal elimination half life of 2 h, this was markedly prolonged in SOM230-treated animals (t(1/2)=23 h). Furthermore, in rats SOM230 demonstrated a much higher efficacy in lowering plasma insulin-like growth factor-I (IGF-I) levels compared with SMS 201-995. The infusion of 10 microg/kg/h of SOM230 using subcutaneously implanted minipumps decreased plasma IGF-I levels far more effectively than SMS 201-995. After 126 days of continuous infusion of SOM230 plasma IGF-I levels were decreased by 75% of placebo-treated control animals. For comparison SMS 201-995, when used under the same experimental conditions, resulted in only a 28% reduction of plasma IGF-I levels, indicating a much higher efficacy for SOM230 in this animal model. It is important to note that the inhibitory effect of SOM230 was relatively selective for GH and IGF-I in that insulin and glucagon secretion was inhibited only at higher doses of SOM230. This lack of potent inhibition of insulin and glucagon release was also reflected in the lack of effect on plasma glucose levels. Even after high dose treatment over 126 days no obvious adverse side effects were noticed, including changes in plasma glucose levels. CONCLUSION: We have identified a novel short synthetic SRIF peptidomimetic, which exhibits high affinity binding to four of the five human SRIF receptor subtypes and has potent, long lasting inhibitory effects on GH and IGF-I release. Therefore SOM230 is a promising development candidate for effective GH and IGF-I inhibition and is currently under evaluation in phase 1 clinical trials.     

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.     

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.     

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.     

The effects of SMS 201-995 (sandostatin) on metabolic profiles in insulin-dependent diabetes mellitus

GH has been implicated in the pathophysiology of various acute and chronic complications of diabetes mellitus. As a consequence, there has been a great deal of interest in developing methods for suppressing GH secretion in diabetes. SMS 201-995 is a long-acting somatostatin analog which inhibits the secretion of numerous hormones, including GH. To determine the metabolic and hormonal responses to SMS 201-995 independent of endogenous insulin suppression, we studied six patients with insulin-dependent diabetes mellitus while they received 150 micrograms SMS 201-995, sc, daily for an 8-week period. This treatment resulted in no change in 24-h glucose profiles, although the mean insulin dose decreased by 19%, while hemoglobin A1c decreased significantly (0.084 +/- 0.023 to 0.067 +/- 0.011, P = 0.04). The 24-h profiles of blood lactate, plasma free insulin, glucagon, FFA, blood glycerol, and beta-hydroxybutyrate were unchanged, whereas that of blood alanine increased significantly (7.8 +/- 0.4 to 10.6 +/- 0.9 mmol/L.h; P = 0.01). GH secretion declined in five of the six patients; the mean values before and during SMS 201-995 treatment were 102 +/- 23 and 68 +/- 12 micrograms/L.h, respectively (P = NS), for the six patients. [In the five patients in whom GH secretion declined, the mean values before and during SMS 201-995 treatment were 115 +/- 23 and 63 +/- 14 micrograms/L.h, respectively (P = 0.01).] These results suggest that SMS 201-995 may be administered to patients with insulin-dependent diabetes mellitus without a deleterious effect on metabolic control.