Faculty Bibliography

OBJECTIVE:To determine the cardiovascular effects of the somatostatin analog octreotide in patients with acromegaly. DESIGN/METHODS:Prospective nonrandomized study. SETTING/METHODS:Referral-based endocrinology clinic. PATIENTS/METHODS:Seven patients with active acromegaly, three of whom had refractory congestive heart failure. The other four patients were free of symptoms associated with heart failure. INTERVENTIONS/METHODS:All patients were treated with octreotide, 100 to 500 micrograms subcutaneously three times daily. The three patients with heart failure continued to receive cardiovascular therapy (angiotensin converting enzyme inhibitors, digitalis, diuretics). MEASUREMENTS AND MAIN RESULTS/RESULTS:During octreotide therapy, patients showed a rapid decrease in growth hormone and insulin-like growth factor 1 (IGF-1): Mean levels (+/- SD) fell from 28.1 +/- 32.7 micrograms/L to 5.2 +/- 8.3 micrograms/L and 740 +/- 126 micrograms/L to 372 +/- 64 micrograms/L, respectively (P less than 0.025). Plasma volume returned to normal and heart rate decreased significantly. In the four patients without heart failure, right-heart catheterization done before and after 3 months of octreotide therapy showed an 18.3% +/- 11% reduction in stroke volume and a return to normal of the cardiac index. The three patients with congestive heart failure, evaluated before and after 40 days and up to 2 years of therapy, showed a dramatic clinical improvement that was associated with an increase in stroke volume (by 24% to 51%). In these patients, the cardiac index remained in the normal range, filling pressures were markedly decreased, and pulmonary wedge pressure returned to normal. This improvement was sustained for up to 3 years in the two patients with heart failure who were receiving long-term treatment. CONCLUSION/CONCLUSIONS:The rapid and sustained cardiac improvement seen in our patients shows that octreotide therapy for patients with acromegaly may be highly beneficial, even in those patients with advanced cardiac failure.

Because of its widespread distribution within the nervous system and gastroenteropancreatic (GEP) system, and its diverse physiological inhibitory actions on various gastrointestinal functions, including endocrine and exocrine secretion, motility, liver and splanchnic blood flow and absorption, native somatostatin has been viewed as a possible therapy for many diseases. However, its short duration of action and consequent limited clinical usefulness have been overcome with the availability of Sandostatin (octreotide, Sandoz Ltd), a long-acting, synthetic octapeptide analog of the naturally occurring hormone. Sandostatin represents a significant advance in the treatment of growth hormone (GH) and thyrotropin (TSH)-secreting pituitary tumors and GEP endocrine tumors (carcinoid tumor, VIPoma, glucagonoma, insulinoma, and gastrinoma). Preclinical in vitro and animal studies have shown the antineoplastic activity of the compound. Moreover, because of a possible direct effect on somatostatin receptor-positive endocrine tumor cells and an indirect effect whereby Sandostatin lowers GH, insulin-like growth factor type 1 (IGF-1), and numerous gastrointestinal peptides, Sandostatin may prove useful as an adjunctive therapy in cancer patients. In vivo labeling of somatostatin receptor-positive tumors with radiolabeled somatostatin analogs now allows localization of such tumors and their metastases. In addition, targeted irradiation of these tumors by beta particle-emitting isotopes attached to such somatostatin analogs may become possible. The use of Sandostatin in acute esophageal variceal bleeding, pancreatic pseudocysts, gastrointestinal, and pancreatic external fistulae, short bowel syndrome, dumping syndrome and acquired immunodeficiency syndrome (AIDS)-related refractory hypersecretory diarrhea has provided encouraging results.(ABSTRACT TRUNCATED AT 250 WORDS)

Three patients with symptomatic metastatic medullary thyroid carcinoma (MTC), one with sporadic form and two with MEN IIa, were treated with the long-acting somatostatin analogue octreotide (SMS 201-995, Sandoz) for 3 to 17 months. Octreotide was administered subcutaneously in a starting dose of 0.6 to 1.0 mg/day by automatic pump (Travax ASH6, Travenol). Symptoms of diarrhoea, weight loss and malaise improved in all patients. Maximal percentage decrease in mean serum calcitonin was 47, 52 and 81% of the basal values, and was observed 1-3 months from the beginning of treatment. Likewise, carcinoembryonic antigen (CEA) levels initially dropped to 45, 60 and 63% of the levels before therapy. A continuing effect was seen in the two patients with MEN IIa after 15 and 17 months of treatment. However, after the initial decrease, calcitonin (CT) levels went up again to 67 and 68% of the basal values and the dose of octreotide had to be increased to 1.5 mg and 2.0 mg/day. CEA also returned to 84 and 105% of the pretreatment titres. Response to 1.5 mg/day octreotide was lost in the patient with the sporadic form of disease after 3 months. Side-effects were minimal. Effects on tumour size could not be evaluated. These suggest that octreotide might be a valuable adjuvant in the long-term management of metastatic MTC. Tachyphylaxis may occur.

Ten patients (seven women, three men) with active acromegaly, five previously treated and five newly diagnosed, were included in an open-label prospective trial of 3 daily subcutaneous injections of the long-acting somatostatin analogue SMS 201-995 (Sandostatin) at increasing doses in order to obtain maximum growth hormone (GH) suppression. Four patients had received surgery, radiotherapy or bromocriptine. SMS 201-995 doses were increased in a stepwise fashion from 100 micrograms every 8 h (three times daily) to 200, 300 and finally 500 micrograms three times daily at monthly intervals if mean serum GH values failed to decrease to undetectable levels in over 75% of the samples. The optimal dose was maintained for up to 28 months. Significant clinical improvement of headache, soft tissue swelling, facial features, hyperhidrosis and paraesthesia occurred in all patients. Mean 12-h GH levels were significantly suppressed in four patients and fell to normal values in four. Suppression of GH levels was not achieved in two patients. Comparison of the mean interindividual GH values shows that the optimal efficacious dose is 100 micrograms t.i.d. in 7/10 patients. Somatomedin-C (SM-C) was also significantly reduced to below 50% of pretreatment levels in nine patients in whom it was measured. The subsequent increments of SMS 201-995 up to 500 micrograms three times daily did not produce further clinically relevant GH or SM-C suppression. Pituitary tumour shrinkage occurred in five patients. Thyroid function remained normal. Impaired glucose tolerance occurred in four patients. Side-effects (diarrhoea, abdominal discomfort) were mild and transient. Asymptomatic gallstones occurred in three patients on 1500 micrograms/day and one patient on 600 micrograms/day after 6-12 months treatment. This dose-finding study shows that 100 micrograms three times daily SMS 201-995 is an effective therapy for most of the acromegalic patients we treated.

The long-acting somatostatin analogue SMS 201-995 has been shown to be efficient in the treatment of somatotropic and thyrotropic adenomas. In some cases, it can suppress adenoma secretion and lead to tumor shrinkage. Pituitary macroadenomas are often associated with a vision-threatening chiasmal syndrome. In this series, SMS 201-995 was administered subcutaneously to eight patients with pituitary macroadenomas of various types responsible for severe long-lasting visual defects. An obvious improvement of both visual fields and acuity occurred in six patients, in two of these during the first 4 to 6 hours of treatment; in two patients, gonadotropic adenomas were unresponsive. Maximal improvement (normalization of visual fields in three cases) occurred within 6 to 45 days and was sustained during the 1- to 12-month follow-up period. This effect seems independent of the type of adenoma since the adenomas secreting growth hormone (GH) and thyroid-stimulating hormone and silent corticotropic-secreting adenomas responded as well as did two of the non-functioning adenomas. In one acromegalic patient visual improvement was obtained while the abnormal GH secretion remained unaltered. In all cases but one, no tumor shrinkage could be demonstrated. These data demonstrate that SMS 201-995 can rapidly improve the chiasmal syndrome due to pituitary macroadenoma, and suggest that this effect might be independent of a reduction in tumor volume.

The marked pituitary tumor shrinkage achieved by continuous sc infusion (CSI) of the long-acting somatostatin analog octreotide in one acromegalic patient led us to treat 16 other acromegalic patients for up to 24 months by CSI. This therapy, given in doses ranging from 100-600 micrograms/day, resulted in normalization of the mean daily serum GH (mGH) and insulin-like growth factor I levels in 9 of the 17 patients (53%). In 7 patients, mean daily serum GH decreased but not to normal; 3 of these patients had hyperprolactinemia which was not influenced by octreotide. One patient was completely unresponsive. In contrast to the biochemical results, 80% of the patients had marked clinical improvement. Side-effects consisted of slightly impaired carbohydrate tolerance in 2 patients and cholelithiasis in 2 patients. Pituitary tumor size decreased in only 3 patients; in 1 of them visual field defects disappeared rapidly. These results suggest that octreotide treatment may prove beneficial before surgery in patients with macroadenomas, although its efficacy varies widely. Potential responsivity can usually be determined by a short course (24 h) of CSI of octreotide.

Sixteen post-menopausal patients with advanced breast cancer were treated with a long acting somatostatin analogue, SMS 201-995 (Sandostatin): 0.1 mg bid sub-cutaneously. The dose was chosen on the basis of efficiency in acromegaly treatment. SMS 201-995 activity was evaluated assaying Insulin Growth Factor 1 (IGF1) plasma concentration. A merely partial IGF1 decrease was noted. To be evaluable for response, patients had to be treated for at least 30 days. Among the 14 evaluable patients, we observed no response to SMS 201-995. However, we noted tumor stabilization in 3 patients after a 90 days treatment period. Side-effects were very mild. This first report on SMS 201-995 treatment of breast cancer suggests that further studies evaluating the effect of other modes of administration or drug association should be warranted.

Diurnal serum GH patterns were determined in 10 acromegalic patients before treatment, after 3 d continuous s.c. pump infusion and then after 3 d with three equal daily s.c. injections in both instances totalling 100 micrograms/24 h. Subcutaneous injections (33 micrograms) induced impressive suppression of serum GH lasting 3-6 h in eight patients followed by escape to pretreatment values before the next injection. In contrast, continuous infusion resulted in greater and more stable 24 h suppression to the levels reached at the nadir between injections. Suppression of mean 24 h serum GH below 5 ng/ml was achieved by pump treatment in four patients, while two patients had mean values between 5 ng/ml and 10 ng/ml. In four patients occasional or all levels were above 10 ng/ml (24 h average 12.4-102 ng/ml) implying either that adequate suppression by the SMS 201-995, was impossible during the 3 d pump infusion period, or that the dose administered was inadequate. Carbohydrate tolerance was unaffected in either regimen, indicating that reduction in insulin antagonistic hormones balanced inhibition of insulin release. Interestingly, and in contrast to somatostatin, SMS 201-995 did not inhibit TSH release. No untoward effects were observed at the moderate dosage and blood clinical chemistry was unchanged. Fairly constant diurnal serum SMS 201-995 values were obtained during pump infusion, while levels undulated inversely with serum GH during injection treatment. Average diurnal serum somatostatin-C immunoreactivity (all patients) decreased from 496 +/- 129 (mean +/- SD) to 385 +/- 100 ng/ml (P less than 0.003) during pump treatment and did not decrease further during the following 3 d injection treatment (363 +/- 76 ng/ml). The normal adult mean is 179 +/- 40 ng/ml. Computer tomographic (CT) scans of the sellar region were performed in all patients before and after the experimental week. Two patients had extracellular tumours whose size decreased from 8.2 to 4.1 cm3 and from 12.6 to 10.5 cm3. The results demonstrate that superior and stable suppression of GH secretion is obtained during continuous s.c. pump infusion of SMS 201-995.

Ten diabetic teenagers were admitted into our hospital for two nights, separated by one week. In a double-blind cross-over randomized study they received either 50 micrograms of the new long-acting somatostatin analogue Sandostatin sc or placebo. All patients were between 12 and 16 years of age, C-peptide negative with a duration of diabetes of at least four years. They had either conventional therapy or insulin pump therapy. Insulin doses and diets were kept unchanged. Blood samples were taken half hourly from 17.00 h until 09.30 h the next morning from an indwelling venous catheter. Hormonal and metabolic profiles on the two nights were evaluated by means of a distribution free time sequential co-movement analysis and by the paired Wilcoxon's signed rank test. After Sandostatin was given at 22.00 h, GH levels were significantly suppressed during 4 h. During that period blood glucose was slightly but significantly lower than after placebo. The free-insulin profiles from both nights were very comparable. Co-movement analysis showed a significant correlation between glucose and free insulin variations with a 30-min backward shift of the glucose curve. However, after Sandostatin administration this relation was lost in the period between 22.00 and 07.00 h, indicating a different effect of insulin on glucose levels during the nights Sandostatin was given. Early morning glucose rises were associated with free insulin levels below 20 mU/l. This association was not altered during the Sandostatin nights. Glucagon was not suppressed by Sandostatin except at 120 min after injection, and remained unchanged during the rest of the observation period.(ABSTRACT TRUNCATED AT 250 WORDS)