Faculty Bibliography

Two patients developed specific IgG antibodies against octreotide after 2-3 years' treatment for acromegaly with this long acting somatostatin analogue. The presence of these antibodies reduced the plasma disappearance rate of total extractable octreotide by 60 and 80% respectively. When compared to that of non-immune acromegalic patients, the plasma half-life of octreotide in these two patients was 300 and 450 vs 110 min in those with no detectable octreotide antibodies. The sole observed consequence of the immunization was a marked prolongation of the interval of maximum GH inhibition from a mean of 5 to 8 and 10 h in the two patients described after octreotide injection.

Seventeen AIDS patients were enrolled in a prospective open-label dose-finding study of octreotide (Sandostatin) therapy for refractory diarrhea. Five were nonevaluable due to progression of AIDS symptomatology, and one was excluded because of lack of confirmation of HIV infection. Five of 11 evaluable patients responded to therapy (45%); two each at 50 micrograms and 100 micrograms, and one at 250 micrograms thrice daily doses. A sixth patient demonstrated a moderate reduction in stool volume at 250 micrograms thrice daily, which, although deemed clinically relevant, did not meet the criteria for response. On discontinuation of therapy, diarrhea recurred in all patients within 1-12 days, and responded to reinitiation of octreotide in those five patients who resumed treatment. Only one of the three patients with concurrent cryptosporidial infection responded to treatment. The drug was well tolerated, with mild symptomatology in three patients. Long-term treatment at a stable dose was effective in three of five treated patients for periods for seven months in one (moderate responder) and one year in two. One patient required dose increases to control symptoms, but after one year of treatment developed severe nausea following injections, which required dose cessation. One patient had partial control of his diarrhea for only three months despite two dose increases. These data suggest that octreotide may be of useful therapeutic value in HIV-associated diarrhea and that further studies are indicated.

To determine whether treatment with a somatostatin analogue can reduce kidney hyperfiltration and hypertrophy in insulin-dependent diabetes mellitus, we studied 11 patients with insulin-dependent diabetes mellitus and glomerular hyperfiltration. The patients were assigned randomly to receive continuous subcutaneous infusion of either octreotide, 300 micrograms/24 h (five patients) or placebo (six patients) for 12 weeks. At baseline, mean glomerular filtration rate and mean total kidney volume were not significantly different in the two groups. However, after 12 weeks of treatment, the mean glomerular filtration rate was significantly lower in the octreotide group (136 mL/min per 1.73 m2; range, 91 to 158 mL/min per 1.73 m2) than in the placebo group (157 mL/min per 1.73 m2; range, 138 to 184 mL/min per 1.73 m2). Furthermore, the mean total kidney volume was significantly lower after treatment in the octreotide group (379 mL/1.73 m2; range, 307 to 454 mL/1.73 m2) than in the placebo group (389 mL/1.73 m2; range, 347 to 465 mL/1.73 m2). Glycemic control did not change significantly in either group. We conclude that subcutaneous infusion of octreotide for 12 weeks reduces increased glomerular filtration rate and kidney size in patients with insulin-dependent diabetes mellitus despite the fact that glycemic control remains unchanged.

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.

Several studies suggest that the somatostatin analog octreotide, or SMS 201-995, may effectively reduce GH hypersecretion. However, no double blind, placebo-controlled study has substantiated these findings. We present the results of a randomized double blind 14-day clinical trial with octreotide in 20 patients with acromegaly. The drug was given sc every 8 h and to the initial dose (50 micrograms) was added another 50 micrograms every other day up to 200 micrograms. GH levels, calculated as the mean values of 12 observations at hourly intervals during 0700-1800 h, and insulin-like growth factor-I (IGF-I) levels were significantly reduced during octreotide treatment. Responses varied from a reduction of 97% of the basal mean GH level to no significant reduction in 2 of 10 patients. There was a good correlation between the reduction of GH and IGF-I levels. The main side-effects were gastrointestinal and well tolerated. We found a spontaneous variation of daily mean GH and IGF-I levels (at 0700 h) in the placebo group, ranging from approximately 150% to 50% of the GH and 120% to 80% of the IGF-I levels noted on day 0. In patients treated with octreotide, the occurrence of GH rises between administration times suggests that it may be desirable to give octreotide every 6 h in some patients.

Ten adolescents (four boys and six girls) aged 11.5 to 17 years, presenting with constitutionally tall stature were treated with twice daily subcutaneous injections of 250 micrograms of SMS 201-995 (Sandostatin). Results are reported after 6 and 12 months of therapy. Reduction of growth rate was obtained in 9 patients and correlated with the reduction of 24-hour growth hormone pulsatility and with the decrease of plasma Somatomedin-C values. Moreover, acceleration of bone maturation on SMS 201-995 therapy occurred in seven patients, and mean bone age increased from 13.3 years to 14.5 and 15.8 years after 6 and 12 months of SMS therapy. The mean reduction of predicted adult height was 4.9 cm at the last evaluation after 6 or 12 months of therapy. The dual effect of SMS 201-995 on growth rate and bone maturation suggests that it may be an alternative treatment to reduce adult height.

We used the long acting somatostatin analogue SMS 201-995 in order to examine the feasibility and effect of medical suppression of growth hormone in nonproliferative diabetic retinopathy. Six insulin-dependent diabetic subjects with nonproliferative retinopathy were studied. After eight weeks of SMS 201-995 administration, 24-hour integrated plasma growth hormone concentrations had declined by 47.0 +/- 9.3% of pretreatment values (p less than 0.01), and insulin requirements fell from 40.7 +/- 6.7 units per day to 32.2 +/- 6.9 units per day (p less than 0.01). Plasma levels of somatomedin-C were low before SMS 201-995 (0.5 +/- 0.1 U/ml) and remained unchanged at eight weeks (0.6 +/- 0.1 U/ml; p = ns). During SMS 201-995 administration, best corrected visual acuity improved in both right eyes (53.8 +/- 2.57 to 59.8 +/- 0.7 letters, p less than 0.05) and left eyes (54.8 +/- 2.8 to 61.7 +/- 1.23 letters, p less than 0.03). Fluorescein angiography and stereo fundus photography demonstrated concurrent improvement in retinopathy level in only two subjects. Following cessation of SMS 201-995 treatment, visual acuity returned to pretreatment levels in both right eyes (54.5 +/- 2.4 letters, p = ns compared to baseline) and left eyes (55.8 +/- 2.6 letters, p = ns compared to baseline). These results demonstrate that growth hormone was only partially suppressed by SMS 201-995 in insulin-dependent diabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

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

Because of its widespread distribution within the nervous system and the gastro-enteropancreatic (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, a long-acting, synthetic octapeptide analogue of the naturally occurring hormone. Sandostatin represents a significant advance in the treatment of GH and TSH secreting pituitary tumours and GEP endocrine tumours (carcinoid tumour, 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 tumour cells and indirect effect whereby Sandostatin lowers GH, IGF-1 and numerous gastrointestinal peptides, Sandostatin may prove useful as an adjunctive therapy in cancer patients. In vivo labelling of somatostatin receptor-positive tumours with radiolabelled somatostatin analogues now allows localisation of such tumours and their metastases. Moreover, targeted irradiation of these tumours by beta particle emitting isotopes attached to such somatostatin analogues may become possible. The use of Sandostatin in acute oesophageal variceal bleeding, pancreatic pseudocysts, gastrointestinal and pancreatic external fistulae, short bowel syndrome, dumping syndrome and AIDS-related refractory hypersecretory diarrhea has provided encouraging results. Preliminary reports indicate efficacy of Sandostatin in psoriasis, autonomic neuropathy (postprandial and orthostatic hypotension) and its ability to reduce height velocity in tall adolescents. The ultimate role of Sandostatin as a therapeutic agent in these disorders is being explored in prospective clinical trials.(ABSTRACT TRUNCATED AT 250 WORDS)