Faculty Bibliography

OBJECTIVE:To evaluate the efficacy of octreotide in the treatment of pituitary thyroid-stimulating hormone (TSH)-secreting adenomas. DATA SOURCES/METHODS:Combination of review and original data. Review data included information supplied by Sandoz Pharmaceuticals from patient case report forms and information from abstracts and articles published in the French or English language between 1987 and 1991. Original data included follow-up data on 15 of 37 previously reported cases and data on 15 new cases provided by 11 investigators. STUDY SELECTION/METHODS:Fifty-two cases from 24 medical centers in nine countries reported between 1987 and 1991. DATA EXTRACTION/METHODS:Chief clinical characteristics of the patients; dose and duration of octreotide treatment; serum TSH, thyroid hormone, and free alpha-subunit levels before and during treatment; serial anatomic evaluation of the pituitary gland by either computed tomographic scanning or magnetic resonance imaging; and side effects. DATA SYNTHESIS/RESULTS:After the first octreotide dose (50 to 100 micrograms), TSH levels decreased in all but 2 patients (mean decrease for the whole group, 55.8% +/- 27%). Levels of alpha-subunit decreased in 15 of the 19 patients who had alpha-subunit assessments (mean decrease, 37.5% +/- 24%). Reduction of TSH levels after short-term treatment (50 or 100 micrograms two or three times daily) was observed in 30 to 33 patients (mean decrease, 74.1%). Thyroid hormone levels were reduced in all patients and returned to normal in 73%. Despite an initial response to therapy, thyroid hormone levels continued to rise ("true escape") in 2 patients receiving short-term therapy and in 3 patients receiving long-term therapy. Partial shrinkage of the adenoma occurred in 11 patients. CONCLUSIONS:Octreotide is an effective treatment for TSH-secreting adenomas. Thyroid-stimulating hormone levels almost always decreased, and thyroid hormone levels reverted to normal in about three quarters of patients. Partial tumor shrinkage was observed in one third of patients receiving long-term octreotide treatment.

The objective of the study was to investigate the effects of a single intravenous injection of the somatostatin analog octreotide on hepatic bile secretion and gallbladder emptying with a quantitative scintigraphic technique. Twelve healthy volunteers received, in a double-blind randomized fashion, either octreotide, 100 micrograms intravenously, or placebo. Ten minutes later, [99mTc]PBIDA was administered intravenously (50 microCi/kg) (time = 0) followed, 60 min later, by the ingestion of a standardized fatty meal. In the liver area, the relative decrease per minute of tracer activity from the time of maximal activity to 60 min was significantly lower in the octreotide group (P = 0.02). In the gallbladder area, after the fatty meal, the ratio of tracer activity at 60 and 90 min (A90/A60) was significantly (P = 0.01) higher in the octreotide group. Our study demonstrates that octreotide slows down liver release of the radiopharmaceutical, probably reflecting decreased bile secretion, and inhibits postprandial gallbladder contraction.

Among somatostatin analogues, octreotide is the most extensively studied. Its pharmacodynamic properties are similar to those of somatostatin, with a wide spectrum of inhibitory effects on anterior pituitary function, pancreas and gut endocrine secretions, and gastrointestinal functions. Compared with the somatostatin, octreotide is highly resistant to enzymatic degradation and has a prolonged plasma half-life of about 100 minutes in humans, allowing its use in the long term treatment of various pathological conditions. Differential effects of octreotide on endocrine secretions such as growth hormone (GH) and insulin in healthy volunteers, as well as variable efficacy in the treatment of endocrine tumours, may relate to the distribution of somatostatin receptor subtypes. The volume of distribution of octreotide ranges from 18 to 30L. Calculated serum distribution half-life ranges from 72 to 98 minutes. In blood, octreotide is mainly distributed in the plasma, 65% being bound to lipoproteins. After subcutaneous injection, absorption appears rapid and complete and bioavailability is about 100%. Mean peak plasma concentrations are between 2 and 4 micrograms/L in patients receiving 50 to 100 micrograms. Peak concentrations are reached within 20 to 30 minutes and are 20 to 40% of corresponding values after intravenous injection. Peak concentrations and values for areas under the plasma concentration-time curve linearly correlate with the dosage. The elimination half-life is about 90 to 110 minutes. Total clearance in healthy individuals is about 160 ml/min (9.6 L/h). Hepatic metabolism of octreotide is extensive (30 to 40%) and about 11 to 20% of the dose is excreted unchanged in the urine. Among pituitary tumours, GH- and thyrotrophin-secreting adenomas are the most sensitive to octreotide. Octreotide has been widely used in the treatment of acromegaly. 50 to 80% of the patients respond to daily multiple subcutaneous injections with insulin-like growth factor-1 (IGF1) levels being normalised in about 40 to 50% of them. Neither desensitisation with long term therapy nor rebound phenomena after octreotide withdrawal have been noticed in these studies. Even in patients with partial response, clinical symptoms improved. Octreotide daily dosages needed to achieve optimum responses may vary greatly from one patient to another. In a minority of patients complete resistance to octreotide was observed and was not always related to the absence of somatostatin receptors in the tumour. The wide spectrum of effects of octreotide in humans accounts for adverse effects seen during long term treatment, primarily cholelithiasis. Other modes of administration are efficient.(ABSTRACT TRUNCATED AT 400 WORDS)

Two acromegalic patients with severe headache were treated with the somatostatin analogue, octreotide (Sandostatin). A double-blind study of octreotide versus placebo in which pain intensity was measured using a visual analogue scale (VAS) was performed initially with these patients. A rapid (within 4-15 min) pain relief occurred lasting 2-8.5 h after injection of 100 micrograms of octreotide, an effect that was not reversed by intravenous (i.v.) naloxone. These 2 acromegalic patients then received treatment for 71 and 82 months, respectively, with doses starting at 500 micrograms/day and 1500 micrograms/day, respectively, without evidence of either tolerance or dependence, although the effect of octreotide on headache appears to be selective. No unwanted sedative effect has been observed. A screening procedure with injection of 50 micrograms of subcutaneous (s.c.) octreotide was performed in 11 other patients with chronic severe pain associated with various conditions. Only 3 patients (2 with diabetic polyneuropathy and 1 with bone pain associated with myelodysplastic syndrome) reported more than 50% pain relief. In the insulin-dependent diabetic patients the double-blind check was not performed due to the risk of octreotide-induced hypoglycemia. In the patient with bone pain the same double-blind check as in the acromegalic patients could not confirm the analgesic effect. It may thus be concluded that octreotide appears to be useful for the treatment of both chronic and acute severe painful conditions in acromegalic patients. However, since its analgesic effect in our patients was confined to headaches only, further controlled studies must be carried out in order to determine appropriate target groups.

This article reports the changes in gallbladder function examined by ultrasonography in 20 Chinese patients with active acromegaly treated with sc injection of the somatostatin analog octreotide in dosages of 300-1500 micrograms/day for a mean of 24.2 +/- 13.9 months. During treatment with octreotide, 17 patients developed sludge, 10 had gallstones, and 1 developed acute cholecystitis requiring surgery. In all of 7 patients examined acutely, gallbladder contractility was inhibited after a single 100-micrograms injection. In 8 patients followed for 24 weeks, gallbladder contractility remained depressed throughout therapy. After withdrawal of octreotide in 10 patients without gallstones, 8 patients assessed had return of normal gallbladder contractility within 1 month. In 8 of the remaining 10 patients who developed gallstones during treatment, gallbladder contractility normalized in 5 patients (3 of whom has disappearance of their stones within 3 weeks), and remained depressed in 3 (2 of whom had stones present at 6 months). Our results suggest that the suppression of gallbladder contractility is the cause of the successive formation of bile sludge, gallstones, and cholecystitis during octreotide therapy in Chinese acromegalic patients. It is therefore very important to follow the changes of gallbladder function during long-term octreotide therapy of acromegalic patients.

Endoscopic sphincterotomy (ES) was performed in 25 patients for common bile duct (CBD) calculi in the absence of stones in the gallbladder. Eighteen of these patients were considered unfit for surgery because of age or concomitant disease. All ES procedures were technically successful with complete evacuation of the CBD in all cases. Early complications occurred in only one patient, a 91-year-old female who died from nonbiliary tract disease. Long-term follow up over a period of 42 months was available in 19 of the 24 patients. Late complications occurred in two patients (10%), both of whom developed cholecystitis; they underwent surgery without subsequent morbidity or mortality. This 10% incidence of long-term complications is similar to that of other series that did not differentiate between patients with isolated CBD calculi and those with stones also present in the gallbladder. The observed complication rate does not justify routine prophylactic cholecystectomy after ES for isolated CBD stones.