Faculty Bibliography

We sought to measure cystic duct diameter in patients without biliary calculi and in those with cholelithiasis or choledocholithiasis. Using endoscopic retrograde cholangiopancreatography (ERCP), we visualized the cystic duct in 168 patients referred to our unit. These patients were distributed into three groups based on findings at ERCP: Group I (N = 57), no calculi in the gallbladder or common bile duct; group II (N = 27), stones found in the gallbladder but absent from the common bile duct; and group III (N = 34), stones present in the common bile duct with or without gallbladder stones. The diameter of the cystic duct was measured at its widest and narrowest dimensions. The largest diameter measured was greater in group III (7.72 +/- 2.29 mm) than in groups I (2.63 +/- 0.67 mm) and II (4.59 +/- 1.13 mm) (P < 0.001). The same differences were found in measurement of the smallest diameter (5.00 +/- 0.99 mm, 3.10 +/- 0.62 mm, and 1.83 +/- 0.53 mm, for groups III, II, and I, respectively) (P < 0.001). Maximal and minimal cystic duct diameter show a progressive increase at each level of disease. This increase in cystic duct size may facilitate the migration of gallstone fragments after lithotripsy and facilitate the instrumentation of the cystic duct during ERCP and laparoscopic cholecystectomy.

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)

Animals studies have demonstrated that in addition to inhibiting growth hormone (GH) secretion octreotide inhibits in a direct manner hepatic or peripheral insulin-like growth factor I (IGF-I) generation. To test this hypothesis in humans we studied ten GH-deficient patients with frequent blood sampling during 38 h on two occasions. Regular GH therapy was discontinued 72 h prior to each study period. At the start of each study a subcutaneous (sc) injection of GH (3 IU/m2) was given (at 18.00 h). In a single-blinded crossover design, patients received a continuous sc infusion of either octreotide (200 micrograms/24 h) or placebo (saline). The pharmacokinetics of GH were similar on the two occasions. The area under the curve +/- SEM of serum GH was 142.5 +/- 53.6 micrograms.l-1 x h-1 (octreotide) and 144.8 +/- 41.8 micrograms.l-1 x h-1 (placebo), (p = 0.73); Cmax (microgram/l) was 12.5 +/- 1.47 (octreotide) and 12.8 +/- 1.42 (placebo) (p = 0.83), and Tmax (h) was 6.1 +/- 0.97 (octreotide) and 5.2 +/- 0.65 (placebo) (p = 0.49). Growth hormone administration was associated with an increase in serum IGF-I (microgram/l), which was identical during the two studies, from 85.3 +/- 19.4 to 174.25 +/- 30.3 for octreotide and from 97.0 +/- 26.4 to 158.8 +/- 28.2 for placebo. Mean IGF-I levels (microgram/l) were 138.2 +/- 25.1 (octreotide) and 134.5 +/- 28.6 (placebo) (p = 0.78). Similarly, the increase in IGF binding protein 3 (IGFBP-3) levels was identical. Mean IGFBP-3 levels (microgram/l) were 2303 +/- 323 (octreotide) and 2200 +/- 361 (placebo) (p = 0.25).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

We sought to examine how the discontinuation of octreotide in long-term octreotide-treated acromegalic patients affects the well-documented side-effect of cholelithiasis. In 14 acromegalic patients, serum growth hormone levels, insulin-like growth factor I levels and percentage of relative gallbladder contractility were measured prior to and after the discontinuation of octreotide. Compared to pretreatment values, the basal growth hormone and 5-h growth hormone profiles were 36% and 24%, and 60% and 56% at the end of 1 and 2 weeks, respectively. Octreotide was found to be eliminated completely from the serum within 3 days after its withdrawal. In all of six patients who did not develop gallstones, the percentage relative gallbladder contractility normalized within 1 week. In eight patients who developed gallstones, four of them had restoration of normal contractility within 2 weeks. Our results show that upon withdrawal of octreotide, gallbladder contractility returns to normal while growth hormone suppression persists for a longer period of time. Therefore, discontinuation of octreotide therapy may allow for the clearance of stagnated bile and hence decrease the incidence of cholelithiasis in acromegalic patients receiving long-term therapy.

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.

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.

Octreotide is routinely used in the treatment of acromegaly and gastroenteropancreatic tumours such as carcinoids and VIPomas. The most promising indications for octreotide appear, at present, to be as an adjunct therapy in the management of acute oesophageal variceal bleeding, AIDS-related refractory, diarrhoea, digestive fistulae and the prevention of postoperative pancreatic complications (e.g. pancreatitis, fistulae...). Its potential role in the treatment of carcinoma is being currently explored in prospective controlled trials.