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.

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)

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.

Octreotide, the first somatostatin analogue developed, has pharmacological properties (it inhibits pituitary GH and TSH secretion, pancreatic and digestive tract endocrine secretion and various gastrointestinal functions) which are qualitatively similar to those of the natural 14 amino acids peptide. Enzymatic structural modification had resulted in a peptide which is very resistant to degradation and has a 90-110 min half-life permitting subcutaneous administration. Following a subcutaneous injection of 50 to 100 micrograms, absorption is rapid and complete. The peak plasma concentration is obtained within 20 to 30 minutes. The drug is degraded mostly in the liver. Among pituitary tumours, GH- and TSH-secreting adenomas constitute the primary indication. Octreotide has been widely tested in the treatment of acromegaly; 50 to 80 percent of patients with that disease respond to a discontinuous administration (usually 3 subcutaneous injections per day), and the IGF1 level is normalized in 50 percent of the cases. No long-term desensitization and no rebound phenomenon after drug withdrawal have been observed. Clinical improvement is obvious, even in cases with partial response to treatment. The dose required to obtain maximum response may vary from one patient to another, and resistance to the peptide has been observed in a few patients. This resistance does not seem to be related solely to the absence of somatostatin receptors on the tumours. The principal side-effect of octreotide treatment is the occurrence of gallstones. In some patients, continuous subcutaneous injection gives a better result with a lower dose. Other ways of administration (nasal or oral) have been tested or are being evaluated.

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.

Severe long-term complaints of dumping occur in a small number of patients after gastric surgery. Dietary modification, fiber preparations, and medical therapy are often ineffective. In these severely affected patients administration of the somatostatin analog octreotide before meals appears to be a promising new strategy. The effects of octreotide on both gastrointestinal transit time and hormonal changes appear to contribute to the benefits seen in dumping syndrome. However, as the majority of studies conducted have employed only a single dose of octreotide, careful long-term assessment of the nutritional and metabolic effects will be required. Recent results suggest that octreotide may be administered up to 2 hr before a meal and therefore has a sufficiently long duration of action to be of practical long-term use. Moreover, general improvements in life-style, as well as beneficial effects on symptoms, have been reported with long-term treatment, although the potential development of diarrhea will require careful monitoring. The development of an oral or nasal formulation should further improve the practical application of octreotide as a treatment for dumping syndrome.

Fifteen acromegalic patients received four single doses of octreotide in random order (500 micrograms, 1000 micrograms, and 2000 micrograms applied intranasally and 100 micrograms given sc). Serum octreotide and GH data were subjected to pharmacokinetic analyses, and local nasal effects were evaluated by acoustic rhinometry. Average areas (+/- SEM) under the serum octreotide curves were: 2000 micrograms: 4597 +/- 536; 1000 micrograms: 1923 +/- 439; 500 micrograms: 957 +/- 168; and 100 micrograms sc: 896 +/- 81 micrograms.L-1.min (n = 13). The calculated relative availability was 27% +/- 0.03; 22% +/- 0.05; 22% +/- 0.03, respectively, for the three nasal doses. The rate of absorption after intranasally administered octreotide was greater than after sc application: t1/2 ka: 7.1 +/- 1.6; 7.9 +/- 1.6; 11.3 +/- 1.9, respectively, vs. 24.1 +/- 2.5 min, whereas the rates of disappearance were similar. GH suppression started immediately after application and reached minimum levels 1-2 h later. The average intervals during which serum GH was below 50% of preadministration values were: 2000 micrograms: 544 +/- 47; 1000 micrograms: 423 +/- 56; 500 micrograms: 289 +/- 52 vs. 351 +/- 34 min after sc injection of 100 micrograms. With 2000 micrograms intranasally all but one of the 15 patients attained constant suppression of serum GH below 5 micrograms/L for 273 to 680 min. Pharmacokinetic analysis demonstrated that 100 micrograms sc and 1000 micrograms intranasally induced the same GH suppressive effect and that 2000 micrograms intranasally approximately doubled the duration of action. Acoustic rhinometry was performed after nasal application of the largest dose of 2000 micrograms and after carrier (n = 9). A highly significant tumescence of the nasal mucosa was maximal after 10 min and gradually receded over the next 2 h. However, this was felt by the patients to be acceptable. The effect was caused by octreotide per se and was probably due to vasodilation.

Octreotide is a long acting synthetic analogue of native somatostatin that exerts a potent inhibitory effect on the release of a wide variety of peptide hormones from the gastroenteropancreatic endocrine system. It represents a new dimension to traditional therapies in the treatment of various conditions characterised by excessive peptide production and secretion, particularly when conventional therapeutic approaches have either been exhausted or have provided suboptimal symptomatic control. While emergency sclerotherapy remains the definitive treatment for both the arrest of acute variceal bleeding episodes and the prevention of further bleeding, its effective use depends on the patients being admitted to a hospital well versed in the procedure. There remains, therefore, a need for an easily administered and effective treatment for acute variceal bleeding emergencies. Although not all investigators agree, it appears that somatostatin is effective, at least for the duration of its administration. Given its evident advantages over somatostatin, octreotide is likely to make a major contribution towards the treatment of variceal bleeding, at least as an emergency treatment during the bleeding crisis. The potential for octreotide in the management of gastrointestinal and pancreatic fistulae is considerable. While sharing the inhibitory actions of native somatostatin on gastrointestinal motility and secretion, it can be administered at home by suitably motivated patients. Suppression of gastrointestinal peptides from the gastrointestinal tract by octreotide appears to parallel symptomatic improvements in patients with dumping syndrome, with normalisation of plasma glucagon and insulin profiles as well as suppression of vasoactive intestinal polypeptide (VIP), motilin, neurotensin, pancreatic polypeptide and C peptide being reported. Release of polypeptide hormones, such as VIP and gastrin, by tumour cells in the gastroenteropancreatic system results in profuse diarrhoea. While the nature of the diarrhoea depends on the specific peptide secreted by the tumour, all possess a common secretory mechanism which makes them sensitive to treatment with octreotide. Octreotide is suitable for the treatment of VIPoma since it inhibits released VIP. Although the available data are derived primarily from small studies and case reports, initial responses are encouraging. By reducing the circulating levels of VIP, octreotide improves diarrhoea in these patients. Octreotide has also been evaluated in several trials in patients with the carcinoid syndrome, with symptomatic improvement being observed in over 75% of cases. Clinically significant improvements in diarrhoea (elimination, or reduction of > 50%) have been observed in the great majority (up to 83%) of treated patients. Slowed tumour growth, as well as an improvement in diarrhoea, has been observed during long term treatment. A number of miscellaneous conditions can give rise to severe secretory diarrhoea, and include long standing neuropathic diabetes mellitus, short bowel syndrome after intestinal resection, intestinal graft-versus-host disease and coeliac plexus block. Idiopathic hypersecretory diarrhoea may also occur, particularly in infants. A number of studies and patient reports have shown octreotide to be a valuable adjunct in the management of patients with such conditions, and to be worthy of further investigation. Now that case report data have been confirmed by clinical trials, it is becoming evident that octreotide is a valuable treatment in the management of otherwise treatment-refractory severe diarrhoea in AIDS patients. © 1992, Adis International Limited. All rights reserved.