Faculty Bibliography

The somatostatin analog, octreotide, is an inhibitor of growth hormone (GH) secretion that has been used to treat patients with GH-producing pituitary tumors. In this study we investigated the in vivo responsiveness to treatment with this analog in patients harboring different morphological types of GH-producing pituitary adenomas. Both GH and insulin-like growth factor I (IGF-I) plasma levels in 30 patients treated with octreotide (300 micrograms/day) for 4 months preoperatively were compared with those from 30 patients who did not receive treatment preoperatively. Tissue samples were studied using ultrastructural and immunohistochemical techniques. Amongst patients harboring densely granulated (DG) adenomas, mean GH levels were reduced to 32 +/- 9% by octreotide, to 30 +/- 7% by surgery and to 26 +/- 9% of baseline by both interventions. Surgery was equally as effective in lowering GH levels in patients with sparsely granulated (SG) adenomas as it was in those with DG adenomas; in patients with SG adenomas, GH levels were reduced by surgery alone to 37 +/- 16% and to 24 +/- 15% when performed following octreotide pretreatment. In contrast, treatment with octreotide alone in patients harbouring SG adenomas reduced GH levels to only 70 +/- 13% of baseline (p < 0.02 compared to surgery alone, or surgery and octreotide). We conclude that the GH inhibitory effects of octreotide are significantly better in patients harboring DG somatotroph adenomas compared with those harboring SG adenomas.

Treatment of acromegaly with intermittent sc injections of octreotide is associated with an increased incidence of cholelithiasis. We investigated the incidence of gallstone formation, the occurrence of gallbladder disease, and the response of gallstones to ursodeoxycholic acid in 30 acromegalic patients who were treated with a continuous sc infusion of octreotide at doses between 200 and 800 micrograms/day for 3-70 months. Of the 30 patients, 28 had pretretment ultrasonography of the biliary tree performed, and all had frequent follow-ups. Nine patients underwent pre- and posttreatment bile sampling. No patient treated for less than 6 months and 18.5% of patients treated for more than 6 months developed new gallstones. No patient developed symptomatic cholelithiasis while receiving octreotide therapy. Of six patients who developed gallstones, four were treated with ursodeoxycholic acid, which dissolved all gallstones. One patient with gallstones experienced an episode of biliary colic when octreotide was withdrawn; however, no cholecystitis was found at subsequent cholecystectomy. Bile sampling showed that 8 (75%) of the 12 patients who were assessed demonstrated microcrystals, whereas in 3 (50%) of 6 patients who were closely analyzed thereafter, microcrystals disappeared once octreotide therapy was stopped. Our results show that continuous sc infusion octreotide therapy increases the incidence of cholelithiasis over normal values, as is the case with intermittent sc injections. Although higher octreotide levels are sustained with continuous sc infusion, this is not associated with an increased risk of gallstone formation compared with intermittent sc octreotide therapy.

BACKGROUND:Octreotide has proven therapeutically effective in carcinoid syndrome, but the rarity of carcinoid tumors has hampered detailed dose-ranging studies. This study analysed published dose-titration data on octreotide use in carcinoid patients to (a) investigate the relation between octreotide dose and efficacy and (b) establish octreotide dosing recommendations for maximum therapeutic benefit. METHOD/METHODS:An exhaustive, computer-assisted literature search for published articles employing octreotide to manage patients with carcinoid syndrome was performed using several databases. The relation between octreotide dose and efficacy in decreasing urinary 5-hydroxyindoleacetic acid (5-HIAA) levels, flushing and diarrhoea was analysed for seven dose ranges by pooling data from selected articles. RESULTS:Analysis of data compiled from 62 published studies revealed that maximum effective therapeutic doses of octreotide effectively controlled symptoms in up to 93% of patients, and that increasing the dose of octreotide is associated with increased benefit with respect to control of flushing, diarrhoea and 5-HIAA levels. CONCLUSIONS:We recommend starting octreotide therapy at 100 micrograms subcutaneously t.d.s. in patients with mild/moderate, non-life-threatening carcinoid syndrome. Since therapeutic response to octreotide varies markedly among patients, we recommend titrating the octreotide dose in increments of 50-100 micrograms every 8 h until adequate symptom control is achieved.

Octreotide is an effective therapeutic option in controlling secretory diarrhea of varied etiology. However, marked patient-to-patient differences in the antidiarrheal effects necessitate titration of octreotide dose in individual patients to achieve optimal symptom control. A consensus development panel established guidelines for octreotide dose titration in patients with secretory diarrhea. Overall, the panel recommended an aggressive approach in selecting the initial octreotide dose and in making subsequent dose escalations in patients with secretory diarrhea due to gastrointestinal tumors (eg, carcinoids, VIPomas), AIDS, dumping syndrome, short bowel syndrome, radiotherapy, or chemotherapy. To avoid hypoglycemia in patients with diabetes mellitus-associated secretory diarrhea, the panel recommended a low initial octreotide dose and a conservative titration regimen with close monitoring a blood glucose levels. The end point of therapy should focus on a reduction in diarrhea (frequency of bowel movements or stool volume) rather than normalization of hormonal profile. Overall, octreotide is well tolerated; principal side effects are transient injection site pain and gastrointestinal discomfort. For many patients with secretory diarrhea, octreotide therapy is expected to improve the overall health and quality of life and in the long run will lessen health care costs.

The somatostatin analog octreotide has proven to be an effective form of treatment for various hypersecretory states including acromegaly. This report describes the effects of escalating doses of octreotide on the growth hormone (GH) profiles, insulin-like growth factor-1 (IGF-1), prolactin (PRL), and adverse effects in 99 patients with acromegaly. Treatment with octreotide was initiated at 50 micrograms sc every 8 h and the dose gradually titrated to a maximum of 1500 micrograms/d if more than 75% of GH determinations in a 12-h day profile were above detection limits. This dose was maintained for the duration of 6 months. Seventy-three percent of patients did not reach the GH reduction criterion at the 300 micrograms dose. Mean GH levels decreased from 33 +/- 4 micrograms/l to 10 +/- 1 microgram/l (p < 0.001) while receiving the 300 micrograms/d dose. The percentage decrease in mean GH levels, however, was dose-independent reaching 50 +/- 5% of baseline with 300 micrograms/d, 55 +/- 5% with 600 micrograms/d, 57 +/- 6% with 900 micrograms/d, and 56 +/- 5% with 1500 micrograms/d. Maximal GH suppression, however, was achieved in 40%, 17%, 7%, and 16% of subjects by the 300 micrograms, 600 mg, 900 micrograms, and 1500 micrograms doses respectively. GH suppression was independent of duration of treatment. While there was a tendency for a greater degree of IGF-1 reduction with the higher doses, the rate of normalization (30-37%) was not influenced by the dose of octreotide administered. Elevated PRL levels also declined with the use of higher doses of octreotide.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of diabetic rats with octreotide can inhibit early diabetic renal hypertrophy. Octreotide administration for 6 months from the day of diabetes induction inhibits renal hypertrophy and diminishes increase in urinary albumin excretion. To investigate the effect of octreotide on manifest diabetic renal changes, octreotide treatment was given for 3 weeks after an untreated diabetic period of 3 or 6 months. In addition, following 6 months of diabetes, a group of diabetic rats was treated with insulin for 3 weeks. Renal and glomerular hypertrophy, and increased urinary albumin excretion were observed in diabetic rats compared to non-diabetic control rats from 3 months and throughout the study period. Octreotide treatment did not affect body weight, food intake, blood glucose or serum fructosamine levels. We observed no effect of octreotide treatment on renal and glomerular hypertrophy or urinary albumin excretion compared to placebo-treated diabetic rats. Insulin treatment for 3 weeks after 6 months of untreated diabetes normalized blood glucose and serum fructosamine levels, and furthermore renal hypertrophy was significantly diminished compared to the placebo-treated diabetic rats. However, insulin treatment had no effect on glomerular hypertrophy or urinary albumin excretion. In conclusion, octreotide treatment for 3 weeks following an untreated diabetic period of 3 or 6 months is unable to reduce the increased renal and glomerular volume or urinary albumin excretion. However, insulin treatment for 3 weeks with induction of euglycaemia diminishes the renal hypertrophy but has no effect on glomerular volume or urinary albumin excretion.

This review evaluates the efficacy, tolerability, and safety of continuous subcutaneous infusion (CSI) relative to intermittent subcutaneous injection (ISI) of the somatostatin analog, octreotide in the treatment of acromegaly. Data was extracted from five clinical series using CSI octreotide in acromegaly, six reports comparing CSI to ISI, and three studies comparing pulsatile subcutaneous infusion (PSI) to ISI. Effects of each drug regimen on the control of growth hormone (GH), insulin-like growth factor (IGF-1), clinical symptomatology, pituitary tumor size, and adverse effects were evaluated. Normalization of serum GH or IGF-1 levels, as well as improvement in clinical symptoms was reported in the majority of the patients studied. Cases in which pituitary adenomas decreased in size were also documented during the study period. When the effects of CSI were compared with ISI, a more pronounced control of GH and IGF-1 was observed. In addition, diurnal GH fluctuation during CSI was significantly reduced relative to ISI in two reports. Moreover, in two patients, CSI achieved similar clinical and biochemical effects at lower doses than when the drug was given by ISI. Finally, adverse effects with CSI may be less severe than with ISI. Continuous subcutaneous infusion of octreotide produced biochemical improvement in 67 of the 88 patients reviewed. When compared with ISI, CSI induced more pronounced biochemical control, often with less fluctuation in GH and IGF-1 levels. Because of a lack of data, definite conclusions regarding the differences between regimens on clinical symptomatology and tolerability could not be discerned. A large prospective, long-term randomized crossover study is recommended to make these determinations.