Faculty Bibliography

The acute effects of single different doses of the somatostatin analog octreotide on the contractility of the gallbladder stimulated by fatty meal were studied in six healthy Chinese volunteers. Gallbladder contraction after a fatty meal was significantly suppressed by octreotide at doses of 50, 25, 12.5, and 5 micrograms. Mean duration of suppression lasted for more than 10 hr at doses of 25 and 50 micrograms, after which the gallbladder contractility was restored at 24 hr in three and four, respectively, of the six subjects. The percentage of relative gallbladder contraction (PRGC) in all subjects receiving 12.5 and 5 micrograms octreotide returned to pretreatment values at 10 hr but had not returned to normal 6 hr after the injection of 5 micrograms octreotide. In summary, octreotide inhibits the contraction of the gallbladder even with a dose as low as 5 micrograms. It appears that it may not be possible to avoid gallbladder dysfunction during long-term octreotide therapy by decreasing the dose. Further studies including modalities to increase the contractility of the gallbladder are recommended.

The separate and combined GH-lowering effects of single doses of octreotide and bromocriptine were assessed in 51 acromegalic patients on 4 occasions each 2 days apart. Patients received sequentially: placebo sc (N = 51), 50 micrograms octreotide sc (N = 51), 2.5 mg bromocriptine po (N = 40) or a combination of both drugs (N = 25). With octreotide, in 28 patients (55%) GH levels were suppressed to less than 5 micrograms/l and 39 of them (76.5%) had a 50% or greater decrease of their basal GH level from 2 to 6 h. During bromocriptine, GH values were suppressed to below 5 micrograms/l in 11 patients (27.5%) and reduced by 50% or more in 21 (52.5%). The combination of both drugs acutely suppressed GH levels to less than 2 micrograms/l in 32%, to less than 5 micrograms/l in 56%, and by more than 50% in 84% of patients. Octreotide produced a stronger and faster suppression of GH levels than bromocriptine in most patients. The combination of both drugs had an additive effect on the lowering of GH levels, especially between 7 and 10 h after drug administration. These results suggest that chronic therapy with a combination of both drugs may be as effective as therapy with higher doses of either compound alone. Albeit transient, octreotide caused a rapid near total suppression of insulin release in the morning, 15 to 45 min after administration. Postprandial glucose rise, between 2 and 3.5 h after breakfast was significantly higher during octreotide than on the control day.

BACKGROUND:We wanted to determine the clinical and biochemical effects of long-term therapy with the somatostatin analog octreotide in 189 acromegalic patients. METHODS:Patients were treated at 23 medical centers for 6 days to 231 weeks (median, 24.2 weeks) with varying octreotide dosages (100 to 1500 micrograms/d; median, 300 micrograms/d). Serum growth hormone and insulin-like growth factor I (IGF-I) concentrations before and at the end of the study were compared, and correlations between the response to treatment with total daily dosage and duration of treatment were sought. RESULTS:The clinical response rate was 88%, irrespective of dosage or treatment duration. Serum growth hormone levels decreased in 172 (94%) of 182 patients and IGF-I levels decreased in 91 (92%) of 99. The mean pretreatment growth hormone level was 39.4 +/- 4.4 micrograms/L and decreased to 12.2 +/- 1.5 micrograms/L. Growth hormone levels decreased to less than 5 micrograms/L in 82 (45%) of 182 patients. The pretreatment IGF-I level was 5.62 +/- 0.41 U/mL and decreased to 2.64 +/- 0.19 U/mL; suppression to 2 U/mL or lower occurred in 46 (46%) of 99 patients. The degree of growth hormone suppression was associated with longer treatment duration but not with the total octreotide dosage per day. In 34 patients studied prospectively, pituitary tumor size decreased by greater than 20% in 15 (44%). Side effects occurred in 37% of patients and were most commonly transient loose alcoholic stools, pain at the injection site, and abdominal discomfort; severity was mild to moderate. Glucose tolerance was unchanged or improved in 52% and declined in 48% of 25 patients evaluated. CONCLUSIONS:Octreotide is an effective treatment for acromegaly that may be used as primary therapy or after surgery and/or pituitary irradiation.

The effect of a schedule of three daily injections of 100 micrograms octreotide (pen treatment) compared with that of a continuous sc infusion of 300 micrograms/24 h on GH and IGF-I suppression, and other GH-dependent parameters was studied in 10 acromegalic patients in a cross-over study. Treatment was administered via a specially designed pen or a pump for 4 weeks. Following a washout period of a further 4 weeks, patients were switched to the other mode of delivery. Mean GH levels decreased from 26.2 +/- 4.7 to 9.9 +/- 3.1 mU/l (p = 0.007) during pen therapy and to 7.7 +/- 2.4 mU/l (p = 0.003) during pump treatment. IGF-I levels decreased from 75.6 +/- 9.5 to 42.0 +/- 9.3 nmol/l (p = 0.003) during pen treatment and to 32.5 +/- 2.5 nmol/l (p = 0.001) during pump treatment. There was a significant difference in IGF-I levels between pen and pump treatments (p = 0.03). In 7 patients the IGF-I levels normalized during pump treatment compared with 3 patients in the pen treatment group. There was no change in the free T4 index levels, but the free T3 index significantly decreased during therapy, without changes in plasma TSH. This study demonstrates that continuous infusion with octreotide results in a better control of GH oversecretion than the intermittent mode of delivery.

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.

The long-acting somatostatin agonist octreotide can control TSH hypersecretion from most thyrotropic adenomas. Octreotide therapy has even been shown to improve chiasmal dysfunction. We report another patient in whom octreotide therapy was associated with gradual suppression of TSH hypersecretion, which escaped partially, dramatic and very rapid and sustained improvement of chiasm compression, and dramatic and sustained shrinkage of an unresectable TSH-secreting pituitary tumour. Unusual and prolonged gastrointestinal adverse reactions eventually disappeared except for steatorrhea. In conclusion, octreotide may be considered as first line treatment in patients with unresectable thyrotropic adenomas.

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.

Ten patients with acromegaly were treated with the long-acting somatostatin analogue, Sandostatin (SMS 201-995, octreotide) for more than one year. Computerized tomography was performed before and on 4 different occasions during the treatment. Sella turcica volumes were calculated in nine patients and showed a gradual decrease in all, averaging 32% +/- 14.6%, P less than 0.001 at the end of the study, which is probably indicative of a simultaneous reduction in adenoma size.