Stimulation of insulin secretion from isolated rat islets by SaRI 59-801.

Oral administration of SaRI 59-801 (DL-alpha-[dimethylaminomethyl]-2-[3-ethyl-5-methyl-4-isoxazolyl]-1H- indole-3-methanol) has been reported to decrease blood glucose in several species and to elevate plasma insulin in rats and mice. In studies with isolated rat pancreatic islets incubated 1 h with 3 mM glucose, 0.05 mM 59-801 produced a significant increase in insulin secretion, and 0.3 mM produced maximum release. 59-801 (0.3 mM) stimulated insulin release 4-5-fold from islets incubated with 0, 3, or 5 mM glucose but had little effect on the high rates of release obtained at 10 or 20 mM glucose. Ten millimolar mannoheptulose, which inhibits phosphorylation of glucose and blocks glucose-stimulated insulin release, had little effect on the stimulation of insulin release by 0.3 mM 59-801 from islets incubated with 3 mM glucose. Stimulation of insulin release in the absence of glucose or in the presence of 3 mM glucose plus 10 mM mannoheptulose suggests that glucose metabolism is not required for the action of 59-801. The rate of conversion of 5 mM [5(-3)H]-glucose to 3H2O by islets, a measure of the rate of glycolysis, was not affected by 59-801. The potency, dependency on glucose concentration, lack of inhibition by mannoheptulose, and lack of effect on glycolysis of 59-801 were similar to that of tolbutamide. However, proinsulin synthesis by islets incubated with 5.55 mM glucose was not affected by 0.5 mM 59-801, but was inhibited 72% and 67% by 0.5 mM tolbutamide and 0.1 mM glibenclamide, respectively.

Safety and efficacy of long-term octreotide therapy of acromegaly: results of a multicenter trial in 103 patients--a clinical research center study.

One hundred and three acromegalic patients from 14 medical centers were enrolled in this study to determine the efficacy and safety of the somatostatin analog, octreotide acetate, during long term treatment. Seventy percent of the patients had undergone previous surgery or radiation treatment. Octreotide was initiated at a dose of 100 micrograms, sc, every 8 h and gradually increased to a maximum of 1500 micrograms daily depending upon the individual patient's clinical and biochemical response [GH and insulin-like growth factor I (IGF-I) reduction]. The mean duration of treatment was 24 months (range, 3-30 months). However, most patients were treated for a mean of 30 months, because this study took place after an initial 6-month study previously reported. Mean serum GH fell from 30.9 micrograms/L (range, 2.7-350) to 5.7 micrograms/L (range, 0.6-59) at the 3 months visit and remained suppressed (P < 0.001). Plasma IGF-I concentrations were also significantly reduced and remained in the normal range for at least half of the treatment visits in 56 of 87 patients (64%) treated for 12-30 months. Patients with higher initial GH concentrations were less likely to normalize IGF-I concentrations during treatment (P < 0.001). There was no evidence of drug tachyphylaxis in those patients who continued taking stable doses of medication. With some exceptions, dose increments above 800 micrograms daily in 31 patients did not provide additional benefit in terms of GH and IGF-I reduction. Headache, excessive perspiration, fatigue, and joint pain were ameliorated in 83-95% of patients. Mean finger circumference was decreased significantly at the 12 month visit (P < 0.05). The most common adverse events reported were diarrhea, abdominal discomfort, loose stools, and nausea; these symptoms usually disappeared within 3 months of treatment. Five patients discontinued octreotide because of adverse events. Of 102 patients with normal baseline ultrasound examinations of the gallbladder, 24 patients (23.5%) developed gallstones (usually during the first year of treatment), and 21 patients developed sludge alone. Gallstone formation was not related to the dose of octreotide. Most patients with cholelithiasis were asymptomatic, and none developed cholecystitis. These observations suggest that octreotide is a valuable long term medical treatment for acromegaly.

Effect of chronic octreotide treatment on intestinal absorption in patients with acromegaly.

The adverse gastrointestinal effects of octreotide, a synthetic analog of somatostatin, have not been fully elucidated. Low-dose octreotide frequently causes adverse gastrointestinal symptoms in normal individuals. We investigated the adverse gastrointestinal effects of high-dose octreotide, which is required for the normalization of growth hormone hypersecretion in some patients with acromegaly. Patients with acromegaly (N = 8) were treated with octreotide, 450 micrograms/day, then 1500 micrograms/day for two months at each dosage. Carbohydrate absorption was assessed using the D-xylose test, and fat absorption using fecal fat excretion and serum carotene concentrations, at baseline, at each dosage of octreotide, and after one month of washout. Ultrasonography was used to monitor for cholelithiasis. Growth hormone and insulin-like growth factor-I concentrations were significantly suppressed at both dosages. Adverse gastrointestinal symptoms were mild and transient. D-Xylose absorption remained normal at each dosage and after one month of washout. Fecal fat excretion increased from 7 +/- 2 to 12 +/- 2 g/24 hr (P < 0.05) after the higher dosage and resumed baseline levels after the washout. Mean fasting serum carotene levels remained normal, and carotene loading test (15,000 units three times a day for three days) was unreliable in identifying patients with high fecal fat. No new cholelithiasis was detected by ultrasonography. One of two patients with preexisting cholelithiasis developed biliary colic several days after the treatment period. Although steatorrhea was common, small intestinal absorptive capacity was otherwise unchanged by four months of high-dose octreotide treatment, which significantly suppressed growth hormone secretion in acromegalic patients.

Octreotide treatment of acromegaly. A randomized, multicenter study.

OBJECTIVE: To determine the effects of the somatostatin analog, octreotide acetate, in patients with acromegaly. DESIGN: Double-blind, randomized trial. SETTING: Fourteen university-affiliated medical centers. PATIENTS: One hundred fifteen acromegalic patients, 70% of whom had persistent disease after pituitary surgery or radiotherapy. INTERVENTION: Subcutaneous octreotide, 100 micrograms, or placebo every 8 hours for 4 weeks. Four weeks after the end of treatment, patients were randomized to receive 100 or 250 micrograms octreotide subcutaneously every 8 hours for 6 months. RESULTS: After 2 weeks of treatment, a single 100-micrograms injection reduced mean serum growth hormone (GH) to 30% of the pretreatment concentration within 2 hours. The integrated mean GH level was reduced over 8 hours from 39 +/- 11 micrograms/L to 9 +/- 2 micrograms/L (P less than 0.001). Mean plasma insulin-like growth factor-1 (IGF-1) was reduced from 5100 +/- 400 U/L to 2400 +/- 400 U/L (P less than 0.001). After 6 months, the mean GH was reduced from 39 +/- 13 to 15 +/- 4 micrograms/L by 300 micrograms of octreotide and from 29 +/- 5 micrograms/L to 9 +/- 2 micrograms/L by 750 micrograms of octreotide daily. The mean IGF-1 concentration was suppressed to 2100 +/- 300 and 2500 +/- 400 U/L after 300 and 750 micrograms octreotide, respectively. Integrated mean GH levels were reduced to < 5 micrograms/L in 53% (95% CI, 39% to 67%) and 49% (CI, 35% to 63%), and IGF-1 levels were normal in 68% (CI, 54% to 82%) and 55% (CI, 40% to 70%) of patients receiving low- and high-dose octreotide, respectively. A substantial decrease in headache, amount of perspiration, joint pain, and finger circumference occurred in two thirds of the patients. The pituitary size was reduced in 19% (CI, 5% to 33%) and 37% (CI, 22% to 52%) of patients receiving 6 months of low- and high-dose octreotide, respectively. Ten percent and 13% of patients in each treatment group developed transient diarrhea; 10% and 14%, biliary sludge; and 6% and 18%, cholelithiasis, respectively. CONCLUSION: Octreotide effectively decreased GH and IGF-1 concentrations in 53% and 68% of patients, respectively. The higher dose resulted in increased frequency of tumor shrinkage but added no biochemical or clinical benefit.