One- and three-month release injectable microspheres of the LH-RH superagonist leuprorelin acetate.

An understanding of the events that occur during GH receptor (GHR) signaling has facilitated the development of a GHR antagonist (pegvisomant) for use in humans. This molecule has been designed to compete with native GH for the GHR and to prevent its proper or functional dimerization-a process that is critical for GH signal transduction and IGF-I synthesis and secretion. Clinical trials in patients with acromegaly show GHR blockade to be an exciting new mode of therapy for this condition, and pegvisomant may have a therapeutic role in diseases, such as diabetes and malignancy, in which abnormalities of the GH/IGF-I axis have been observed. This review charts the discovery and development of GHR antagonists and details the experience gained in patients with acromegaly.

/pdf/growth-hormone-receptor-antagonists-discovery-development-2yxz67a3oo.pdf

Growth Hormone Receptor Antagonists: Discovery, Development, and Use in Patients with Acromegaly

I. Introduction THE PRESENCE of GH-inhibitory substances in hypothalamic extracts was originally detected accidentally by Krulich et al. (1) during investigations into the distribution of GH-releasing factors throughout the rat hypothalamus. Several years later Brazeau et al. (2) isolated and characterized this somatotropin releaseinhibiting factor, called somatostatin (SRIF), which turned out to be a cyclic peptide consisting of 14 amino acids. SRIF was the first hormone to broaden the classic concepts of endocrinology because it has physiological effects both at the periphery and the central nervous system (3). Several reviews and proceedings from international symposia are available, which summarize the developments in the field of SRIF (4–12). In recent years SRIF analogs have been developed which can be used clinically. In the present review the physiological role of SRIF in the regulation of anterior pituitary function has been summarized as far as it contributes to the understanding of the use and ...

The Role of Somatostatin in the Regulation of Anterior Pituitary Hormone Secretion and the Use of Its Analogs in the Treatment of Human Pituitary Tumors

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 1500μg/d; median, 300 μg/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 μg/L and decreased to 12.2 ±1.5 μg/L. Growth hormone levels decreased to less than 5 μg/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 acholic 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. ( Arch Intern Med . 1991;151:1573-1578)

Long-term treatment of 189 acromegalic patients with the somatostatin analog octreotide. Results of the International Multicenter Acromegaly Study Group.

A European multicentre, open-label 12-month study with Sandostatin® LAR® administered intramuscularly at 4-week intervals was initiated in 151 acromegalics responsive to octreotide. All patients received 3 injections of the 20 mg dose, following which the dose was adjusted to 10 mg in patients with mean 4-hour GH serum concentrations below 1 µg/L (N: 29) and to 30 mg in patients with concentrations above 5 µg/L (N: 22). The GH level suppression was significant in the 20 mg dose group (p<0.01) and for all 151 patients (p<0.004), and was consistently maintained in all patients for the duration of the study. The suppression of the mean serum GH concentration to below 2.5 µg/L was recorded in 69.8% of patients at the endpoint treatment with Sandostatin® LAR® and 65.8% during prior treatment with Sandostatin® SC. A consistent suppression of serum IGF-I levels was also achieved. The number of patients with headache, fatigue, perspiration, joint pains and paresthesias had decreased significantly (p<0.05) after the 6th injection of Sandostatin® LAR® vs. previous SC treatment. No patient discontinued the study because of drug-related adverse events. The most frequently reported adverse events were mild diarrhea, abdominal pain and flatulence. The local tolerability was very good. No impairment of safety hematology, biochemistry and thyroid function tests and no increased incidence of gallstone formation was recorded. Well tolerated and at least as efficacious as the SC formulation, Sandostatin® LAR® might become an alternative primary treatment to pituitary surgery and radiotherapy.

Results of a European multicentre study with Sandostatin LAR in acromegalic patients. Sandostatin LAR Group.

SUMMARY
Diurnal serum GH patterns were determined in 10 acromegalic patients before treatment, after 3 d continuous s.c. pump infusion and then after 3 d with three equal daily s.c. injections in both instances totalling 100 μg/24 h. Subcutaneous injections (33 μg) induced impressive suppression of serum GH lasting 3-6 h in eight patients followed by escape to pretreatment values before the next injection. In contrast, continuous infusion resulted in greater and more stable 24 h suppression to the levels reached at the nadir between injections. Suppression of mean 24 h serum GH below 5 ng/ml was achieved by pump treatment in four patients, while two patients had mean values between 5 rig/ml and 10 ng/ml. In four patients occasional or all levels were above 10 ng/ml (24 h average 12.4-102 ng/ml) implying either that adequate suppression by the SMS 201-995, was impossible during the 3 d pump infusion period, or that the dose administered was inadequate. Carbohydrate tolerance was unaffected in either regimen, indicating that reduction in insulin antagonistic hormones balanced inhibition of insulin release. Interestingly, and in contrast to somatostatin, SMS 201-995 did not inhibit TSH release. No untoward effects were observed at the moderate dosage and blood clinical chemistry was unchanged. Fairly constant diurnal serum SMS 201-995 values were obtained during pump infusion, while levels undulated inversely with serum GH during injection treatment. Average diurnal serum somatostatin-C immunoreactivity (all patients) decreased from 496 ± 129 (mean ± SD) to 385 ± 100 ng/ml (P < 0 003) during pump treatment and did not decrease further during the following 3 d injection treatment (363 ± 76 ng/ml).

Continuous subcutaneous pump infusion of somatostatin analogue SMS 201-995 versus subcutaneous injection schedule in acromegalic patients.

Twenty-five acromegalic patients were studied during 6 years of treatment with octreotide, with a particular focus on the following parameters: (1) Administration schedule: in 10 patients, continuous subcutaneous (SC) octreotide infusion was compared with injections of octreotide at three dose levels ( 100, 250, and 1,500 μ g 24 h ) and was found to induce a greater and less-fluctuating 24-hour growth hormone (GH) suppression. (2) Carbohydrate tolerance: average 24-hour blood glucose levels were unaffected by octreotide, regardless of administration schedule. Oral carbohydrate tolerance and intravenous (IV) glucose tolerance were unaffected by continuous octreotide infusion. However, octreotide injection given shortly before the tests reduced carbohydrate tolerance. (3) Thyroid function: octreotide and somatostatin acutely reduce the response of thyroid-stimulating hormone (TSH) to thyrotropin-releasing hormone (TRH). After a few days of treatment, it was demonstrated that octreotide slightly inhibits iodothyronine deiodination and induces a transient reduction in serum triiodothyronine (T3), rapidly compensated for by a persistent slight elevation of serum TSH. (4) Fat absorption was estimated as 24-hour fecal fat content and found to be in the same high-normal range before and after octreotide treatment. Vitamin K and D absorption were unaffected by octreotide. The incidence of gallstone formation was not greater than in the general Danish population, possibly due to the schedule used for octreotide injections. (5) Foot volume was regularly estimated and found to decrease with time, on average by 12% during the first 18 months. (6) Sellar volume was studied by computed tomography (CT) and found to decrease during octreotide treatment and also in patients with microadenoma, probably due to decreased adenoma volume with reduced pressure on the bony structures. (7) Antibodies against octreotide were found in two of 25 acromegalic patients after approximately 2.5 years of treatment. They were IgGs, did not cross-react with native somatostatin, and did not have any apparent effects except for prolonging octreotide half-life and GH suppression.

Long-term efficacy and tolerability of octreotide treatment in acromegaly.

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<0.001 at the end of the study, which is probably indicative of a simultaneous reduction in adenoma size.

Reduction in sella turcica volume. An effect of long-term treatment with the somatostatin analogue, SMS 201-995, in acromegalic patients.

We bring our experiences with and results of octreotide treatment for 0.5 to seven years in 26 highly selected acromegalic patients, i.e. they had almost all been operated upon before or were for other reasons not first-choice neurosurgical candidates. Sixteen patients responded immediately to octreotide and achieved good control of symptoms and average serum growth hormone levels below 5 micrograms/l. Five additional patients responded adequately to octreotide after a renewed neurosurgical attempt, and two other patients achieved satisfactory control after successful neurosurgery. Thus we had to resort to radiation therapy in three out of these 26 patients. We should like to emphasize the fact that acromegalic patients, who initially do not respond adequately to octreotide therapy, may often do so after a renewed partial adenomectomy. Octreotide therapy has in our hands been practically without side effects, apart from gastrointestinal symptoms during the initial days of treatment. All 26 patients had an ultrasound-scan of the gallbladder and biliary tracts before and during long-term octreotide administration, and with the exception of one patient with gallbladder sediment, in whom no pretreatment scanning had been performed, we had no development of biliary tract abnormalities in these up to 65 year old patients. This may be due to composition and timing of meal intake in relation to that of octreotide. Fecal fat excretion, D-vitamin metabolites in serum and prothrombin time were similar in octreotide-treated and untreated acromegalic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

[Long-term treatment with octreotide of patients with acromegaly].

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Continuous subcutaneous pump infusion of somatostatin analogue SMS 201-995 versus subcutaneous injection schedule in acromegalic patients.

Long-term efficacy and tolerability of octreotide treatment in acromegaly.

Reduction in sella turcica volume. An effect of long-term treatment with the somatostatin analogue, SMS 201-995, in acromegalic patients.

[Long-term treatment with octreotide of patients with acromegaly].