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1.
Lancet ; 358(9295): 1754-9, 2001 Nov 24.
Article in English | MEDLINE | ID: mdl-11734231

ABSTRACT

BACKGROUND: Pegvisomant is a new growth hormone receptor antagonist that improves symptoms and normalises insulin-like growth factor-1 (IGF-1) in a high proportion of patients with acromegaly treated for up to 12 weeks. We assessed the effects of pegvisomant in 160 patients with acromegaly treated for an average of 425 days. METHODS: Treatment efficacy was assessed by measuring changes in tumour volume by magnetic resonance imaging, and serum growth hormone and IGF-1 concentrations in 152 patients who received pegvisomant by daily subcutaneous injection for up to 18 months. The safety analysis included 160 patients some of whom received weekly injections and are excluded from the efficacy analysis. FINDINGS: Mean serum IGF-1 concentrations fell by at least 50%: 467 mg/L (SE 24), 526 mg/L (29), and 523 mg/L (40) in patients treated for 6, 12 and 18 months, respectively (p<0.001), whereas growth hormone increased by 12.5 mg/L (2.1), 12.5 mg/L (3.0), and 14.2 mg/L (5.7) (p<0.001). Of the patients treated for 12 months or more, 87 of 90 (97%) achieved a normal serum IGF-1 concentration. In patients withdrawn from pegvisomant (n=45), serum growth hormone concentrations were 8.0 mg/L (2.5) at baseline, rose to 15.2 mg/L (2.4) on drug, and fell back within 30 days of withdrawal to 8.3 mg/L (2.7). Antibodies to growth hormone were detected in 27 (16.9%) of patients, but no tachyphylaxis was seen. Serum insulin and glucose concentrations were significantly decreased (p<0.05). Two patients experienced progressive growth of their pituitary tumours, and two other patients had increased alanine and asparate aminotransferase concentrations requiring withdrawal from treatment. Mean pituitary tumour volume in 131 patients followed for a mean of 11.46 months (0.70) decreased by 0.033 cm(3) (0.057; p=0.353). INTERPRETATION: Pegvisomant is an effective medical treatment for acromegaly.


Subject(s)
Acromegaly/drug therapy , Receptors, Somatotropin/antagonists & inhibitors , Receptors, Somatotropin/therapeutic use , Adult , Blood Glucose/drug effects , Cohort Studies , Drug Administration Schedule , Female , Growth Hormone/blood , Human Growth Hormone/analogs & derivatives , Humans , Insulin/blood , Insulin-Like Growth Factor I/metabolism , Male , Middle Aged
2.
J Clin Endocrinol Metab ; 86(2): 478-81, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11157994

ABSTRACT

We describe the case of an acromegalic subject, who was the first patient ever treated with the GH receptor antagonist pegvisomant. Furthermore, in this particular patient, progression in tumor size was encountered during treatment with pegvisomant. The patient described did benefit from cotreatment with pegvisomant and octreotide, including decreased GH levels, normalization of serum insulin-like growth factor I concentrations, and improvement of visual field defects.


Subject(s)
Acromegaly/etiology , Adenoma/drug therapy , Antineoplastic Agents, Hormonal/therapeutic use , Human Growth Hormone/analogs & derivatives , Human Growth Hormone/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Octreotide/therapeutic use , Pituitary Neoplasms/drug therapy , Acromegaly/drug therapy , Adenoma/complications , Adenoma/surgery , Adult , Drug Therapy, Combination , Human Growth Hormone/blood , Humans , Insulin-Like Growth Factor I/metabolism , Male , Pituitary Neoplasms/complications , Pituitary Neoplasms/surgery , Receptors, Somatotropin/antagonists & inhibitors
3.
J Clin Endocrinol Metab ; 85(8): 2958-61, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10946911

ABSTRACT

Transsphenoidal surgical resection is the primary therapy for acromegaly caused by GH secreting pituitary adenomas. Medical therapy for patients not controlled by surgery includes primarily somatostatin analogs and secondarily dopamine agonists, both of which inhibit pituitary growth hormone secretion. A novel GH receptor antagonist (pegvisomant) binds to hepatic GH receptors and inhibits peripheral insulin-like growth factor-1 generation. Six patients resistant to maximal doses of octreotide therapy received pegvisomant - three received placebo or pegvisomant 30 mg or 80 mg weekly for 6 weeks and three received placebo and pegvisomant 10-20 mg/d for 12 weeks. Thereafter, all patients received daily pegvisomant injections of doses determined by titrating IGF-1 levels. Serum total IGF-1 levels were normalized in all six acromegalic patients previously shown to be resistant to somatostatin analogs via a novel mechanism of peripheral GH receptor antagonism. The GH receptor antagonist is a useful treatment for patients harboring GH-secreting tumors who are resistant to octreotide.


Subject(s)
Acromegaly/drug therapy , Human Growth Hormone/analogs & derivatives , Acromegaly/blood , Adult , Bromocriptine/therapeutic use , Drug Resistance , Female , Hormone Antagonists/therapeutic use , Human Growth Hormone/therapeutic use , Humans , Insulin-Like Growth Factor I/analysis , Male , Octreotide/therapeutic use , Receptors, Somatotropin/antagonists & inhibitors , Treatment Failure
4.
N Engl J Med ; 342(16): 1171-7, 2000 Apr 20.
Article in English | MEDLINE | ID: mdl-10770982

ABSTRACT

BACKGROUND: Patients with acromegaly are currently treated with surgery, radiation therapy, and drugs to reduce hypersecretion of growth hormone, but the treatments may be ineffective and have adverse effects. Pegvisomant is a genetically engineered growth hormone-receptor antagonist that blocks the action of growth hormone. METHODS: We conducted a 12-week, randomized, double-blind study of three daily doses of pegvisomant (10 mg, 15 mg, and 20 mg) and placebo, given subcutaneously, in 112 patients with acromegaly. RESULTS: The mean (+/-SD) serum concentration of insulin-like growth factor I (IGF-I) decreased from base line by 4.0+/-16.8 percent in the placebo group, 26.7+/-27.9 percent in the group that received 10 mg of pegvisomant per day, 50.1+/-26.7 percent in the group that received 15 mg of pegvisomant per day, and 62.5+/-21.3 percent in the group that received 20 mg of pegvisomant per day (P<0.001 for the comparison of each pegvisomant group with placebo), and the concentrations became normal in 10 percent, 54 percent, 81 percent, and 89 percent of patients, respectively (P<0.001 for each comparison with placebo). Among patients treated with 15 mg or 20 mg of pegvisomant per day, there were significant decreases in ring size, soft-tissue swelling, the degree of excessive perspiration, and fatigue. The score fortotal symptoms and signs of acromegaly decreased significantly in all groups receiving pegvisomant (P< or =0.05). The incidence of adverse effects was similar in all groups. CONCLUSIONS: On the basis of these preliminary results, treatment of patients who have acromegaly with a growth hormone-receptor antagonist results in a reduction in serum IGF-I concentrations and in clinical improvement.


Subject(s)
Acromegaly/drug therapy , Human Growth Hormone/analogs & derivatives , Receptors, Somatotropin/antagonists & inhibitors , Acromegaly/blood , Adenoma/drug therapy , Adenoma/pathology , Adult , Autoantibodies/blood , Double-Blind Method , Female , Human Growth Hormone/adverse effects , Human Growth Hormone/blood , Human Growth Hormone/immunology , Human Growth Hormone/therapeutic use , Humans , Insulin-Like Growth Factor I/metabolism , Male , Middle Aged , Pituitary Neoplasms/drug therapy , Pituitary Neoplasms/pathology
5.
J Clin Endocrinol Metab ; 84(6): 2098-103, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10372717

ABSTRACT

B2036-PEG, a GH receptor (GH-R) antagonist, is an analog of GH that is PEG-modified to prolong its action. Nine mutations alter the binding properties of this molecule, preventing GH-R dimerization and GH action. A potential therapeutic role of B2036-PEG is to block GH action, e.g. in refractory acromegaly. A phase I, placebo-controlled, single rising-dose study was performed in 36 normal young men (ages, 18-37 yr; within 15% ideal body weight). Four groups received a single s.c. injection of either placebo (n = 3 in each group, total n = 12) or B2036-PEG (0.03, 0.1, 0.3, or 1.0 mg/kg; n = 6 each dose). B2036-PEG and GH concentrations were measured 0, 0.25, 0.5, 1, 3, 6, 9, 12, 24, 36, 48, 72, 96, 120, and 144 h after dosing. Serum insulin-like growth factor-I was measured before and 1-7 days after dosing. All doses were well tolerated, with no serious or severe adverse reactions. B2036-PEG, at 1.0 mg/kg, reduced insulin-like growth factor-I by 49 +/- 6% on day 5 (P < 0.001 vs. placebo). GH was measured by two independent methods: 1) modified Nichols chemiluminescence assay (empirically corrected for B2036-PEG cross-reactivity); and 2) direct GH two-site immunoassay, using monoclonal antibodies that did not react with B2036-PEG. There was good agreement between the two methods. GH did not change substantially at any B2036-PEG dose, suggesting that B2036-PEG does not interact with hypothalamic GH-Rs to block short-loop feedback. B2036-PEG may thus block peripheral GH action without enhancing its secretion.


Subject(s)
Human Growth Hormone/analogs & derivatives , Human Growth Hormone/antagonists & inhibitors , Human Growth Hormone/metabolism , Insulin-Like Growth Factor I/metabolism , Adolescent , Adult , Antibodies, Monoclonal , Humans , Immunoassay , Iodine Radioisotopes , Luminescent Measurements , Male , Stimulation, Chemical
6.
J Clin Dent ; 4(3): 101-5, 1993.
Article in English | MEDLINE | ID: mdl-8003236

ABSTRACT

Four independent clinical studies were conducted to compare the short- and long-term effectiveness of three commercially available toothbrushes. Two of the four studies compared plaque removal in a single-use, crossover design, and two studies compared plaque and gingivitis reduction efficacy for a long-term, three-month use. The Turesky modification of the Quigley-Hein Plaque Index and the modified Gingival Index were used to assess plaque and gingivitis levels, respectively. The two long-term studies directly compared the Oral-B P-35 and Crest Complete toothbrushes, while the two single-use studies compared the Oral-B P-35, Crest Complete and Colgate Precision toothbrushes. In all four studies, there were no significant differences found between any of the toothbrushes.


Subject(s)
Toothbrushing/instrumentation , Analysis of Variance , Dental Plaque Index , Evaluation Studies as Topic , Female , Humans , Male , Periodontal Index , Regression Analysis
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