title: Evaluation in vivo of a potent parathyroid hormone antagonist: [Nle8,18,D-Trp12,Tyr34]bPTH(7-34)NH2.
abstract: In an effort to design and select potent parathyroid hormone (PTH) antagonists suitable for clinical utility, a PTH analog was evaluated in vivo in an animal model to assess its properties in preparation for human studies. The previously described PTH antagonist, [Nle8,18,D-Trp12,Tyr34]bPTH(7-34)NH2, which is highly active in vitro, was documented in these studies to be an effective antagonist of the PTH-stimulated calcemic response in vivo. In thyroparathyroidectomized (TPTX) rats, the efficacy of the antagonist was demonstrated to be dose-dependent. Inhibition was demonstrated when intravenous administration of antagonist started 1 h prior to coinfusion with the PTH agonist [Nle8,18,Tyr34]bPTH(1-34)NH2. Maximal inhibition by antagonist (an 84% decline in serum calcium levels compared with agonist alone) of the calcemic response was observed when a 200-fold molar excess of antagonist (12 nmol/h) was administered. At dose ratios of antagonist:agonist as low as 10:1, a 40-50% inhibition of PTH-stimulated calcemic response is evident, provided a longer (2 h) lead time for antagonist infusion is allowed. Based on these and related studies, the antagonist [Nle8,18,D-Trp12,Tyr34]bPTH(7-34)NH2 has displayed sufficient potency to obtain approval from the appropriate institutional and regulatory agencies for clinical trials in hypercalcemic states of parathyroid and tumor origin.
authors.affiliation: Division of Bone & Mineral Metabolism, Charles A. Dana Laboratory, Boston, Massachusetts, USA.
authors.forename: R
authors.initials: R
authors.lastname: Dresner-Pollak
authors.forename: Q M
authors.initials: QM
authors.lastname: Yang
authors.forename: V
authors.initials: V
authors.lastname: Behar
authors.forename: C
authors.initials: C
authors.lastname: Nakamoto
authors.forename: M
authors.initials: M
authors.lastname: Chorev
authors.forename: M
authors.initials: M
authors.lastname: Rosenblatt
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000097:blood; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005069:Evaluation Studies as Topic; D008297:Male; D010280:Parathyroid Glands / Q000502:physiology*; D010281:Parathyroid Hormone / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D016105:Parathyroidectomy; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013961:Thyroid Gland / Q000502:physiology*; D013965:Thyroidectomy
chemical_list: D010281:Parathyroid Hormone; D010446:Peptide Fragments; C102816:parathyroid hormone (7-34)amide, Nle(8,18)-Trp(12)-Tyr(34)-; D002118:Calcium