EVALUATION IN-VIVO OF A POTENT PARATHYROID-HORMONE ANTAGONIST - [NLE(8,18), D-TRP(12), TYR(34)]BPTH(7-34)NH2

In an effort to design and select potent parathyroid hormone (PTH) ant agonists suitable for clinical utility, a PTH analog was evaluated in vivo in an animal model to assess its properties in preparation for hu man studies, The previously described PTH antagonist, [Nle(8,18),D-Trp (12),Tyr(34)]bPTH(7-34)NH2, which is highly active in vitro, was docum ented in these studies to be an effective antagonist of the PTH-stimul ated calcemic response in vivo. In thyroparathyroidectomized (TPTX) ra ts, the efficacy of the antagonist was demonstrated to be dose-depende nt, Inhibition was demonstrated when intravenous administration of ant agonist started 1 h prior to coinfusion with the PTH agonist [Nle(8,18 ),Tyr(34)]bPTH(1-34)NH2. Maximal inhibition by antagonist (an 84% decl ine in serum calcium levels compared with agonist alone) of the calcem ic response was observed when a 200-fold molar excess of antagonist (1 2 nmol/h) was administered, At dose ratios of antagonist:agonist as lo w 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 [Nle(8,18) ,D-Trp(12),Tyr(34)]bPTH(7-34)NH2 has displayed sufficient potency to o btain approval from the appropriate institutional and regulatory agenc ies for clinical trials in hypercalcemic states of parathyroid and tum or origin.