Evaluation in vivo of a potent parathyroid hormone antagonist: [Nle8,18, D-Trp12, Tyr34]bPTH(7-34)NH2
| Autor: | Vered Behar, Michael Chorev, Michael Rosenblatt, Chizu Nakamoto, Rivka Dresner-Pollak, Qui-Ming Yang |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Agonist medicine.medical_specialty medicine.drug_class Endocrinology Diabetes and Metabolism Drug Evaluation Preclinical Thyroid Gland Parathyroid hormone chemistry.chemical_element Calcium Parathyroid Glands Rats Sprague-Dawley Non-competitive inhibition In vivo Internal medicine medicine Animals Potency Orthopedics and Sports Medicine Parathyroidectomy Analysis of Variance Antagonist Peptide Fragments In vitro Rats Disease Models Animal Endocrinology chemistry Evaluation Studies as Topic Parathyroid Hormone Thyroidectomy |
| Zdroj: | Journal of Bone and Mineral Research. 11:1061-1065 |
| ISSN: | 0884-0431 |
| DOI: | 10.1002/jbmr.5650110804 |
| Popis: | 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, [Nle 8,18 ,D-Trp 12 ,Tyr 4 ]bPTH(7-34)NH 2 , 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 [Nle 8,18 ,Tyr 34 ]bPTH(1-34)NH 2 . 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 [Nle 8,18 ,D-Trp 12 ,Tyr 34 ]bPTH(7-34)NH 2 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. |
| Databáze: | OpenAIRE |
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