Pharmacodynamic Actions of a Long‐Acting PTH Analog (LA‐PTH) in Thyroparathyroidectomized (TPTX) Rats and Normal Monkeys |
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Authors: | Masaru Shimizu Eri Joyashiki Hiroshi Noda Tomoyuki Watanabe Makoto Okazaki Miho Nagayasu Kenji Adachi Tatsuya Tamura John T Potts Jr Thomas J Gardella Yoshiki Kawabe |
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Institution: | 1. Research Division, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan;2. Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA |
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Abstract: | Hypoparathyroidism is a disease of chronic hypocalcemia and hyperphosphatemia due to a deficiency of parathyroid hormone (PTH). PTH and analogs of the hormone are of interest as potential therapies. Accordingly, we examined the pharmacological properties of a long‐acting PTH analog, Ala1,3,12,18,22, Gln10,Arg11,Trp14,Lys26]‐PTH(1‐14)/PTHrP(15‐36) (LA–PTH) in thyroparathyroidectomized (TPTX) rats, a model of HP, as well as in normal monkeys. In TPTX rats, a single intravenous administration of LA‐PTH at a dose of 0.9 nmol/kg increased serum calcium (sCa) and decreased serum phosphate (sPi) to near‐normal levels for longer than 48 hours, whereas PTH(1‐34) and PTH(1‐84), each injected at a dose 80‐fold higher than that used for LA‐PTH, increased sCa and decreased sPi only modestly and transiently (<6 hours). LA‐PTH also exhibited enhanced and prolonged efficacy versus PTH(1‐34) and PTH(1‐84) for elevating sCa when administered subcutaneously (s.c.) into monkeys. Daily s.c. administration of LA‐PTH (1.8 nmol/kg) into TPTX rats for 28 days elevated sCa to near normal levels without causing hypercalciuria or increasing bone resorption markers, a desirable goal in the treatment of hypoparathyroidism. The results are supportive of further study of long‐acting PTH analogs as potential therapies for patients with hypoparathyroidism. © 2016 American Society for Bone and Mineral Research. |
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Keywords: | HYPOPARATHYROIDISM LONG‐ACTING PTH ANALOG PTH RECEPTOR HORMONE REPLACEMENT THERAPY THYROPARATHYROIDECTOMIZED RATS CALCIUM HOMEOSTASIS |
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