title: Pharmacodynamic Actions of a Long-Acting PTH Analog (LA-PTH) in Thyroparathyroidectomized (TPTX) Rats and Normal Monkeys.
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, [Ala(1,3,12,18,22) , Gln(10) ,Arg(11) ,Trp(14) ,Lys(26) ]-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.
authors: Research Division, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
authors: Masaru
authors: M
authors: Shimizu
authors: Research Division, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
authors: Eri
authors: E
authors: Joyashiki
authors: Research Division, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
authors: Hiroshi
authors: H
authors: Noda
authors: Research Division, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.|Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA.
authors: Tomoyuki
authors: T
authors: Watanabe
authors: Research Division, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
authors: Makoto
authors: M
authors: Okazaki
authors: Research Division, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
authors: Miho
authors: M
authors: Nagayasu
authors: Research Division, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
authors: Kenji
authors: K
authors: Adachi
authors: Research Division, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
authors: Tatsuya
authors: T
authors: Tamura
authors: Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA.
authors: John T
authors: JT
authors: Potts
authors: Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA.
authors: Thomas J
authors: TJ
authors: Gardella
authors: Research Division, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
authors: Yoshiki
authors: Y
authors: Kawabe
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001862:Bone Resorption / Q000097:blood; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D053565:Hypercalciuria / Q000097:blood; D007011:Hypoparathyroidism / Q000097:blood / Q000188:drug therapy*; D008252:Macaca fascicularis; D008297:Male; D010281:Parathyroid Hormone / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D016105:Parathyroidectomy; D051381:Rats
chemical_list: D015415:Biomarkers; D003692:Delayed-Action Preparations; D010281:Parathyroid Hormone
keywords: CALCIUM HOMEOSTASIS; HORMONE REPLACEMENT THERAPY; HYPOPARATHYROIDISM; LONG-ACTING PTH ANALOG; PTH RECEPTOR; THYROPARATHYROIDECTOMIZED RATS