1,25-(OH)₂-16ene-23yne-D₃ Reduces Secondary Hyperparathyroidism in Uremic Rats with Little Calcemic Effect

Abstract

Objectives: To compare the effects of vitamin D analogs versus calcitriol on serum levels of Ca, P and parathyroid hormone (PTH). A compound better than calcitriol should increase the Ca x P product less than calcitriol for an equivalent decrease in PTH levels. Methods: Biological activity of 4 vitamin D analogs, 1,25-(OH)₂-16ene- D₃ (RO₁), 1,25-(OH)₂-16ene-23yne-D₃ (RO₂), 1,25-(OH)₂-26,27-hexafluoro-16ene-23yne-D₃ (RO₃) and 1,25-(OH)₂-16ene-23yne-26,27-hexafluoro-19nor-D₃ (RO₄) was tested vs. calcitriol in parathyroidectomized rats. In a second set of experiments, the effects of RO₂, RO₄ and calcitriol were studied in 5/6 nephrectomized rats with secondary hyperparathyroidism. Results: In parathyroidectomized rats, all analogs (250 pmol/day) led calcemia to rise after 7 days. In uremic rats, all treatments reduced PTH levels. RO₄ revealed toxicity. RO₂ was as effective as calcitriol in suppressing PTH in a dose dependent manner. Mean plasma ionized calcium did not change from baseline to day 14 and day 28 on RO₂ (250 or 500 pmol/day) whereas it increased significantly on RO₂ (1,000 pmol/day) and calcitriol (125 or 250 pmol/day). Increasing the dose of calcitriol led Ca × P to rise more dramatically than increasing the dose of RO₂, which appears to have a wider therapeutic window than calcitriol. Conclusion: 1,25-(OH)₂-16ene-23yne-D₃ (RO₂) may represent a novel candidate for the treatment of renal osteodystrophy in humans.

Selective inhibition of cyclooxygenase‐2 (COX‐2) by 1α,25‐dihydroxy‐16‐ene‐23‐yne‐vitamin D3, a less calcemic vitamin D analog

“…Furthermore, 1α,25(OH) 2 ‐16‐ene‐23‐yne‐D 3 has been shown to inhibit the growth of prostate [Schwartz et al, 1995] and colon cancer cells [Shabahang et al, 1994]. It was also shown that 1α,25(OH) 2 ‐16‐ene‐23‐yne‐D 3 reduces PTH levels in uremic rats without producing hyper‐calcemia [Lippuner et al, 2004]. At present, the mechanisms responsible for the dissociation of the calcemic from non‐calcemic actions of various synthetic vitamin D analogs is an active area of research.…”

Vitamin D analogs: Therapeutic applications and mechanisms for selectivity

“…1,25(OH) 2 -16-ene,23-yne-D 3 (Fig. 2) was as effective as calcitriol in suppressing PTH levels in uremic rats, but was much less calcemic with a lower Ca  P product, indicating that this analog has a wider therapeutic window that calcitriol (Lippuner et al, 2004). 1a(OH)-3-epi-D 3 , an analog of alfacalcidol with inverted stereochemistry at carbon 3, is a potent suppressor of PTH levels in uremic rats but with much less calcemic activity than calcitriol or alfacalcidol .…”

Vitamin D analogs for secondary hyperparathyroidism: What does the future hold?

“…Lippuner et al [26] demonstrated that 1,25(OH) 2 -16-ene-23-yne-D 3 (Fig. 3) was as nearly as effective as 1,25(OH) 2 D 3 in suppressing PTH in uremic rats, but was much less calcemic with a lower Ca × P product.…”

“…Overall, the findings from the clinical studies indicate that OCT [23][24][25][26][27][28][29] and calcitriol appear to be similarly effective and safe, suppressing PTH and exhibiting positive effects on bone formation [10,11]. Hypercalcemic episodes with OCT were generally considered to be dose dependent, and close monitoring was recommended.…”