Biomedical subjects

Alex J Brown

Publications and source records attributed to Alex J Brown.

21 records · Page 2Linked to original sources

PubMed2002

[Renal failure and vitamin D].

Secondary hyperparathyroidism (2HPT), a common disorder in patients with chronic renal failure, develops in response to phosphate retention and low serum 1,25-dihydroxyvitamin D(3) [1,25 (OH) (2)D(3), calcitriol] . Replacement therapy with calcitriol or its precursor 1alpha-hydroxyvitamin D(3) [1alpha (OH) D(3), alfacalcidol] often produces hypercalcemia and hyperphosphatemia in these patients. Several vitamin D analogues have been developed that retain the direct suppressive action of 1,25 (OH) (2)D(3) on the parathyroid glands but have less calcemic activity, therapy offering a safer and more effective means of controlling 2HPT. 1,25-D dihydroxy-19-norvitamin D(2) (19-nor D(2)) and 1alpha-hydroxyvitamin D(2) (1alphaOHD(2)) are available in the United States and 1,25-dihydrox-22-oxavitamin D(3) (22-oxacalcitriol, OCT) and 1,25-dihydroxy-26,26,26,27,27,27-hexafluorovitamin D(3) [1,25 (OH)(2)26,27F(6)D(3), falecalcitriol] have been approved for use in Japan. Animal studies have demonstrated that OCT and 19-nor D(2) have a wider therapeutic window for suppression of parathyroid hormone (PTH) because of their lower calcemic activities of OCT has been attributed to its rapid clearance which prevents sustained effects on intestinal calcium absorption and bone resorption, but still allows a prolonged suppression of PTH gene expression and parathyroid cell growth. The calcemic activity of 19-norD(2) diminishes with the duration of treatment by as yet unknown mechanisms. The lower toxicity of 1alphaOHD(2), compared 1alphaOHD(3). has also been noted with chronic, but not acute administration, perhaps due to differential metabolism. The unique actions of falecalcitriol may also result from altered metabolism. A clear understanding of the molecular basis for the selectivity of vitamin D analogues on parathyroid function may allow the design of even more effective analogues.

English Abstract↗

PubMed2000

1,25-Dihydroxy-19-nor-vitamin D(2), a vitamin D analog with reduced bone resorbing activity in vitro.

1,25-Dihydroxy-19-nor-vitamin D(2) (19-norD(2)), a new analog of 1,25(OH)(2)D(3), suppresses parathyroid hormone in renal failure patients and in uremic rats but has less calcemic activity than 1,25(OH)(2)D(3). Although 19-norD(2) has high affinity for the vitamin D receptor and similar pharmacokinetics to those of 1,25(OH)(2)D(3), it has much less bone resorbing activity in vivo. The intrinsic activity of 19-norD(2) on osteoclastogenesis and activation of bone resorption in mouse bone marrow cultures was examined to determine the mechanism involved. 19-norD(2) and 1,25(OH)(2)D(3) (10 nM) were equivalent in stimulating the formation and maintenance of large multinucleated, tartrate-resistant acid phosphatase-positive cells. However, the amount of bone resorbed by osteoclasts stimulated by 10 nM 19-norD(2), as measured by pit-forming assays, was reduced 62% compared with 10 nM 1,25(OH)(2)D(3)-stimulated osteoclasts (P < 0. 05). This difference could not be attributed to enhanced catabolism or to downregulated vitamin D receptor. The rate of degradation of 19-norD(2) in cultures was approximately 20% greater than 1, 25(OH)(2)D(3), not enough to account for the different effects on bone resorption. The VDR levels were identical in cultures that were treated with 19-norD(2) and 1,25(OH)(2)D(3). In summary, 19-norD(2) is less effective than 1,25(OH)(2)D(3) in stimulating mouse marrow osteoclasts to resorb bone. The reason for this difference is not clear but seems to involve the late maturation and/or activation of osteoclasts as the number of pits produced by each tartrate-resistant acid phosphatase-positive cell is reduced under stimulation by 19-norD(2) compared with 1,25(OH)(2)D(3).

Animals↗

PubMed2000

Calcemic activity of 19-Nor-1,25(OH)(2)D(2) decreases with duration of treatment.

19-Nor-1,25(OH)(2)D(2) (19-norD(2)) has been shown to suppress parathyroid hormone effectively, but with lower calcemic activity than 1,25(OH)(2)D(3). The present study investigated potential mechanisms to explain the reduced calcemic response to 19-norD(2). Tissue localization of [(3)H]19-norD(2) or[(3)H]1,25(OH)(2)D(3) after a single injection was not different. Intestinal calcium absorption and bone mobilization, measured in vitamin D-deficient rats 24 h after single injections of 60 or 600 pmol of 19-norD(2) or 1,25(OH)(2)D(3), were enhanced to a similar degree by the two compounds. However, when normal rats were treated every other day with 240 pmol of 19-norD(2) or 1,25(OH)(2)D(3), increases in serum calcium were identical 24 h after the first injection but diverged thereafter with significantly lower serum calcium in the 19-norD(2)-treated rats by 5 d. Intestinal calcium absorption and bone calcium mobilization were reassessed in vitamin D-deficient rats after seven daily injections of 600 pmol of 19-norD(2) or 1, 25(OH)(2)D(3), and both parameters were significantly lower in the 19-norD(2)-treated rats. Pharmacokinetic analysis after seven daily injections of 600 pmol of 19-norD(2) or 1,25(OH)(2)D(3) showed similar localization to the intestine and bone. In addition, intestinal vitamin D receptor levels were not different after 1 wk of treatment with 19-norD(2) or 1,25(OH)(2)D(3). In conclusion, the low calcemic activity of 19-norD(2) seems to be due to an acquired, postreceptor resistance of the intestine and bone to chronic treatment with the analog.

Animals↗