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Biomedical subjects

M F Holick

Publications and source records attributed to M F Holick.

At least 199 records · Page 11Linked to original sources
PubMed1975

Synthesis of (6-3H)-1alpha-hydroxyvitamin D3 and its metabolism in vivo to (3H)-1alpha,25-dihydroxyvitamin D3.

[6-3H]-1alpha-Hydroxyvitamin D3 was chemically synthesized and its full biological activity and radiochemical purity were demonstrated. With the use of this preparation it has been possible to demonstrate in vivo that in rats the [6-3H]-1Alpha-hydroxyvitamin D3 is converted to [6-3H]-1alpha,25-dihydroxyvitamin D3, the natural hormone. In fact, in the intestine and bone of rats given 32 picomoles of [6-3H]-1alpha-hydroxyvitamin D3 each day for 6 days, more than 80 percent of the lipid-soluble radioactivity exists as [6-3H]-1alpha,25-dihydroxyvitamin D3, a finding that suggests that much of the biological effectiveness of 1alpha-hydroxyvitamin D3 is due to its conversion to 1alpha,25-dihydroxyvitamin D3.

Animals↗
PubMed1975

Treatment of hypoparathyroidism and pseudohypoparathyroidism with metabolites of vitamin D: evidence for impaired conversion of 25-hydroxyvitamin D to 1 alpha,25-dihydroxyvitamin D.

In hypoparathyroidism and pseudohypoparathyroidism, pharmacologic doses of vitamin D correct hypocalcemia, but the mechanism is unknown. In two children with hypoparathyroidism and one with pseudohypoparathyroidism we tested the hypothesis that in these conditions there is a defect in synthesis of 1 alpha,25-dihydroxyvitamin D3, the principal active metabolite of vitamin D. In both conditions, minute doses of the metabolite (0.04 to 0.08 mug per kilogram of body weight per day) quickly corrected hypocalcemia and increased intestinal calcium absorption. On the other hand, the effective dose of 25-hydroxyvitamin D3 to maintain normocalcemia was 3 to 4 mug per kilogram per day in the two conditions. Thus, the dosage ratio of 25-hydroxyvitamin D3 to 1 alpha,25-dihydroxyvitamin D3 approximated 100:1. By contrast this ratio was approximately 3:1 in two infants with vitamin D deficiency, a condition in which optimal metabolism of vitamin D would be expected. These findings suggest an impaired conversion of 25-hydroxyvitamin D to 1 alpha,25-dihydroxyvitamin D in both hypoparathyroidism and pseudohypoparathyroidism.

Administration, Oral↗
PubMed1975

1-alpha-hydroxyvitamin D3 in chronic renal failure. A potent analogue of the kidney hormone, 1,25-dihydroxycholecalciferol.

In chronic renal disease, the synthesis of the kidney hormone, 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), is impaired, thus contributing to the development of renal osteodystrophy. The clinical use of 1,25-(OH)2D3 is limited, due to the complexity and expense of its chemical synthesis. This study reports the use of 1-alpha-hydroxyvitamin D3 (1-alpha-OH-D3), an active analogue of 1,25-(OH)2D3, in eight patients with chronic renal failure, five of whom were undergoing long-term hemodialysis. The drug was given orally for 6 to 260 days at a dosage of 1mug to 4mug/day. Short-term (21 days) balance studies showed an increase in intestinal calcium absorption and a simultaneous fall in serum parathyroid hormone levels during administration of 1-alpha-OH-D3. In two long-term studies (160 and 260 days), roentgenographic improvement of renal osteodystrophy was seen after 45 and 185 days, respectively. The data indicate that 1-alpha-OH-D3 holds considerable promise for the prevention and treatment of renal osteodystrophy.

Administration, Oral↗
PubMed1975

Effect of I,25-dihydroxycholecalciferol in renal osteodystrophy.

A 23-year-old man with medullary cystic disease had been undergoing hemodialysis for 5 years and had become confined to a wheelchair because of renal osteodystrophy. He was treated with 125-dihydroxycholecalciferol, 2.0 mug (later 1.0 mug) three times a week, administered by way of the venous end of the dialysis machine. Within 1 month bone pain lessened and his ability to stand and walk improved. By 3 months he was walking short distances and by 5 months, long distances. Calcium balance was near zero before treatment and was strongly positive during treatment. Bone mineral content in the lower femur, measured by photon absorptiometry, increased at a rate of 32.2% per year. In contrast, 26 other patients on long-term hemodialysis had a mean loss of bone mineral content of 14.0% per year. Radiographs taken during treatment showed a decrease in subperiosteal bone resorption and healing of a pseudofracture. A significant decrease in the mean serum alkaline phosphatase value was noted during treatment, but no significant changes in mean serum calcium or phosphorus values were seen.

Adult↗
PubMed1975

Relationship of 25-hydroxyvitamin D3 side chain structure to biological activity.

27-nor-25-Hydroxyvitamin D3, 26,27-bisnor-25-hydroxyvitamin D3, and 22-27-hexanor-20-hydroxyvitamin D3 and the corresponding 5,6-trans isomers have been synthesized. All compounds were tested for their ability to induce intestinal calcium transport and bone calcium mobilization in normal and anephric rats. The 27-nor- and 26,27-bisnor-25-hydroxyvitamin D3 analog are capable of stimulating intestinal calcium transport and bone calcium mobilization in normal rats but are 10 to 100 times less active than 25-hydroxyvitamin D3. Although these analogs are inactive in anephric rats, their corresponding 5,6-trans isomer are capable of stimulating both intestine and bone activity in these animals. The 22-27-hexanor-20-hydroxyvitamin D3 and its corresponding 5,6-trans isomer are incapable of stimulating either intestinal calcium transport or bone calcium mobilization. These results suggest that minor alterations in the side chain significantly decrease the biopotency of 25-hydroxyvitamin D3. Since these analogs are biologically active in normal but not in anephric animals, it appears that the kidney 1alpha-hydroxylation is necessary for activity. Since 22-27-hexanor=20-hydroxyvitamin D3 and its corresponding 5,6-trans analog are biologically inactive, it is likely that at least part of the side chain is necessary for 25-hydroxyvitamin D3 to stimulate intestinal calcium transport and bone calcium mobilization.

Animals↗
PubMed1975

Effects of 1alpha-hydroxy-vitamin D3 and 1,25-dihydroxy-vitamin D3 on calcium and phosphorus metabolism in hypoparathyroidism.

The effects of 1alpha-OH D3 or 1,25-(OH)2D3 on calcium and phosphorus metabolism have been evaluated in five hypoparathyroid patients to establish the direct effects of these compounds in adult humans, uncomplicated by compensatory changes in parathyroid hormone secretion. Doses of 1-2.5 mug/day in four patients (5 mug/day in a fifth patient on diphenylhydantoin and phenobarbital) caused a marked increase in serum calcium concentration and urinary calcium excretion, without significant changes in renal calcium clearance or urinary hydroxyproline excretion. These results suggest that the correction of hypocalcemia involved primarily a stimulation of intestinal calcium absorption rather than a stimulation of skeletal calcium resorption. Simultaneously, there were increases in urinary phosphorus excretion and variable changes in serum inorganic phosphate concentration. These effects were produced by doses of 1alpha-OH D3 and 1,25-(OH)2D3 which approach the dose needed to prevent rickets, in contrast to the very large doses of vitamin D or 25-OH D3 required for comparable effects in hypoparathyroid patients. The increased relative effectiveness of these one-hydroxylated forms of vitamin D reveals a deficiency of vitamin D one-hydroxylation in hypoparathyroidism. The rapidity of action of 1alpha-OH D3 and 1,25-(OH)2D3 was also striking. Apart from its physiologic implications, the potency of the one-hydroxylated forms of vitamin D offers significant therapeutic advantages in some patients whose hypoparathyroidism is difficult to control with vitamin D itself.

Adult↗
PubMed1975

1,25-dihydroxyvitamin D3 and 1, alpha-hydroxyvitamin D3 in children: biologic and therapeutic effects in nutritional rickets and different types of vitamin D resistance.

This investigation confirms the high level of biologic activity and the similarity of the effects of small doses of 1,25-dihydroxyvitamin D3 (1,25-(OH)2-D3) and of its analog 1alpha-hydroxyvitamin D3 (1alpha-OH-D3) on children with nutritional rickets, "pseudodeficiency" rickets (PDR), hereditary hypophosphatemia, chronic idiopathic hypoparathyroidism, and chronic renal failure. It also shows that cystinotic patients may develop, at the end stage of the disease, a certain degree of resistance to 1,25-(OH)2-D3. The comparison of the therapeutic effects of long term oral administration of 1,25-(OH)2-D3 or 1alpha-OH-D3 to two D-deficient children and two sibs with PDR demonstrates differences in sensitivity. In the patients with nutritional rickets, 0.5 mug/24 hr of either drug corrects the biochemical abnormalities, initiates healing of skeletal lesions in 28 days, and cures the metaphyseal le lesions in 60 days of therapy. In contrast, it appears that doses of either drug that are curative in D deficiency rickets are only partly active in PDR. These observations indicate that the hypothesis of a deficit in 25-hydroxycholecalciferol 1alpha-hydroxylase in patients with PDR must await for confirmation more direct evidences, and that such a deficit, even if proven, may not account for all of the biochemical and skeletal alterations seen in patients with this inherited disorder.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1974

The acute effect of 25-hydroxycholecalciferol on renal handling of phosphorus. Evidence for a parathyroid hormone-dependent mechanism.

The acute effect of i.v. and direct intrarenal arterial infusion of 25-hydroxycholecalciferol (25HCC) and 1,25-dihydroxycholecalciferol (1,25-DHCC) on renal handling of phosphorus was evaluated in the following groups of rats: (a) intact animals, (b) parathyroidectomized (PTX) hypocalcemic rats, (c) PTX rats in which normocalcemia was maintained with calcium supplements and (d) PTX animals in which urinary phosphorus was augmented by (i) i.v. sodium phosphate, (ii) expansion of the extracellular fluid volume with normal saline, and (iii) i.v. parathyroid hormone (PTH). Clearances of inulin (C(In)), phosphorus (C(P)), and fractional clearances of phosphorus (C(P)/C(In)) of the experimental groups were compared with those of the corresponding control groups, and the clearances of the infused kidneys with those of the contralateral kidneys. In intact animals, i.v. 25HCC decreased C(P)/C(In) from 0.29+/-0.04 (mean +/-SE) to 0.19+/-0.04, and i.v. 1,25-DHCC decreased C(P)/C(In) from 0.25+/-0.04 to 0.15+/-0.02. The intrarenal infusion of both 25HCC and 1,25DHCC into intact animals failed to produce a unilateral change; however, it decreased C(P)/C(In) bilaterally. i.v. and intrarenal infusions of 25HCC or 1,25DHCC in PTX hypocalcemic and normocalcemic rats, and i.v. infusions of 25HCC in PTX rats receiving either sodium phosphate or normal saline, all failed to produce significant changes in C(P)/C(In). In contrast, 24HCC given i.v. to PTX animals receiving exogenous PTH was associated with a significant fall in C(P)/C(In), from 0.34+/-0.08 to 0.13+/-0.02. These results indicate that 25HCC enhances tubular reabsorption of phosphorus in rats, only in the presence of either endogenous or exogenous circulating PTH, but not in its absence and thus imply a PTH-dependent mechanism of 25HCC action on the kidney. This effect does not appear to be related to the conversion of 25HCC into 1,25DHCC, since the latter fails to affect tubular reabsorption of phosphorus in PTX rats.

Animals↗