Biomedical subjects

L R Halstead

Publications and source records attributed to L R Halstead.

28 records · Page 2Linked to original sources

PubMed1979

Cortisol enhancement of PTH-stimulated cyclic AMP accumulation in cultured fetal rat long bone rudiments.

Cortisol in concentrations from 10 nM to 10 microM produced a dose-related inhibition of basal and PTH1-stimulated 45Ca and [3H]-hydroxyproline release from cultured fetal rat forelimb rudiments. PTH-stimulated cyclic AMP generation however was not diminished by cortisol; in contrast, at a concentration of 1 microM cortisol produced a 57% increase in PTH-stimulated bone cyclic AMP content. The stimulatory effect of cortisol on cyclic AMP content appeared to be the result of reduced phosphodiesterase activity, since this effect was not seen in the presence of 10 mM theophylline. It is concluded that cortisol inhibition of PTH-induced resorption in long bones is not accompanied by reduced cyclic AMP generation.

Animals↗

PubMed1979

Disordered mineral metabolism produced by ketogenic diet therapy.

Vitamin D and mineral metabolism status was examined in five children maintained chronically on combined ketogenic diet-anticonvulsant drug therapy (KG), and the results compared to those obtained in 18 patients treated with anticonvulsant drugs alone (AD) and 15 normal controls. KG patients exhibited biochemical findings of vitamin D deficiency osteomalacia: decreased serum 25-hydroxyvitamin D (25OHD) and calcium concentrations, elevated serum alkaline phosphatase and parathyroid hormone concentrations, decreased urinary calcium and increased urinary hydroxyproline excretion, and decreased bone mass. Although the KG and AD groups demonstrated similar reductions in serum 25OHD concentration, the KG patients exhibited a significantly greater reduction in bone mass. In response to vitamin D supplementation (5000 IU/day), mean bone mass in the KG group increased by 8.1 +/- 0.9% (P less than 0.001) over a 12-month period. These results suggest that ketogenic diet and anticonvulsant drug therapy have additive deleterious effects on bone mass and that these effects are partially reversible by vitamin D treatment.

Acidosis↗

PubMed1979

Effect of lithium on parathyroid hormone-induced calcium release from bone rudiments.

Lithium treatment of humans and animals has been associated with adverse effects on bone and mineral metabolism. In order to determine whether lithium was altering the skeletal response to parathyroid hormone, we incubated bone rudiments for 5 days in the presence or absence of the drugs. Lithium had no effect on either parathyroid hormone-induced cyclic AMP generation or 45Ca release from the bone rudiments. The data are consistent with the hypothesis that the skeletal effects of lithium are not mediated via inhibition of the parathyroid hormone-adenyl cyclase-cyclic AMP system.

Animals↗

PubMed1979

Anticonvulsant drug-induced osteomalacia: alterations in mineral metabolism and response to vitamin D3 administration.

Parameters of mineral metabolism were examined in 6 patients with moderately severe anticonvulsant drug-induced osteomalacia. Compared to 15 matched controls, the patients exhibited significantly reduced serum calcium, inorganic phosphate, and 25-hydroxyvitamin D concentration, elevated serum alkaline phosphatase and immunoreactive parathyroid hormone (iPTH) concentration, reduced intestinal 47Ca absorption, reduced urinary calcium and increased urinary hydroxyproline excretion, and reduced forearm bone mass. Intestinal absorption of vitamin D3 was normal. Following 4 months of treatment with vitamin D3 (4000 units/day), serum 25-OHD concentration was increased to 3 times mean normal values and all parameters except serum iPTH, urinary calcium excretion, and forearm bone mass were returned to levels not significantly different from normal. Serum iPTH concentration was reduced by 39% (P less than 0.05); 24-h urinary calcium excretion rose by 98% (P less than 0.001), and forearm bone mass increased by 5.6% (P less than 0.05). It is concluded that moderate-dose vitamin D3 supplementation is effective in normalizing parameters of mineral metabolism in this disorder, despite evidence of resistance to the biologic effects of vitamin D.

Adult↗

PubMed1979

Reduced serum 25-hydroxyvitamin D concentration and disordered mineral metabolism in patients with cystic fibrosis.

Vitamin D and mineral metabolism were studied in 21 adolescents and young adults with cystic fibrosis and the results were compared to those in 21 matched controls. All CF patients had been maintained on standard multivitamin supplements in combination with pancreatic enzyme replacement. Despite this supplementation, relative to control subjects the CF patients had a 36% reduction in serum 25-hydroxyvitamin D concentration, a slight but significant reduction in serum calcium concentration, evidence of calcium malabsorption with secondary hyperparathyroidism, and a 14% decrease in bone mass measured by the photon absorption technique. Currently accepted modes of pancreatic enzyme replacement and vitamin D supplementation are often inadequate to maintain normal mineral homeostasis in CF patients; additional measurements may be required to reduce the risk of clinically significant osteopenia concomitant with prolonged survival in CF.

Adolescent↗

PubMed1979

Altered mineral metabolism in glucocorticoid-induced osteopenia. Effect of 25-hydroxyvitamin D administration.

Parameters of mineral and bone metabolism were studied in 17 patients treated chronically with supraphysiologic doses of glucocorticoids. When compared to 15 matched normal subjects, the patient group exhibited similar serum 25-hydroxyvitamin D (25-OHD) levels, decreased intestinal 47Ca absorption, increased serum immunoreactive parathyroid hormone, and decreased forearm bone mass. Iliac crest bone biopsies revealed a decreased bone formation rate and increased osteoclast number. Treatment with 25-OHD (mean dose 4.03 micrograms/d) and calcium (500 mg/d) in nine patients produced a 46% increase in 47Ca absorption (P less than 0.001) and a 54% decrease in serum immunoreactive parathyroid hormone (P less than 0.001) by 3 mo. In addition, by 12 mo the treatment group exhibited (a) a 13.2 +/- 5.1% increase in metaphyseal (P less than 0.001) and a 2.1 +/- 0.4% increase in diaphyseal (P less than 0.05) forearm bone mass, and (b) significant decreases in cortical and endosteal osteoclast number. Biochemical and bone mass changes persisted through 18 mo. No significant changes in any parameter occurred in eight control patients administered calcium 100 mg/d. It is concluded that treatment with 25-OHD and calcium can significantly improve parameters of mineral and bone metabolism in patients with glucocorticoid-induced osteopenia.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗

PubMed1978

Interaction of diphenylhydantoin (phenytoin) and phenobarbital with hormonal mediation of fetal rat bone resorption in vitro.

Chronic administration of high doses of anticonvulsant drugs frequently produces classic osteomalacia with bone histologic changes characteristic of increased parathyroid hormone (PTH) effect in man. However, several reports have documented defects in calcified tissue metabolism suggestive of an end-organ resistance to PTH after chronic anticonvulsant drug therapy. To examine the direct action of anticonvulsant drugs on bone resorption, we investigated the effects of diphenylhydantoin (phenytoin) (DPH) (100-200 mug/ml) and phenobarbital (10-400 mug/ml) on basal and hormonally mediated resorption 5-day cultures of fetal rat forelimb rudiments. In this system both drugs significantly inhibited basal and PTH-stimulated (45)Ca and [(3)H]hydroxyproline release, as well as 1,25-dihydroxyvitamin D(3)-stimulated (45)Ca release. The effects of DPH and phenobarbital were additive, with DPH exhibiting a several-fold more potent inhibitory effect than phenobarbital. Whereas DPH exhibited a striking synergism with the inhibitory effects of human calcitonin (HCT) on PTH-induced resorption, the effect of phenobarbital was merely additive to that of HCT. PTH and PTH plus HCT-induced increases in bone cyclic AMP (cAMP) content were significantly inhibited by DPH but not by phenobarbital. However, in contrast to effects on (45)Ca release, DPH inhibition of cAMP generation was not accentuated in the presence of HCT. It is concluded that: (a) both DPH and phenobarbital can directly inhibit basal and hormonally stimulated bone resorption, with DPH being much more potent in this regard; (b) DPH appears to inhibit bone resorption via a cAMP-independent mechanism and has an additional suppressive effect on PTH-induced cAMP generation; and (c) the synergistic interaction of DPH and HCT in inhibiting (45)Ca release occurs at a site independent of cAMP generation.

Animals↗

PubMed1977

Serum 25-hydroxyvitamin D concentrations in patients receiving chronic corticosteroid therapy.

Serum 25-hydroxyvitamin D (25OHD) concentrations were measured by competitive protein-binding assay in 21 patients who were receiving chronic prednisone therapy and who demonstrated radiologic osteopenia. Results were compared to values obtained in 19 matched non-steroid-treated control subjects. Serum 25OHD values in control and steroid-treated subjects were virtually identical and showed a similar positive correlation with vitamin D intake. To rule out possible assay interference by postulated steroid-induced abnormal vitamin D metabolites, 25OHD was specifically isolated from pooled extracts of control and steroid-treatment patient sera by silicic acid column chromatography. 25OHD levels were again identical in both groups, and there was no evidence of radioassayable abnormal metabolites. It is concluded that the maintenance of normal serum levels of 25OHD is not altered by chronic moderate dose corticosteroid therapy.

Adrenal Cortex Hormones↗

PubMed1975

Parathyroid hormone status and renal responsiveness in familial hypophosphatemic rickets.

Basal serum and urinary biochemical parameters and their response to PTH or calcium infusion were examined in 14 untreated patients with familial hypophosphatemic rickets (FHR) from 5 kindreds and 9 normal control subjects after a period of dietary equilibration. FHR subjects exhibited significantly elevated basal serum iPTH levels (FHR: 11.4 +/- 0.8, controls: 5.1 +/- 0.5 ng/ml, P less than 0.001) and urinary cAMP excretion (FHR: 7.83 +/- 0.81, controls: 3.78 +/- 0.46 nmol/mg creatinine P less than 0.001). In response to PTH infusion (6 units/kg over 4 hours) FHR subjects exhibited a mean 34% decrease in TRP and a 22-fold increase in cAMP excretion, both comparable to the control response. Calcium infusion (10 mg/kg over 1 h) rapidly suppressed serum iPTH and urinary cAMP values in FHR subjects. However, TRP remained inappropriately low for the level of serum phosphate. Basal and post-calcium infusion serum iPTH levels correlated positively with urinary cAMP in FHR subjects and controls. Pre- and post-calcium infusion iPTH levels correlated with serum calcium in FHR subjects. Mean Salivary phosphate concentration was significantly reduced in FHR subjects (FHR: 12.68 +/- 0.87, controls: 22.47 +/- 2.16 mg/100 ml, P less than 0.001). However, calculated salivary phosphate clearance rates were similar in FHR and control subjects. PTH or calcium infusion did not significantly alter salivary phosphate concentration or clearance rates in either patients or controls. We concluded that untreated FHR patients exhibit a state of mild secondary hyperparathyroidism and an at least normal renal phosphaturic response to PTH. In addition, there is no evidence for increased salivary phosphate excretion in FHR.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗

PubMedDate not supplied

Serum dihydroxyvitamin D metabolite concentrations in patients on chronic anticonvulsant drug therapy: response to pharmacologic doses of vitamin D2.

We examined the effects of chronic anticonvulsant drug administration on the serum concentrations of dihydroxyvitamin D metabolites and the response of these metabolite levels to short-term treatment with pharmacologic doses of vitamin D2. Twelve patients maintained on chronic combined diphenylhydantoin and phenobarbital therapy were studied before and after the administration of vitamin D2, 75,000 units/week for 6 weeks. Prior to vitamin D2 administration, the patient group demonstrated decreased serum calcium (P less than 0.01) and increased serum iPTH (P less than 0.02) concentrations relative to 18 matched controls. Serum 25OHD and 24,25(OH)2D concentrations in the patient group were reduced by 38% and 75% (P less than 0.001), while serum 1,25(OH)2D concentration was increased by 27% (P less than 0.05) relative to control values. After vitamin D administration serum calcium and iPTH concentrations in the patient group were restored to values that were not significantly different from control levels. Serum 25OHD and 24,25(OH)2D concentrations were increased by 4.6- and 6.3-fold, respectively, to supranormal levels. Serum 1,25(OH)2D concentration exhibited an unexpected further 30% increase over pretreatment values, resulting in a return of the serum 1,25(OH)2D/24,25(OH)2D concentration ratio to a normal value. These data indicate that in patients treated chronically with anticonvulsant drugs, serum 25OHD concentration responds appropriately to vitamin D2 administration, but regulation of renal dihydroxy metabolite formation may be altered.

25-Hydroxyvitamin D 2↗