maxacalcitol and Vitamin-D-Deficiency

A strict control of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) is indicated to avoid serious complications linked to osteitis fibrosa and other parathyroid-hormone (PTH)-related bodily disturbances. However, such a control is often achieved only at the price of unacceptably high plasma calcium and phosphorus levels and the risk of soft tissue calcification, even when using the novel, so-called 'non-hypercalcemic' vitamin D analogs. The advent of a new class of drugs, the calcimimetics, should allow a more adequate control of the disturbed calcium-phosphorus metabolism in CKD patients. In my opinion, the calcimimetics will not replace currently used medications but will be a valuable supplement to presently available treatment options for this major complication in patients with renal failure.

Topics: Calcitriol; Cinacalcet; Clinical Trials as Topic; Drug Synergism; Ergocalciferols; Humans; Hydroxycholecalciferols; Hypercalcemia; Hyperparathyroidism, Secondary; Intestinal Absorption; Kidney Failure, Chronic; Liver; Naphthalenes; Phosphates; Receptors, Calcitriol; Receptors, Calcium-Sensing; Vitamin D; Vitamin D Deficiency

In dialysis patients, deficiency of calcitriol down regulates vitamin D receptor (VDR) and decreases density of Ca sensing receptor, resulting right shift of set point of extra cellular Ca concentrations to release of parathyroid hormone. And then, renal hyperparathyroidism occurs and progresses. The purpose of pulse therapy with calcitriol or its analogue is elevating extra cellular calcitriol level up to supra physiological level, which up regulates VDR and shift the set point to left. The extra cellular calcitriol level after injection of calcitriol cannot compare with the level after oral administration of calcitriol at the same dose. The left shift of set point is investigated 4 weeks after intravenous pulse therapy with calcitriol or maxacalcitol, and degree of shift to the left depends on the single dose of these medicines. There is another advantage of intravenous pulse therapy, which takes no account of drug compliance or existence of malabsorption of lipid soluble vitamins.

Topics: Calcitriol; Calcium; Humans; Hyperparathyroidism, Secondary; Infusions, Intravenous; Kidney Failure, Chronic; Parathyroid Hormone; Pulse Therapy, Drug; Receptors, Calcitriol; Receptors, Calcium-Sensing; Renal Dialysis; Up-Regulation; Vitamin D Deficiency

Vitamin D and its analogues are administered to patients with secondary hyperparathyroidism (SHPT) in chronic renal failure (CRF). Hypercalcemia is one of the complications of this therapy, and is thought to be not rare, though its frequency is not clearly documented. There is a need to monitor serum corrected (ionized) calcium concentration and parathyroid hormone (PTH) in order to administer vitamin D and its analogues safely. Intravenous administration of vitamin D provides advantages over oral administration, though no definite evidence could show which is better. Calcitriol and maxacalcitol are administered intravenously, and the latter is more likely to increase serum calcium concentration than the former. It must be very careful to administer vitamin D to patients with predialysis CRF because hypercalcemia can accelerate progression of renal dysfunction.

Topics: Administration, Oral; Calcitriol; Calcium; Drug Administration Schedule; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Infusions, Intravenous; Kidney Failure, Chronic; Monitoring, Physiologic; Parathyroid Hormone; Phosphorus; Pulse Therapy, Drug; Vitamin D; Vitamin D Deficiency

1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] is known to influence cell proliferation/maturation, whereas epidermal growth factor (EGF) is a potent stimulant of proliferation. Recently, hypocalcemia of vitamin D (D) deficiency was shown to significantly perturbe hepatic regeneration, which could be only partly restored by normalizing extracellular calcium, whereas normalization of 1,25-(OH)2D3 fully restored the process. To define the calcium- and/or D3-sensitive mechanisms associated with liver growth, a study of the initial events transduced by EGF was initiated by probing EGF receptor (EGFR) density and affinity, its subsequent autophosphorylation, and the level of its steady state transcript. Studies were carried out in D-depleted rats kept either untreated or supplemented with D3, 1,25-(OH)2D3, or calcium alone. The hepatic EGFR number (picomoles per mg microsomal protein) was significantly affected by hypocalcemic D-depleted (0.82 +/- 0.2), but responded with similar increases to calcium (1.7 +/- 0.09; P < 0.05), D3 (1.6 +/- 0.3; P < 0.05), and 1,25-(OH)2D3 (2.1 +/- 0.3; P < 0.01). The EGFR mRNA level revealed, however, no significant effect of the calcium or D3 status, indicating that posttranscriptional events were playing an important role. Phosphorylation studies showed that EGFR autophosphorylation and tyrosine protein kinase activity paralleled receptor density, with the lowest autophosphorylation values obtained in hypocalcemic D-depleted rats (D-depleted hypocalcemic vs. D3 repleted, P < 0.007). When normalized for receptor number, however, EGFR autophosphorylation increased in D-depleted hypocalcemic rats to a level comparable to that observed in all other groups. To dissociate the effect of the D3 hormone from that of calcium alone on EGFR, D-depleted rats were treated with the nonhypercalcemic 1,25-(OH)2D3 analog 22-OXA-1,25-(OH)2D3 (OCT), with or without calcium supplementation. Hypocalcemic OCT-treated rats did not exhibit any increase in EGFR number (0.6 +/- 0.1) compared to D-depleted hypocalcemic rats, but the addition of dietary calcium to OCT restored extracellular calcium concentrations and EGFR density (1.8 +/- 0.2; P < 0.002) to values comparable to those observed after D3 or 1,25-(OH)2D3 treatment. EGFR autophosphorylation was also decreased in hypocalcemic OCT-treated animals (P < 0.03), but after normalization for receptor density, full restoration of EGFR autophosphorylation was achieved. Our data demonstrate that in normal hepat

Topics: Animals; Calcitriol; Calcium; Cholecalciferol; Epidermal Growth Factor; ErbB Receptors; Female; Hypocalcemia; Liver; Male; Phosphorylation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transforming Growth Factor alpha; Vitamin D Deficiency

22-Oxacalcitriol (OCT) is one of several new analogs of vitamin D that retain many of the therapeutically useful properties of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], but have much less calcemic activity. In the present study we examined the actions of OCT on intestinal calcium absorption and calbindin D9k mRNA in vitamin D-deficient rats. After ip injection of OCT (1 microgram/kg), calcium absorption increased significantly by 2 h and was maximal at 4 h (2.5-fold above control), but returned to pretreatment levels by 16 h. In contrast, the same dose of 1,25-(OH)2D3 caused a 3-fold increase in calcium absorption, which lasted more than 48 h. The transient effect of OCT on calcium absorption was also observed when the analog was infused at a dose of 1 micrograms/kg.day for 3 days. At the end of the infusion period, calcium absorption was 3-fold higher than that in vehicle-infused controls, but fell to pretreatment levels by 24 h after removing the minipumps. The time courses for induction of calbindin D9k mRNA were similar for OCT and 1,25-(OH)2D3, with no change observed until more than 4 h after injection. However, calbindin mRNA levels returned to pretreatment values more rapidly in the OCT-treated rats. Consistent with these findings, we observed that a 1 microgram/kg dose of [3H] OCT was completely cleared by 4-6 h after injection. This was paralleled by a loss of [3H]OCT associated with the intestinal vitamin D receptor. The rapid clearance of OCT is probably due to its low affinity for the serum vitamin D-binding protein. This low affinity would also be expected to allow greater accessibility to target cells. In support of this, we found that higher amounts of OCT than 1,25-(OH)2D3 were associated with the intestinal vitamin D receptor after the injection of several doses of these tritiated ligands. In summary, our results indicate that the pharmacokinetic properties of OCT are responsible at least in part for its low calcemic activity. Furthermore, comparison of the transient elevation of calcium absorption by OCT with its more prolonged effects on PTH and calbindin D9k indicates that each action of vitamin D compounds has a distinct biological half-life. The short circulating half-life of OCT can exploit these differences to provide a therapeutic advantage in the treatment of vitamin D-responsive diseases.

Topics: Animals; Calbindins; Calcitriol; Calcium; Intestinal Absorption; Intestinal Mucosa; Intestines; Kinetics; Male; Rats; Rats, Sprague-Dawley; Receptors, Calcitriol; Receptors, Steroid; RNA, Messenger; S100 Calcium Binding Protein G; Vitamin D Deficiency

Protein binding properties of 22-oxa-1 alpha,25-dihydroxyvitamin D3 (22-oxa-1,25-D3), a synthetic analogue of 1 alpha,25-dihydroxyvitamin D3 (1,25-D3), were compared with those of vitamin D3 derivatives. The order of binding affinity to the chick embryonic intestinal receptor was 1,25-D3 greater than 22-oxa-1,25-D3 greater than 25-hydroxyvitamin D3 (25-D3) greater than 24R, 25-dihydroxyvitamin D3 (24, 25-D3) greater than vitamin D3 (D3), while that to the rat plasma vitamin D-binding protein (DBP) was 25-D3 greater than 24,25-D3 greater than D3 greater than 1,25-D3 greater than 22-oxa-1,25-D3. The binding potencies of 22-oxa-1,25-D3 to the receptor and DBP were about 1/8 and 1/600 of the respective values of 1,25-D3. When the distribution of the tritiated compounds in human plasma components was examined by an in vitro polyacrylamide gel electrophoretic method, [3H]-22-oxa-1,25-D3 was found to bind only to the lipoproteins including chyromicron. These results suggest that the replacement of a carbon atom into an oxygen atom in the side chain structure of 1,25-D3 results significant decrease in the binding affinity to DBP and that 22-oxa-1,25-D3 is transported as a complex-form not with DBP but with lipoprotein to the target tissues.

Topics: Animals; Binding, Competitive; Calcitriol; Chick Embryo; Humans; In Vitro Techniques; Kinetics; Receptors, Cell Surface; Vitamin D Deficiency; Vitamin D-Binding Protein