maxacalcitol and Body-Weight

Recent evidence suggests that 1α,25-dihydroxyvitamin D3 (calcitriol, VD3), the active form of vitamin D (VD), can inhibit the proliferation of microorganisms. In the present study, we conducted in vitro experiments and utilized in vivo murine models to investigate the antimalarial activity of VD3 and its analog, 22-oxacalcitriol (22-OCT), which was designed to cause less hypercalcemia than VD3. VD3 and 22-OCT treatments effectively resolved a Plasmodium chabaudi (Pc) infection in wild-type mice. Reduced parasitemia was observed during the acute phase of infection in the presence of VD3 and 22-OCT, followed by a delayed peak during the chronic stage of infection. Some anti-Pc activity was observed in VD receptor knockout (KO) mice. VD3 and 22-OCT also completely inhibited the proliferation of P. falciparum (Pf) in human red blood cells in vitro. Plasma levels of interferon (IFN)-γ in VD3-treated B10 and B6 mice were lower than those in vehicle-treated animals, and VD3 resolved a Pc infection in IFN-γ-KO mice, which greatly improved survival. These data suggest that the protective effects of VD3 are elicited through an IFN-γ-independent mechanism. Effective antiplasmodial doses of VD3 and 22-OCT resulted in a loss of body weight in mice. This loss in body weight occurred concomitantly with the development of hypercalcemia. Zoledronic acid partially attenuated VD3-induced hypercalcemia and abrogated the antiparasitic effects of VD3. This study highlights a potential therapeutic role for VD3 in the treatment of malarial infections and shows that hypercalcemia is excellent indicator of the antiplasmodial activity of VD3.

Topics: Acute Disease; Animals; Antimalarials; Body Weight; Calcitriol; Cholecalciferol; Chronic Disease; Diphosphonates; Erythrocytes; Humans; Hypercalcemia; Imidazoles; Interferon-gamma; Malaria; Mice; Mice, Inbred BALB C; Mice, Knockout; Parasitemia; Plasmodium chabaudi; Receptors, Calcitriol; Zoledronic Acid

We have previously reported the merits of chronopharmacological effect of 1-alpha(OH) vitamin D3 in aged stroke-prone spontaneously hypertensive rat (SHRSP), a model of osteoporosis [Eur. J. Pharmacol. 428 (2001) 283.]. In this study, the chronopharmacological effect of 22-oxacalcitriol, a newly developed active vitamin D3 analogue with less calcemic activity, was evaluated by a single and repeated dosing of the drug in aged SHRSP. Animals (7 months old) were kept in rooms with a 12-h light/dark cycle. Single (12.5 microg/kg, i.v.) and repeated (5 microg/kg, i.v. three times a week for 12 weeks) dosing of 22-oxacalcitriol or vehicle was given at either 2 h after lights on (2HALO) or 14 h after lights on (14HALO). The severity of adverse reactions such as the changes of body weight, hypercalcemia and hyperphosphatemia, was significantly mild when the drug was given at 14HALO. Especially, the increase of serum Ca concentration was not detected at 14HALO trial. Serum concentrations of total (protein-bound and unbound) 22-oxacalcitriol and albumin (a major binding protein of the drug) of the 2HALO and 14HALO trials did not significantly differ. The decrease of parathyroid hormone (PTH) concentration was greater in the 14HALO trial while the increase in urinary ratio of Ca to creatinine was greater in the 2HALO trial. The increase in bone density of both femurs at the end of the study was greater in the 14HALO trial. The suppression of urinary excretion of deoxypyridinoline, an index of bone resorption capacity of osteoclast, was greater in the 14HALO trial, which indicates that the efficacy of 22-oxacalcitriol for suppressing bone resorption might vary with the dosing time. This is the first study to show the dosing-time-dependent changes in the efficacy and toxicity of 22-oxacalcitriol in the animal model of osteoporosis. Chronopharmacological differences seem to be more prominent than those of other vitamin D analogues. To use 22-oxacalcitriol at an adequate timing might provide better efficacy and safety than other vitamin D3 analogues for the treatment of osteoporosis.

Topics: Absorptiometry, Photon; Amino Acids; Animals; Body Weight; Bone Density; Calcitriol; Calcium; Creatinine; Dose-Response Relationship, Drug; Male; Osteoporosis; Parathyroid Hormone; Phosphorus; Rats; Rats, Inbred SHR; Serum Albumin; Time Factors

Since Slatopolsky et al. (J Clin Invest 1984; 74: 2136-2143) reported the effect of active vitamin D, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), on secondary hyperparathyroidism (2HPT) which accompanies chronic renal failure, there have been several studies of the therapeutic effects of 1,25(OH)(2)D(3) in this disease. Although parathyroid hormone (PTH) is suppressed by treatment with 1,25(OH)(2)D(3), long-term treatment with 1,25(OH)(2)D(3) tends to induce hypercalcaemia. Therefore, an analogue of 1,25(OH)(2)D(3), 1,25-dihydroxy-22-oxavitamin D(3) (22-oxacalcitriol, OCT) with less calcaemic activity, was developed for the treatment of 2HPT.. In order to clarify the differences between the effects of 1,25(OH)(2)D(3) and OCT on 2HPT associated with chronic renal failure, these compounds were administered by intermittent i.v. injection for 2 weeks in rats with mild to moderate uraemia.. 1,25(OH)(2)D(3) markedly suppressed PTH levels, but increased serum calcium (Ca). OCT also markedly suppressed PTH levels, but induced only a slight increase in serum Ca. 1,25(OH)(2)D(3) caused a dose-dependent decrease in body weight, whereas OCT had no effect on body weight in uraemic rats. Based on those doses of OCT and 1,25(OH)(2)D(3), which resulted in a 60% suppression of PTH, and induced hypercalcaemia, we consider the relative ratios for efficacy and Ca-elevating activity between OCT and 1,25(OH)(2)D(3) to be 1 : 8 and 1 : 48, respectively.. OCT suppressed PTH levels with a slight increase in serum Ca without changing the body weight in uraemic rats. This observation suggests that OCT might be a useful vitamin D analogue for 2HPT management in long-term clinical treatment.

Topics: Animals; Body Weight; Calcitriol; Calcium; Kidney Failure, Chronic; Male; Nephrectomy; Parathyroid Hormone; Rats; Rats, Sprague-Dawley; Uremia

1,25-Dihydroxy-22-oxavitamin D(3) (22-oxacalcitriol, OCT) is an analogue of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3), calcitriol) with less calcaemic activity, thus more suitable than 1,25(OH)(2)D(3) for the control of parathyroid hormone (PTH) secretion in chronic dialysis patients. As the low-calcaemic action of OCT has been mainly attributed to its short half-life in the blood stream, the number of doses per week is the key factor to effective OCT therapy toward suppression of PTH secretion and hypercalcaemia. Thus, we investigated a comparison between daily and thrice-weekly i.v. administration of OCT regarding suppression of PTH secretion and calcaemic action in 5/6 nephrectomized rats as a model for chronic renal failure.. Model rats of chronic renal failure were made by 5/6 nephrectomy. At 3 months after surgery, they were administered either vehicle or OCT intravenously, daily (0.125 or 0.625 microg/kg) or thrice-weekly (0.6 or 3.0 microg/kg) for 2 weeks.. The data show that 0.625 microg/kg/day (=4.375 microg/kg/week) suppresses PTH secretion with significant increase in calcium levels at 24 h after the final administration, on the other hand, 3.0 microg/kg/ thrice-weekly (=9.0 microg/kg/week) suppresses PTH secretion, although moderate compared with 0.625 microg/kg/day, with a slight (not significant) increase in calcium.. The current clinical mode of OCT therapy, i.v. thrice-weekly administration, is a practically recommendable protocol.

Topics: Animals; Blood Urea Nitrogen; Body Weight; Calcitriol; Calcium; Creatinine; Disease Models, Animal; Drug Administration Schedule; Injections, Intravenous; Male; Nephrectomy; Parathyroid Hormone; Phosphates; Rats; Rats, Sprague-Dawley; Uremia

Using a mouse model (Hyp) of human hypophosphatemic vitamin D-resistant rickets [X-linked hypophosphatemia (XLH)], we compared the effects of 22-oxa-1,25-dihydroxyvitamin D3 (OCT) and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on restoring defects in mineral and skeletal metabolism. Hyp/Y mice received OCT or 1,25(OH)2D3 at doses of 0.05-0.25 micron.kg-1.day-1 for 4 wk. OCT normalized serum calcium levels, whereas 1,25(OH)2D3 produced hypercalcemia in Hyp/Y. OCT and 1,25(OH)2D3 also normalized serum phosphate levels and increased urinary calcium levels. Additionally, OCT and 1,25(OH)2D3 reduced elevated urinary pyridinoline levels and suppressed urinary adenosine 3',5'-cyclic monophosphate levels to normal. Bone ash content was low in Hyp/Y, and OCT was more effective than 1,25(OH)2D3 in reversing this defect. Histomorphometric analysis of bone turnover, mineralization rate, and osteoid content demonstrated comparable responses with OCT and 1,25(OH)2D3, although the highest dose of 1,25(OH)2D3 resulted in increased osteoid content and delayed mineralization. OCT appears to be more effective and definitely less toxic than 1,25(OH)2D3 in reversing skeletal lesions in Hyp/Y mice and may prove to be the drug of choice in the treatment of childhood XLH.

Topics: Animals; Blood; Body Weight; Bone and Bones; Calcitriol; Genetic Linkage; Hypophosphatemia; Male; Mice; Mice, Inbred C57BL; Urine; X Chromosome

The effects of a new derivative of vitamin D3, 22-oxa-1 alpha,25-dihydroxyvitamin D3 (OCT), on rheumatoid arthritis was investigated using collagen-induced arthritis in rat, as an experimental model of the disease. Peroral administration of OCT significantly suppressed the incidence of arthritis and inhibited hind-paw-swelling. The levels of IgM and IgG antibodies against Type II collagen in sera were found to decrease in the OCT treated-group. The production of immunoglobulin against Type II collagen from rat spleen cells was also decreased in this group. These immunological effects of OCT on collagen-induced arthritis were more remarkable than those of 1 alpha-hydroxyvitamin D3. These findings indicated that OCT may have a therapeutic value as an immunoregulatory agent for patients with rheumatoid arthritis through inhibition of the autoimmune response to Type II collagen.

Topics: Administration, Oral; Animals; Antibody Formation; Arthritis, Rheumatoid; Autoantibodies; Body Weight; Calcitriol; Collagen; Disease Models, Animal; Male; Rats; Rats, Inbred Lew

The effect of 22-oxa-1 alpha,25-dihydroxyvitamin D3 (22-oxa-1,25(OH)2D3) on the growth of autochthonous rat mammary tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) was examined on the basis of our previous finding that this synthetic vitamin D3 analog has a potent angiogenesis inhibitory effect. Two doses of 22-oxa-1,25(OH)2D3, 0.1 and 1 microgram/kg of body weight, due to the limited amount of the compound available, were used. The daily administration of 22-oxa-1,25(OH)2D3 at the dose of 1 microgram/kg/day resulted in significant inhibition of the growth of these mammary tumors at 1, 2 and 3 weeks after the administration of this agent, although the agent caused little or no regression of the tumors. After daily administration for 3 weeks, a significant antitumor effect was also observed in the group treated with 0.1 microgram/kg/day. Treatment with 22-oxa-1,25(OH)2D3 did not affect the serum calcium levels in the treated rats. The lower dose of 22-oxa-1,25(OH)2D3 neither affected weight gain nor caused a decrease in body weight, while the higher dose, although having some effect on weight gain, did not induce a decrease in body weight. There were no significant differences in the weights of adrenals, uteri and ovaries between the treated groups and controls. These results suggest that 22-oxa-1,25(OH)2D3 has a significant growth inhibitory effect on DMBA-induced autochthonous mammary tumors in rats, without producing severe side effects, including hypercalcemic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Body Weight; Calcitriol; Calcium; Female; Mammary Neoplasms, Experimental; Neovascularization, Pathologic; Organ Size; Rats; Rats, Inbred Strains