cholecalciferol and maxacalcitol

Topics: Calcitriol; Cholecalciferol; Drug Design; Ergocalciferols; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Vitamin D

Topics: Adult; Aged; Aged, 80 and over; Calcitriol; Cholecalciferol; Dermatologic Agents; Dihydroxycholecalciferols; Female; Humans; Male; Middle Aged; Psoriasis; Treatment Outcome

Combining phototherapy with topical vitamin D3 analogues is a useful therapy for the treatment of psoriasis by reducing the cumulative UV dose required for clearance of lesions. Experimental investigations demonstrated that calcipotriol is degraded by UV radiation, and suggested that calcipotriol should be applied after phototherapy but not immediately before.. Calcipotriol or maxacalcitol ointment was topically applied to psoriatic plaques of six patients immediately before or after phototherapy on the right or left side of the body, respectively.. Topical application of vitamin D3 analogues either before or after irradiation by psoralen and UVA radiation (PUVA) or narrow-band (NB)-UVB showed exactly similar effects in all patients.. Therapeutic effects of vitamin D3 analogues are not clinically inactivated by subsequent irradiation with PUVA or NB-UVB phototherapy.

Topics: Administration, Cutaneous; Adult; Calcitriol; Cholecalciferol; Combined Modality Therapy; Dermatologic Agents; Female; Humans; Male; Middle Aged; Prospective Studies; Psoriasis; Severity of Illness Index; Treatment Outcome; Ultraviolet Therapy

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

The active form of vitamin D3 (1α,25(OH)2D3, also known as calcitriol) controls the expression of target genes via the vitamin D receptor (VDR). Vitamin D-dependent rickets type II (VDDRII) is a congenital disease caused by inactivating mutations in the VDR The condition is treated with high doses of calcitriol, but the therapeutic effects of other synthetic VD3 analogs have not yet been investigated. In the present study, we analyzed the transcriptional activity of seven different VD3 analogs with VDRs carrying ligand-binding domain mutations identified in VDDRII patients. Wild-type VDR (WT-VDR) and seven mutant VDRs were expressed in TSA201 human embryonic kidney cells, HepG2 human liver cancer cells, and MC3T3-E1 mouse calvaria cells, and their transcriptional activation with VD3 analogs were analyzed by performing transient expression assays, western blotting, and quantitative real-time PCR. The results demonstrated that falecalcitriol stimulated significantly higher transcriptional activation of the WT-VDR and some mutant VDRs than did calcitriol. Calcitriol showed almost no transcriptional activation of the VDR with the I268T mutation identified in a severe case of VDDRII, whereas falecalcitriol caused a dose-dependent increase in the activation of this mutant VDR. Our findings demonstrate that falecalcitriol has a VDR activation profile distinct from that of calcitriol and may exhibit therapeutic effects even on difficult-to-treat VDDRII cases resistant to calcitriol. It is also possible that VDDRII patients responding to high doses of calcitriol could be appropriately treated with low doses of falecalcitriol.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Animals; Calcitriol; Cell Line; Cholecalciferol; Gene Expression Regulation; Humans; Mice; Mutation; Promoter Regions, Genetic; Receptors, Calcitriol; RNA, Messenger; Transcription, Genetic

Psoriasis is a chronic inflammatory skin disease of unknown aetiology, and an active form of vitamin D(3) (1α,25-dihydroxyvitamin D(3)) and its analogues (VD3As) are widely used topical reagents for psoriasis treatment. Besides their well-known calcium homeostasis functions, VD3As have been shown to have various immune-modulating effects including the induction of thymic stromal lymphopoietin (TSLP), a master cytokine for inducing Th2 inflammation, in mouse models, but not yet in human psoriasis. VD3As also have been shown to induce cathelicidin, an antimicrobial peptide and strong inducer of innate immunity. Cathelicidin is overexpressed in psoriatic skin lesions; however, its role in this disease seems as yet inconclusive.. To clarify whether topical VD3As induce TSLP and cathelicidin, and to examine the modulation of expression patterns of related cytokines in human psoriatic lesions.. Skin biopsy samples from psoriatic lesions with or without VD3A treatment were subjected to immunohistochemical staining and quantitative reverse transcription-polymerase chain reaction analyses to measure the expression levels of various cytokines.. Significantly higher levels of TSLP, thymus and activation-related chemokine and CCR4 expression were observed in VD3A+ skin samples than in VD3A- samples. In contrast, significantly lower levels of interleukin (IL)-12/23 p40, IL-1α, IL-1β and tumour necrosis factor (TNF)-α expression were observed in the VD3A+ samples than in the VD3A- samples. Expression of cathelicidin was elevated in VD3A+ samples.. Topical VD3As induce TSLP and cathelicidin in psoriatic lesions, resulting in suppression of IL-12/23 p40, IL-1α, IL-1β and TNF-α, thereby ameliorating psoriatic plaques.

Topics: Administration, Cutaneous; Adult; Aged; Antimicrobial Cationic Peptides; Blotting, Western; Calcitriol; Cathelicidins; Cholecalciferol; Cytokines; Dermatologic Agents; Dihydroxycholecalciferols; Drug Therapy, Combination; Female; Humans; Interleukins; Male; Middle Aged; Psoriasis; Thymic Stromal Lymphopoietin; Tumor Necrosis Factor-alpha

Recently, epimerization of the hydroxyl group at C-3 has been identified as a unique metabolic pathway of vitamin D compounds. We measured C-3 epimerization activity in subcellular fractions prepared from cultured cells and investigated the basic properties of the enzyme responsible for the epimerization. C-3 epimerization activity was detected using a NADPH-generating system containing glucose-6-phosphate, NADP, glucose-6-phosphate dehydrogenase, and Mg(2+). The highest level of activity was observed in a microsomal fraction prepared from rat osteoblastic UMR-106 cells but activity was also observed in microsomal fractions prepared from MG-63, Caco-2, Hep G2, and HUH-7 cells. In terms of maximum velocity (V(max)) and the Michaelis constant (K(m)), 25-hydroxyvitamin D(3) [25(OH)D(3)] exhibited the highest specificity for the epimerization at C-3 among 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], 25(OH)D(3), 24,25-dihydroxyvitamin D(3) [24,25(OH)(2)D(3)], and 22-oxacalcitriol (OCT). The epimerization activity was not inhibited by various cytochrome P450 inhibitors and antiserum against NADPH cytochrome P450 reductase. Neither CYP24, CYP27A1, CYP27B1 nor 3(alpha-->beta)hydroxysteroid epimerase (HSE) catalyzed the epimerization in vitro. Based on these results, the enzyme(s) responsible for the epimerization of vitamin D(3) at C-3 are thought to be located in microsomes and different from cytochrome P450 and HSE.

Topics: Animals; Base Sequence; Calcitriol; Cations, Divalent; Cells, Cultured; Cholecalciferol; Cytochrome P-450 Enzyme System; Glucose-6-Phosphate; Glucosephosphate Dehydrogenase; Hydrogen-Ion Concentration; Isomerism; Magnesium; Microsomes; NADP; Osteoblasts; Racemases and Epimerases; Rats; Subcellular Fractions; Substrate Specificity; Time Factors

Recently, there have been many vitamin D3 analogues synthesized and tried in the treatment of psoriasis. In the experiments reported here we observed and compared their effects on normal and psoriatic epidermis in organ culture in vitro. We employed a new vitamin D3 analogue, 22-oxa-calcitriol (OCT), the effect of which was compared with that of calcitriol (1,25-D3). Both caused suppression of proliferation of normal and psoriatic epidermis, dependent upon concentration and culture time. Histologically, in the presence of the agents, degeneration started from the top of the epidermis downwards. This is the first report of cell degeneration as a direct effect of vitamin D. The nature of the degeneration was evaluated by electron microscopy (EM) and by the in situ nick end labeling technique (TUNEL), and these studies revealed that the degeneration involved necrosis rather than apoptosis. This in vitro method may be useful to assess the effectiveness of newly synthesized vitamin D3 analogues in the treatment of psoriasis.

Topics: Apoptosis; Bromodeoxyuridine; Calcitriol; Cholecalciferol; Dermatologic Agents; Dose-Response Relationship, Drug; Epidermis; Humans; Microscopy, Electron; Organ Culture Techniques; Psoriasis

Topical vitamin D3 has relatively recently been introduced for the treatment of psoriasis. Synthetic vitamin D3 analogues with a high potential for inducing differentiation of cells, but with a low hypercalcemic effect have recently been developed. One such synthetic analogue of 1,25-dihydroxyvitamin D3 (calcitriol), 22-oxacalcitriol (OCT), is a novel agent for the topical treatment of psoriasis. The activity of OCT in vitro was investigated and compared with that of a series of vitamin D3 analogues as to their ability to inhibit murine T lymphocyte proliferation stimulated by con-A, to suppress IL-6 and IL-8 production by keratinocytes stimulated with IL-1alpha and TNFalpha, and to inhibit AP-1- and NFkappaB-dependent reporter gene expression. OCT inhibited the proliferation of lymphocytes and suppressed IL-8 and IL-6 production by keratinocytes to the same extent as the other vitamin D3 analogues. It also inhibited AP-1- and NFkappaB-controlled luciferase activity to the same extent as the other vitamin D3 analogues, which demonstrates its mechanism of action in the suppression of inflammatory processes.

Topics: Animals; Calcitriol; Cell Division; Cholecalciferol; Concanavalin A; Humans; Immune System; Interleukin-6; Interleukin-8; Jurkat Cells; Keratinocytes; Lymphocytes; Mice; Mice, Inbred C3H; NF-kappa B; Transcription Factor AP-1; Transcription, Genetic

Four vitamin D3 analogues, 1 alpha,24(S)- and 1 alpha,24(R)-dihydroxy-22-oxavitamin D3 (5 and 6) and their 20(R)-epimers (7 and 8) were synthesized from the 20(S)-alcohol (10). In tests of activity to induce differentiation of human myeloid leukemia cells (HL-60) to macrophages, 5 showed comparable activity to 1 alpha,25-dihydroxy-22-oxavitamin D3 (OCT) (2), and the other three analogues (6, 7 and 8) were less active than OCT (2). The binding properties of these analogues to the chick embryonic intestinal 1 alpha,25-dihydroxyvitamin D3 (1) receptor were evaluated. Furthermore, 20(R)-OCT (9) was synthesized and its biological properties were compared with those of OCT(2) and the 20(R)-epimers (7 and 8).

Topics: Animals; Antineoplastic Agents; Calcitriol; Cell Differentiation; Chick Embryo; Cholecalciferol; Humans; Isomerism; Leukemia, Myeloid; Macrophages; Receptors, Calcitriol; Tumor Cells, Cultured

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

Six analogues of 1 alpha,25-dihydroxy-22-oxavitamin D3 (OCT) (2), 26,27-dimethyl OCT (5), 26,27-diethyl OCT (6), 24-norOCT (7), 24-homoOCT (8), 24-dihomoOCT (9), and 24-trihomoOCT (10) were synthesized from the 20(S)-alcohol (11) as the common starting material. In the activity inducing differentiation of human myeloid leukemia cells (HL-60) into macrophages, 26,27-dimethyl OCT (5) and 24-homoOCT (8) showed the highest activities. The binding properties of these analogues to the chick embryonic intestinal 1 alpha,25-dihydroxyvitamin D3 (1) receptor are also described.

Topics: Animals; Calcitriol; Cell Differentiation; Chick Embryo; Cholecalciferol; Intestines; Superoxides; Tumor Cells, Cultured

The effects of vitamin D3 and two analogues on embryonic angiogenesis were studied in 4.5-day-old chick embryo chorioallantoic membranes. The active metabolite of vitamin D3, 1 alpha,25-dihydroxyvitamin D3, and a synthetic vitamin D3 analogue, 22-oxa-1 alpha,25-dihydroxyvitamin D3, inhibited angiogenesis in a dose-dependent manner, the inhibition occurring in the picomolar range. In contrast, vitamin D3 was not effective. The results suggest that these two vitamin D3 analogues might be promising anti-angiogenic agents for controlling the angiogenesis which occurs in several pathological conditions, including tumor development.

Topics: Animals; Calcitriol; Chick Embryo; Cholecalciferol; Neovascularization, Pathologic

We examined the immunoregulating effect of 22-oxa-1 alpha,25-dihydroxyvitamin D3 (22-oxa-1 alpha,25(OH)2D3), a synthetic analogue of vitamin D3 with an oxygen atom at C22 in the side chain skeleton, on spontaneously developing autoimmune disorders in MRL/Mp-lpr/lpr (MRL/l) mice. The oral administration of the compound significantly prolonged the average life span of the mice and showed a significant reduction in proteinuria. Histopathological investigations also revealed that pathological conditions such as renal arteritis, granuloma or arthritis of the knee joints were much lighter in the treated group than in the untreated group. Furthermore, the lymphocyte phenotypes in thymus, lymphnode, and spleen were partially normalized and became similar to those found in young control animals by the treatment with 22-oxa-1 alpha,25(OH)2D3. These results suggest that this compound inhibits the development of lupus nephritis in MRL/l mice and may be therapeutically effective on the mice.

Topics: Animals; Antigens, Surface; Antineoplastic Agents; Autoimmune Diseases; Calcitriol; Cholecalciferol; Kidney; Knee Joint; Male; Mice; Mice, Inbred Strains; Organ Specificity; Proteinuria; Specific Pathogen-Free Organisms

The in vivo immunoregulating activity and the hypercalcemic action of 4 synthetic analogues of vitamin D3 with an oxygen atom in the side chain were compared with those of 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] in mice. Oral administration of these vitamin D3 compounds augmented the primary immune response, induced by immunization with a suboptimal number of sheep erythrocytes, without inducing hypercalcemia. The order of the in vivo potency to induce the immune response was 22-oxa-1 alpha,25(OH)2D3 greater than 1 alpha,25(OH)2D3 not equal to 20-oxa-1 alpha,25(OH)2D3 not equal to 22-oxa-1 alpha(OH)D3 greater than 1 alpha(OH)D3 not equal to 20-oxa-1 alpha(OH)D3. 22-Oxa-1 alpha,25(OH)2D3 was about 50 times more potent than 1 alpha,25(OH)2D3 in inducing the in vivo primary immune response, but the former was only 1/100 as active as the latter in inducing hypercalcemia. These results suggest that the immunoregulating activity of vitamin D compounds can be separated structurally from their hypercalcemic action in vivo.

Topics: Animals; Calcitriol; Calcium; Cholecalciferol; Dose-Response Relationship, Drug; Ergocalciferols; Female; Hypercalcemia; Immune System; Mice; Mice, Inbred BALB C