1-alpha-24-dihydroxyvitamin-d3 and calcipotriene

The treatment of vitiligo is still one of the most difficult dermatological challenges, although there are many therapeutic options. Narrow band ultraviolet B (NB-UVB) phototherapy is considered to be a very important modality for generalized vitiligo.. The aim of this study was to explore whether a combination of NB-UVB and topical agents would be superior to NB-UVB alone for treating vitiligo.. We searched the electronic databases such as PUBMED, EMBASE, Cochrane Library, and Web of Science. The primary outcome was the proportion of ≥50% repigmentation (a clinical significance), and secondary outcome was the proportion of ≥75% repigmentation (an excellent response).. Seven randomized controlled trials (RCTs) involving 240 patients (413 lesions) were included in this meta-analysis. The study showed no significant difference between NB-UVB combination therapy (NB-UVB and topical calcineurin inhibitor or vitamin D analogs) and NB-UVB monotherapy in the outcomes of ≥50% repigmentation and ≥75% repigmentation. However, lesions located on the face and neck had better results in ≥50% repigmentation (RR = 1.40, 95% CI 1.08-1.81) and ≥75% repigmentation (RR = 1.88, 95% CI 1.10-3.20) with NB-UVB and topical calcineurin inhibitor combination therapy vs. NB-UVB monotherapy.. The meta-analysis suggested that adding neither topical calcineurin inhibitors nor topical vitamin-D3 analogs on NB-UVB can yield significantly superior outcomes than NB-UVB monotherapy for treatment of vitiligo. However, addition of topical calcineurin inhibitors to NB-UVB may increase treatment outcomes in vitiligo affecting face and neck.

Topics: Administration, Cutaneous; Calcineurin Inhibitors; Calcitriol; Chemoradiotherapy; Dermatologic Agents; Dihydroxycholecalciferols; Facial Dermatoses; Humans; Neck; Randomized Controlled Trials as Topic; Skin Pigmentation; Tacrolimus; Ultraviolet Therapy; Vitamin D; Vitiligo

Topics: Adult; Antibodies, Monoclonal; Calcitriol; Dermatologic Agents; Dihydroxycholecalciferols; Fumarates; Humans; Psoriasis; Ultraviolet Therapy; Vitamins

Within the past decade it has been shown that psoriasis can be treated topically with analogs of vitamin-D3. Impaired differentiation and increased proliferation of keratinocytes are key features in psoriatic lesions together with a local activation of T lymphocytes. Evidence has accumulated showing that analogs of vitamin D3 increase differentiation and inhibit proliferation of keratinocytes. Therefore, analogs of vitamin D3 have been investigated in a number of trials showing improvement of psoriasis. It has been shown that vitamin D analogs are better than their vehicle and show the same potency as potent topical steroids. However, vitamin D analogs have been proven efficacious and without side effects also when used on long term basis. Vitamin D analogs can be used both as monotherapy and in combination topical steroids, UVB, PUVA, retinoids and cysclosporine. The vitamin D3 analog calcipotriol has been investigated in most detail and is available as an ointment, a creme and as a scalp solutation. From clinical studies involving thousands of patients, it can be concluded that calcipotriol is efficacious, safe, well tolerated and can be used on a long term basis. Other analogs are available, however, these analogs have not been studied in greater details yet.

Topics: Calcitriol; Cholecalciferol; Dermatologic Agents; Dihydroxycholecalciferols; Drug Therapy, Combination; Humans; Psoriasis

Vitamin D3 analogs interfere with various aspects of epidermal growth, inflammation, and cellular differentiation. Most data are derived from in vitro studies. In the present review, the in vivo effects of vitamin D3 analogues on the psoriatic plaque are discussed. Calcipotriol, tacalcitol, and calcitriol in ointment modulate aspects of epidermal growth, differentiation, and inflammation. Immunohistochemical studies suggest that the inflammatory changes might be more expressed after treatment with calcitriol and tacalcitol. Flow cytometric quantification of the percentage of cells in SG2M phase and of keratin 10-positive cells revealed that calcipotriol reduced both indices significantly during treatment of psoriatic plaques. Flow cytometric analysis of epidermal cell suspensions using triple labeling for epidermal proliferation, expression of keratin 10, and vimentin permits a quantitative assessment of DNA synthesis selectively in the basal cells of the epidermis, an estimation of the distribution of the basal and suprabasal compartments, and a quantification of the distribution of mesenchymal and nonmesenchymal cells. Using this approach, the interference of tacalcitol with growth control of basal cells was demonstrated. Remarkably, recompartmentalization of basal and suprabasal cells and mesenchymal and nonmesenchymal cells proved to be inconspicuous during this treatment.

Topics: Calcitriol; Dihydroxycholecalciferols; Epidermis; Flow Cytometry; Humans; Immunohistochemistry; Inflammation; Psoriasis

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

This pilot randomized intra-patient side to side trial was designed to assess the antipsoriatic efficacy, safety and tolerability of once daily versus the separate application of a vitamin D3 analogue and a powerful corticosteroid.. Twenty patients with plaque type psoriasis were enrolled. Two similar symmetrical lesions were randomized to be treated with an application of an ointment containing calcipotriol 50 µg/g plus betamethasone dipropionate 0.5 mg/g once daily or the application of budesonide 0.25 mg/g cream in the morning and tacalcitol 4 µg/g ointment in the evening.. Eighteen patients completed the study. Both treatments proved to be effective but budesonide cream and tacalcitol ointment gave a faster improvement of lesions and itching relief at t1 and were better tolerated.. The separate daily regimen may represent a suitable treatment option for patients who need a faster improvement and a better moisturizing activity. Further studies which compare the efficacy and safety of these regimens need to be developed.

Topics: Administration, Cutaneous; Adult; Aged; Betamethasone; Budesonide; Calcitriol; Dermatologic Agents; Dihydroxycholecalciferols; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Ointments; Pruritus; Psoriasis; Time Factors; Young Adult

Three high-concentration vitamin D3 ointments are currently available in Japan for the treatment of psoriasis. The aim of the present study is to investigate the efficacy of high-concentration tacalcitol in patients with psoriasis vulgaris who have already been treated with another high-concentration vitamin D3 ointment, calcipotriol or maxacalcitol. The psoriasis area and severity index score was improved in more than half the patients after changing to the tacalcitol ointment. Many patients treated with maxacalcitol once a day achieved greater clinical improvement by changing to high-concentration tacalcitol. In contrast, some patients who had responded to a high-concentration tacalcitol ointment showed exacerbation after changing to maxacalcitol once a day. Interviews with 50 patients (including the 34 patients enrolled in the present study) indicated that high-concentration tacalcitol ointment was an acceptable therapy in terms of the number of daily applications and drug cost. The results of this clinical study suggest that high-concentration tacalcitol ointment meets the preference of many patients who wish to use an ointment once a day.

Topics: Calcitriol; Dihydroxycholecalciferols; Drug Administration Schedule; Humans; Ointments; Patient Acceptance of Health Care; Prescription Fees; Psoriasis; Severity of Illness Index; Treatment Outcome

Daivobet is a once-daily treatment of psoriasis vulgaris containing betamethasone dipropionate and calcipotriol in a new ointment vehicle.. To assess the cost-effectiveness of once-daily treatment with Daivobet (4 weeks) followed by calcipotriol (4 weeks) compared to tacalcitol (8 weeks).. Resource utilization was assessed within a double-blind 8-week clinical trial (all treatments for psoriasis, adverse events and concomitant dermatological medication), estimated from the French societal perspective.. Total direct medical costs for psoriasis were comparable (Daivobet: EUR 107.53 and tacalcitol EUR 113.50) despite a higher acquisition cost for Daivobet. The probability of > or =75% reduction in the Psoriasis Area and Severity Index (effectiveness criterion) was 46.6% with Daivobet and 13.9% with tacalcitol at 4 weeks, and 44.6 and 23.8%, respectively, at 8 weeks (both: p < 0.001). Over 8 weeks, Daivobet was almost twice as cost-effective as tacalcitol (EUR 241.22 per successful treatment vs. EUR 476.70); this result was robust to sensitivity assumptions.. Daivobet is more effective and less costly than tacalcitol for treating psoriasis.

Topics: Administration, Topical; Adult; Aged; Betamethasone; Calcitriol; Confidence Intervals; Cost-Benefit Analysis; Dihydroxycholecalciferols; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Drug Costs; Europe; Female; Follow-Up Studies; Humans; Male; Middle Aged; Ointments; Probability; Psoriasis; Reference Values; Risk Factors; Severity of Illness Index; Treatment Outcome

A two-compound product containing calcipotriol 50 microg/g and betamethasone dipropionate 0.5 mg/g (Daivobet, Dovobet) has been demonstrated to be an effective, once daily, treatment for psoriasis vulgaris.. To compare the efficacy and safety of treatment with the two-compound product for 4 weeks followed by calcipotriol for 4 weeks, with that of tacalcitol for 8 weeks in patients with stable psoriasis vulgaris.. 501 patients were randomised to double-blind treatment with the two-compound product followed by calcipotriol 50 microg/g once daily, or to tacalcitol 4 microg/g once daily.. Treatment with the two-compound product/calcipotriol was significantly more effective than tacalcitol in terms of mean percentage PASI reduction (65.0 vs. 33.3% at week 4 and 59.0 vs. 38.4% at week 8; p < 0.001 for both).. A treatment regimen comprising calcipotriol/betamethasone ointment (Daivobet) for 4 weeks followed by calcipotriol for 4 weeks is superior to tacalcitol ointment for 8 weeks in patients with psoriasis vulgaris.

Topics: Administration, Topical; Adolescent; Adult; Betamethasone; Calcitriol; Confidence Intervals; Dihydroxycholecalciferols; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Middle Aged; Odds Ratio; Prospective Studies; Psoriasis; Reference Values; Risk Assessment; Severity of Illness Index; Statistics, Nonparametric; Treatment Outcome

Psoriasis is an immunogenetic disorder. Factor XIIIa+ dermal dendrocytes (DD) are part of the pathobiological changes in the plaque type of the disease.. The present study aimed at comparing the effect of 3 vitamin D(3) derivatives on the epidermis, microvasculature and DD in psoriasis.. Twenty men suffering from chronic plaques of psoriasis on the trunk were enrolled in this study. They applied twice a day for 3 weeks calcipotriol, tacalcitol and calcitriol, each to one plaque. Another similar lesion received petrolatum as a placebo treatment. Skin biopsies were taken at entry and at completion of the 3-week treatment phase. Immunohistochemistry was performed using the lectin of Ulex europaeus and an antibody to factor XIIIa. Computerized image analysis served to measure the stratum Malpighii area, the microvasculature area and the DD numerical density in the papillary dermis.. At entry in the study, the 4 test sites were indistinguishable with regard to the stratum Malpighii area, the papillary microvasculature area and the papillary DD density. The 3 histometric parameters appeared correlated with each other. At completion of the 3-week treatment phase, the 3 vitamin D derivatives had decreased the size of the stratum Malpighii. In addition, calcitriol had also reduced the DD density in the papillary dermis. No other significant changes were yielded.. As assessed by histometry, the psoriatic epidermis responded to a short treatment using the 3 vitamin D derivatives. The better result compared to the control site was achieved by calcitriol. DD appeared to be most controlled by the same drug. The microvasculature did not appear to be decreased at the 3-week time point in treatment.

Topics: Adult; Calcitriol; Calcium Channel Agonists; Dermatologic Agents; Dihydroxycholecalciferols; Humans; Male; Psoriasis; Statistics, Nonparametric

Once daily topical treatment of psoriasis with tacalcitol ointment (4 micrograms/g) was compared with twice daily treatment with calcipotriol ointment (50 micrograms/g) in a double-blind, randomized study over a treatment period of 8 weeks. The severity of pruritus, erythema, infiltration and scaling was scored on a scale from 0 to 4. These features were scored at the initiation of treatment, after 2, 4, 6 and 8 weeks of treatment, and at 4 weeks after discontinuation of treatment. The sum score was the total score for erythema, infiltration and scaling. Serum levels of calcium, phosphate, ionized calcium and intact parathyroid hormone were used as safety parameters. Two hundred and eighty-seven adults with stable plaque psoriasis participated and were treated at least once. Both tacalcitol and calcipotriol ointments effectively reduced the severity of psoriasis. The mean reduction in the sum score in the intention-to-treat population of 287 patients was 4.03 in the group treated with tacalcitol compared with 5.05 in the group treated with calcipotriol. The mean baseline sum scores were 7.64 and 7.15, respectively. The acceptability of both ointments was excellent, and none of the patients had adverse effects in terms of increased serum calcium or other alterations in calcium metabolism. Although less effective than calcipotriol ointment used twice daily, tacalcitol ointment is an effective and useful once daily treatment of chronic plaque psoriasis.

Topics: Adolescent; Adult; Aged; Calcitriol; Calcium; Dermatologic Agents; Dihydroxycholecalciferols; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Patient Satisfaction; Psoriasis; Severity of Illness Index; Treatment Outcome

Topics: Animals; Calcitriol; Dihydroxycholecalciferols; Dog Diseases; Dogs; Skin Cream

Topics: Anastrozole; Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Calcitriol; Dihydroxycholecalciferols; Female; Humans; MCF-7 Cells; Mice; Mice, SCID; Xenograft Model Antitumor Assays

Low vitamin D status is considered as a risk factor for breast cancer and has prognostic significance. Furthermore, vitamin D deficiency increases after adjuvant cancer therapy, which alters bone metabolism increasing the risk of osteoporosis. It is now postulated that vitamin D supplementation in breast cancer treatment delays the recurrence of cancer thereby extending survival. We evaluated the impact of calcitriol and its low-calcemic analogs, PRI‑2191 and PRI‑2205, on the tumor growth, angiogenesis, and metastasis of 4T1 mouse mammary gland cancer. Gene expression analysis related to cancer invasion/metastasis, real‑time PCR, ELISA, western blotting, and histochemical studies were performed. In vitro studies were conducted to compare the effects of calcitriol and its analogs on 4T1 and 67NR cell proliferation and expression of selected proteins. Calcitriol and its analogs increased lung metastasis without influencing the growth of primary tumor. The levels of plasma 17β-estradiol and transforming growth factor β (TGFβ) were found to be elevated after treatment. Moreover, the results showed that tumor blood perfusion improved and osteopontin (OPN) levels increased, whereas vascular endothelial growth factor (VEGF) and TGFβ levels decreased in tumors from treated mice. All the studied treatments resulted in increased collagen content in the tumor tissue in the early step of tumor progression, and calcitriol caused an increase in collagen content in lung tissue. In addition, in vitro proliferation of 4T1 tumor cells was not found to be affected by calcitriol or its analogs in contrast to non-metastatic 67NR cells. Calcitriol and its analogs enhanced the metastatic potential of 4T1 mouse mammary gland cancer by inducing the secretion of OPN probably via host cells. In addition, OPN tumor overexpression prevailed over the decreasing tumor TGFβ level and blood vessel normalization via tumor VEGF deprivation induced by calcitriol and its analogs. Moreover, the increased plasma TGFβ and 17β-estradiol levels contributed to the facilitation of metastatic process.

Topics: Animals; Calcitriol; Cell Growth Processes; Cell Line, Tumor; Dihydroxycholecalciferols; Female; Lung Neoplasms; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Neovascularization, Pathologic; Real-Time Polymerase Chain Reaction; Tumor Microenvironment

The active form of vitamin D (1α,25-dihydroxyvitamin D) acts as a steroid hormone and binds to the vitamin D receptor. This receptor is expressed in most cell types including cells in the central nervous system (CNS). Vitamin D has several functions in the body including effects on brain development, neuroprotection and immunological regulation. It has been shown that vitamin D has antiproliferative activities in different cancer cell lines. Tacalcitol and calcipotriol are synthetic analogues of 1α,25-dihydroxyvitamin D with reduced effect on calcium metabolism. The aim of this study was to analyse the effects of tacalcitol and calcipotriol on cell viability, proliferation and migration in the human glioblastoma cell line T98G. Glioblastoma is the most lethal type of primary tumours in the CNS. Both analogues decreased cell viability and/or growth, dose-dependently, in concentrations between 1 nM and 10 μM. Manual counting indicated suppressive effects by the vitamin D analogues on proliferation. Treatment with tacalcitol strongly suppressed thymidine incorporation, indicating that the vitamin D analogues mainly inhibit proliferation. Also, effects on cell migration were measured with wound-healing assay. Both calcipotriol and tacalcitol reduced the migration rate of T98G cells compared to vehicle-treated cells. However, they had no effect on caspase-3 and -7 activities, suggesting that their mechanism of action does not involve induction of apoptosis. The current results indicate that the vitamin D analogues tacalcitol and calcipotriol strongly reduce proliferation and migration of human glioblastoma T98G cells, suggesting a potential role for this type of compounds in treatment of brain cancer.

Topics: Antineoplastic Agents; Calcitriol; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Dihydroxycholecalciferols; Drug Evaluation, Preclinical; Glioblastoma; Humans; Receptors, Calcitriol

In our previous study, calcitriol and its analogs PRI-2191 and PRI-2205 stimulated 4T1 mouse mammary gland cancer metastasis. Therefore, we aimed to analyze the inflammatory response in 4T1-bearing mice treated with these compounds. Gene expression analysis of the splenocytes and regional lymph nodes demonstrated prevalence of the T helper lymphocytes (Th2) response with an increased activity of regulatory T (Treg) lymphocytes in mice treated with these compounds. We also observed an increased number of mature granulocytes and B lymphocytes and a decreased number of TCD4⁺, TCD4⁺CD25⁺, and TCD8⁺, as well as natural killer (NK) CD335⁺, cells in the blood of mice treated with calcitriol and its analogs. Among the splenocytes, we observed a significant decrease in NK CD335⁺ cells and an increase in TCD8⁺ cells. Calcitriol and its analogs decreased the levels of interleukin (IL)-1β and IL-10 and increased the level of interferon gamma (IFN-γ) in the plasma. In the tumor tissue, they caused an increase in the level of IL-10. Gene expression analysis of lung tissue demonstrated an increased level of osteopontin (

Topics: Animals; B-Lymphocytes; Calcitriol; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cells, Cultured; Dihydroxycholecalciferols; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Granulocytes; Immunosuppressive Agents; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Osteopontin; Real-Time Polymerase Chain Reaction; Transforming Growth Factor beta

Vitamin D analogues and NBUVB phototherapy are both well-established modalities of treatment in psoriasis. The objective of this open label, intraindividual, left right study was to compare two different vitamin D analogues, calcipotriol and tacalcitol, in combination with NBUVB phototherapy in chronic stable plaque psoriasis.. Thirty patients with stable plaque psoriasis were enrolled for a 12-week clinical trial. The target lesion on left side was treated topically with tacalcitol ointment once daily, while that on the right side was treated with calcipotriol ointment twice daily. NBUVB phototherapy was given thrice weekly. Efficacy was assessed by target plaque scoring.. Both therapies resulted in statistically significant reduction in erythema, scaling, thickness and target plaque score, seen as early as 2 weeks into therapy. However, calcipotriol combination led to an earlier clearance of plaques and a lesser relapse rate than tacalcitol combination. The number of treatment sessions and cumulative NBUVB doses were significantly lower in the calcipotriol-treated group.. Both vitamin D analogues appear to be safe, effective and cosmetically acceptable, calcipotriol being more efficacious, well tolerated with a rapid onset of action and a better maintenance of response.

Topics: Adult; Calcitriol; Combined Modality Therapy; Dermatologic Agents; Dihydroxycholecalciferols; Female; Humans; Male; Ointments; Prospective Studies; Psoriasis; Severity of Illness Index; Ultraviolet Therapy; Young Adult

This study was aimed to determine whether hypocalcemic analogs of active forms of vitamins D modulate expression of genes related to stem-like phenotype in colon cancer cell lines HT-29 and HCT-116 undergoing renewal after the treatment with 5-fluorouracil (5-FU). Both lines express vitamin D receptor, but differ in differentiation stage and vitamin D sensitivity. Cells that resisted the 5-FU exposure were treated with synthetic analog of 1,25-dihydroxyvitamin D2 (PRI-1906) and analogs of 1,25-dihydroxyvitamin D3 (PRI-2191 and PRI-2205). Proliferative activity was more profoundly affected by vitamin D analogs in HT-29/5-FU than in HCT-116/5-FU cells. In HT-29/5-FU cells, analogs PRI-1906 and PRI-2191 downregulated the expression of genes related to survival, re-growth, and invasiveness during renewal, while PRI-2205 increased expression of genes related to differentiation only. In HCT-116/5-FU cells, PRI-2191 decreased the expression of stemness- and angiogenesis-related genes, whereas PRI-1906 augmented their expression. The effects in HCT-116/5-FU cells were observed at higher concentrations of the analogs than those used for HT-29/5-FU cells. Out of the series of analogs studied, PRI-2191 might be used to counteract the renewal of both moderately and poorly differentiated cancer cells following conventional treatment.

Topics: Antimetabolites, Antineoplastic; Calcitriol; Cell Self Renewal; Cell Survival; Colonic Neoplasms; Dihydroxycholecalciferols; Drug Resistance, Neoplasm; Drug Synergism; Epithelial-Mesenchymal Transition; Ergocalciferols; Fluorouracil; Gene Expression; HCT116 Cells; HT29 Cells; Humans; Neoplastic Stem Cells; Neovascularization, Pathologic

Topics: Administration, Cutaneous; Anti-Inflammatory Agents; Attitude of Health Personnel; Betamethasone; Calcitriol; Clobetasol; Dihydroxycholecalciferols; Dose-Response Relationship, Drug; Drug Prescriptions; Gels; Humans; Immunosuppressive Agents; Medication Adherence; Practice Patterns, Physicians'; Psoriasis

In the present study, we evaluated the antitumor effect of two synthetic analogs of vitamin D, namely PRI-2191 [(24R)-1,24-dihydroxyvitamin D3] and PRI-2205 (5,6-trans calcipotriol), in combined human colon HT-29 cancer treatment with 5-fluorouracil (5-FU). Mice bearing HT-29 tumors transplanted subcutaneously or orthotopically were injected with vitamin D analogs and 5-FU in various schedules. A statistically significant inhibition of subcutaneous or orthotopic tumor growth was observed as a result of combined therapy. In HT-29 tumors and in cells from in vitro culture, we observed increased vitamin D receptor (VDR) expression after treatment with either PRI-2205 or 5-FU alone, or in combination. Moreover, PRI-2205 decreased the percentage of cells from intestinal tumors in G2/M and S stages and increased sub-G1. Increased VDR expression was also observed after combined treatment of mice with 5-FU and PRI-2191. Moreover, our docking studies showed that PRI-2205 has stronger affinity for VDR, DBP and CAR/RXR ligand binding domains than PRI-2191. PRI-2191 analog, used with 5-FU, increased the percentage of subcutaneous tumor cells in G0/G1 and decreased the percentage in G2/M, S and sub-G1 populations as compared to 5-FU alone. In in vitro studies, we observed increased expression of p21 and p-ERK1/2 diminution via use of both analogs as compared to use of 5-FU alone. Simultaneously, PRI-2191 antagonizes some pro-apoptotic activities of 5-FU in vitro. However, in spite of these disadvantageous effects in terms of apoptosis, the therapeutic effect expressed as tumor growth retardation by PRI-2191 is significant. Our results suggest that the mechanism of potentiation of 5-FU antitumor action by both analogs is realized via increased p21 expression and decreased p-ERK1/2 level which may lead to diminution of thymidylate synthase expression. Higher binding affinity for VDR, DBP, but also for CAR\\RXR ligand binding domain of PRI-2205 may, in part, explain its very low toxicity with sustained anticancer activity.

Topics: Animals; Antimetabolites, Antineoplastic; Calcitriol; Cell Cycle; Colonic Neoplasms; Dihydroxycholecalciferols; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Mice; Mice, Inbred NOD; Receptors, Calcitriol; Signal Transduction; Vitamin D; Xenograft Model Antitumor Assays

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

The synthesis of the clinically important drug calcipotriol (2, MC903) is described as an example of a new and efficient approach to C24-hydroxylated analogs and metabolites of vitamin D3 (1). The key step of the process is the generation of the C24 stereocenter by DAIB [(-)-3-exo-(dimethylamino)isoborneol]-catalyzed addition of the alkenylzinc derivative of alkyne 3 to cyclopropylcarboxaldehyde.

Topics: Alcohols; Calcitriol; Catalysis; Cell Differentiation; Chemistry, Pharmaceutical; Dihydroxycholecalciferols; Drug Design; Humans; Models, Chemical; Molecular Conformation; Psoriasis; Stereoisomerism

Psoriasis is a very common dermatological disease affecting a large part of the world population. In its most common form, psoriasis vulgaris, many topical drugs are available to treat the localized forms, and the recurrence of the dermatosis. Among topicals, tacalcitol has been proven to be effective and devoid of side effects which are typical of Vitamin-D3 analogues or derivates. The aim of this retrospective study was to evaluate the efficacy of topical tacalcitol vs. calcipotriol and emollient treatment of the first recurring lesion in order to induce a longer remission period before the retreatment with nb-UVB phototherapy in a population of 90 psoriatic patients. In this trial, the time between the first relapsing plaque appearance and retreatment with nb-UVB resulted in 25, 16 and 11 days for tacalcitol, calcipotriol and emollient respectively, with a statistically significant difference for tacalcitol (p < 0.0001). These results proved that tacalcitol treatment is effective in increasing the time interval in consecutive phototherapy cycles and in reducing the total amount of UV exposure.

Topics: Administration, Topical; Adult; Calcitriol; Cohort Studies; Dermatologic Agents; Dihydroxycholecalciferols; Female; Humans; Male; Middle Aged; Psoriasis; Retrospective Studies; Treatment Outcome; Ultraviolet Therapy

The active vitamin D3 regulates proliferation and differentiation of epidermal keratinocytes. Recently topical vitamin D3, tacalcitol, calcipotriol, and maxacalcitol are widely used for psoriasis.. To examine the effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on cultured normal keratinocytes (NHK) and compared its effect with those of various vitamin D3 analogues.. Cell proliferation of NHK cells was analyzed by MTS, BrdU and 3H-thymidine incorporation. The expression of involucrin, transglutaminase 1, keratin 5 and keratin 1 was investigated by western blot and PCR amplification and quantitative assay. Furthermore, we performed cornified cell envelope (CE) formation assay.. 1,25(OH)2D3, tacalcitol, calcipotriol, and maxacalcitol decreased NHK cell proliferation in a concentration-dependent manner and the maximal effect was observed at 10(-7) M. There was no significant difference in the anti-proliferative effect among the active vitamin D3 analogues. The expression of involucrin and transglutaminase 1 were induced by 1,25(OH)2D3 and its analogues in mRNA and protein levels. CE formation was also induced by 1,25(OH)2D3 and its analogues. There was no significant difference in the potency among these chemicals. Keratin 5 and 1 expression was not altered by these active vitamin D3 analogues.. The present study demonstrated that active vitamin D3 analogues, tacalcitol, calcipotriol, and maxacalcitol, suppress keratinocyte proliferation and induce differentiation with similar potency.

Topics: Calcitriol; Cell Differentiation; Cell Division; Cells, Cultured; Dermatologic Agents; Dihydroxycholecalciferols; Humans; Keratinocytes; Protein Precursors; Transglutaminases

Hyperkeratosis lenticularis perstans (HLP) or Flegel's disease is a rare dermatosis characterized by asymptomatic hyperkeratotic papules predominantly located on the lower extremities. Lesional and non-lesional epidermis samples were studied by light- and electron-microscopic examination. The main ultrastructural finding was the presence of structurally altered Odland bodies/membrane-coating granules. Different therapeutic options for HLP have been reported, but none of the treatments was shown to be consistently effective. Here, we report on a patient with Flegel's disease who did respond to topical 5-fluorouracil, whereas topical vitamin D(3) synthetics were ineffective.

Topics: Calcitriol; Dermatologic Agents; Dihydroxycholecalciferols; Female; Humans; Keratosis; Leg Dermatoses; Microscopy, Electron; Middle Aged; Skin; Treatment Outcome

To study the effect of calcitriol [1,25(OH)2D3] and its analogues on the interaction of monocyte chemoattractant protein-1 (MCP-1) and in vitro generated monocyte-derived dendritic cells (MoDC).. MoDC were obtained by differentiating monocytes in exposure to GM-CSF and IL-4 for 5 d. mRNA expression of MCP-1 and its receptors were analyzed by RT-PCR, and protein production of MCP-1 by ELISA and migratory ability of MoDC in response to MCP-1 by a micromultiwell chemotaxis chamber assay.. MoDC can express MCP-1 mRNA, and secret a low level of MCP-1 protein and has the ability to migrate to MCP-1 in corresponding to its expression of MCP-1 receptors. Calcitriol and its analogues with the same affinity to vitamin D receptor up-regulated the gene expression of both MCP-1 and its receptors, enhanced MCP-1 protein production and promoted the migratory ability of MoDC to MCP-1.. The interaction of DC and MCP-1 found in this study may suggest a possible auto-regulatory role between DC and MCP-1 and the modulatory effect of calcitriol and its analogues on DC and MCP-1 might provide an understanding of their positive role in tumors.

Topics: Calcitriol; Cell Movement; Cells, Cultured; Chemokine CCL2; Dendritic Cells; Dihydroxycholecalciferols; Humans; Receptors, CCR2; Receptors, Chemokine; RNA, Messenger

Sphingomyelin hydrolysis seems to be a ubiquitous pathway generating ceramide, an important cell response modifier. Upon agonist-stimulation this pathway is linked to biological responses as inhibition of proliferation, promotion of differentiation and induction of apoptosis. One of the agonists described is 1alpha,25-dihydroxyvitamin D3. Recently, we could demonstrate the existence of sphingomyelin hydrolysis in human primary keratinocytes as well as in the human keratinocyte cell line HaCaT after treatment with 1alpha,25-dihydroxyvitamin D3. In the present study we tested four vitamin D analogues on HaCaT keratinocytes for their ability to inhibit cell proliferation and to induce sphingomyelin hydrolysis. These analogues, calcipotriol, EB 1213, GS 1500 and tacalcitol inhibit cell growth after 48 hrs. of incubation and trigger the hydrolysis of sphingomyelin. Moreover, all analogues tested induce apoptotic cell death in HaCaT keratinocytes after 24 hrs. of incubation. This study indicates that sphingomyelin hydrolysis, subsequently leading to the elevation of cellular ceramide levels, may represent an important signal transduction pathway for 1alpha,25-dihydroxyvitamin D3 and its analogues in human keratinocytes. Possible differences of the mechanism underlying vitamin D-induced sphingomyelin hydrolysis has to be studied in more detail and may contribute to the antipsoriatic action of these analogues.

Topics: Apoptosis; Calcitriol; Cell Division; Cell Line; Dihydroxycholecalciferols; Humans; Keratinocytes; Psoriasis; Sphingomyelins; Vitamin D

Calcipotriol, 1,25(OH)2D3 and 1,24(OH)2D3 are potent drugs for the treatment of psoriasis. It has recently been published that these compounds induce epidermal hyperproliferation in hairless mouse skin.. The aim of our study was to examine the effect of vitamin D3 derivatives on epidermal growth, keratinization and permeability barrier function in vivo.. Calcipotriol, 1,25(OH)2D3 and 1,24(OH)2D3 in isopropanol or in an ointment formula were applied to normal hairless mouse skin. Transepidermal water loss (TEWL), a marker of cutaneous barrier function, and epidermal proliferation were determined at different time points 0-264 h after treatment. In addition, light and electron microscopy studies were performed.. A single treatment in solution led to a transient (2- to 3-fold) increase in TEWL after application of calcipotriol or 1,25(OH)2D3 and to a 3- to 6-fold increase in epidermal proliferation after application of each of the compounds. Repeated applications also resulted in an up to 3-fold increase in TEWL which persisted for 3 days after the end of the treatment. By light microscopy an increase in epidermal thickness was observed. There was no sign of inflammation. Electron microscopy studies showed the formation of a transitional cell zone as a sign of a premature keratinization.. These results demonstrate that in normal mouse skin vitamin D3 and its analogues disrupt the epidermal permeability barrier by induction of epidermal proliferation and premature keratinization but without morphological signs of inflammation.

Topics: 1-Propanol; Administration, Cutaneous; Animals; Calcitriol; Cell Division; Cholecalciferol; Dermatologic Agents; Dihydroxycholecalciferols; Epidermis; Keratins; Male; Mice; Mice, Hairless; Microscopy, Electron; Ointments; Permeability; Psoriasis; Skin; Time Factors; Water Loss, Insensible

The irritant potential of calcipotriol, 1 alpha,24-dihydroxyvitamin D3 (tacalcitol) and 1 alpha,25-dihydroxy-vitamin D3 (calcitriol) was compared in a hairless guinea pig model, Randomized, occlusive patch testing for 2 days was used. Each group of 8 animals was tested simultaneously with the 3 substances and a placebo vehicle. 3 dose levels i.e. 500 micrograms/ml, 50 micrograms/ml and 5 micrograms/ml were used. Test sites were evaluated at day 2 (2 h after removal of the patches) and again at day 3. Evaluation was blinded and based on a multiple parameter assessment of skin irritancy, comparing clinical scoring, skin perfusion using high resolution laser Doppler image scanning, skin colour (a*, Minolta ChromaMeter) and skin thickening (20 MHz ultrasound) indicating oedema. Skin biopsies were taken for histological preparation and assessment of epidermal hyperplasia. No difference was observed between the irritant potential for calcipotriol, tacalcitol and calcitriol based on clinical scoring as well as objective non-invasive measuring techniques. All 3 substances showed a dose-dependent and equal increase in clinical irritation score, cutaneous blood flow, skin colour and epidermal hyperplasia. The cutaneous inflammatory reaction was dominated by vasodilation and increased cutaneous perfusion. Oedema formation was only seen at the highest dosages tested. Skin barrier damage was not induced as TEWL remained unaffected. The hairless guinea pig appears a valid model to test irritancy of topical D-vitamins since the same profile of irritancy was previously established in humans for 2 of the compounds tested, calcitriol and calcipotriol.

Topics: Administration, Topical; Analysis of Variance; Animals; Calcitriol; Dermatitis, Irritant; Dermatologic Agents; Dihydroxycholecalciferols; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Guinea Pigs; Laser-Doppler Flowmetry; Patch Tests; Random Allocation; Reference Values; Skin; Ultrasonography

Topics: Administration, Topical; Calcitriol; Cross Reactions; Dermatitis, Allergic Contact; Dermatologic Agents; Dihydroxycholecalciferols; Humans; Hypersensitivity, Delayed; Male; Middle Aged; Patch Tests; Psoriasis

To investigate and compare the effects on calcium metabolism of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and the synthetic vitamin D analogs tacalcitol and calcipotriol after topical treatment, we treated groups of rats topically once daily with three dose levels of each test compound in a vehicle of propylene glycol plus ethanol for 28 d. The urinary calcium excretion was measured after 14 d, and serum calcium and parathyroid hormone were measured at termination. The rats were autopsied, and the kidneys were examined microscopically for mineralizations. Based on the urinary calcium excretion and the serum calcium level, calcipotriol was found to be 60 times less calcemic, and tacalcitol was slightly less calcemic, than 1,25(OH)2D3 after repeated topical application to rats. Serum parathyroid hormone was suppressed to a lower degree by calcipotriol and tacalcitol than by 1,25(OH)2D3, and the incidence and severity of renal corticomedullary mineralization were higher in rats treated with 1,25(OH)2D3 and tacalcitol than with calcipotriol. We conclude that calcipotriol is much less calcemic than 1,25(OH)2D3 or tacalcitol when applied topically to rats in a vehicle that enhances penetration into the skin. We attribute the lower calcemic effect of calcipotriol to the pharmacokinetic profile of the compound, particularly its rapid metabolization into inactive compounds.

Topics: Administration, Topical; Animals; Calcitriol; Calcium; Dihydroxycholecalciferols; Female; Mice; Parathyroid Hormone; Rats; Rats, Inbred Lew