Calcipotriol

Calcipotriol is an analogue of vitamin D3. [1]

Calcipotriol is a ligand of VDR-like receptors and is used as a first-line topical agent in the treatment of psoriasis.[1-2] Calcipotriol is much less effective in causing hypercalcemia.[3] The vitamin D receptor is found on the cells of many different tissues including T cells of the immune system. T cells are known to play a role in psoriasis, and the binding of calcipotriol to VDR modulates the T cells gene transcription of cell differentiation and proliferation related genes. Calcipotriol induced apoptosis in eratinocytes isolated from psoriatic plaques at 100 nM for 20 h.[4] Calcipotriol also induced autophagy in both HeLa cells and keratinocytes.[2] Calcipotriol inhibited the proliferation of HL-60 and MCF-7 cells dose-dependently from 1 nM-1000 nM.[5] Calcipotriol is a potent inducer of terminal differentiation in cultured human keratinocytes.[3] Calcipotriol also decreased the mRNA expression/production of human cathelicidin antimicrobial protein (hCAP18) and LL37 peptide by IL-17A/IL-22-stimulated keratinocytes at 40 nM.[6]

References:
1. M. R. Klaber, P. E. Hutchinson, A. Pedvis-Leftick, K. Kragballe, T. L. Reunala, P. C. Van de Kerkhof, M. K. Johnsson, L. Molin, M. S. Corbett and N. Downess, Br J Dermatol 1994, 131, 678-683.
2. R. C. Wang and B. Levine, J Invest Dermatol 2011, 131, 990-993.
3. K. Kragballe and I. L. Wildfang, Arch Dermatol Res 1990, 282, 164-167.
4. R. Tiberio, C. Bozzo, G. Pertusi, F. Graziola, M. Gattoni, P. Griffanti, P. Boggio, E. Colombo and G. Leigheb, Clin Exp Dermatol 2009, 34, e972-974.
5. M. Milczarek, M. Chodynski, B. Filip-Psurska, A. Martowicz, M. Krupa, K. Krajewski, A. Kutner and J. Wietrzyk, Cancers (Basel) 2013, 5, 1355-1378.
6. J. Sakabe, T. Umayahara, M. Hiroike, T. Shimauchi, T. Ito and Y. Tokura, Acta Derm Venereol 2014, 94, 512-516.

A Topical Treatment Optimization Programme (TTOP) improves clinical outcome for calcipotriol/betamethasone gel in psoriasis: results of a 64-week multinational randomized phase IV study in 1790 patients (PSO-TOP).[Pubmed:28301043]

Br J Dermatol. 2017 Jul;177(1):197-205.

BACKGROUND: Around two-thirds of patients with psoriasis do not adhere to topical treatment. The Topical Treatment Optimization Programme (TTOP), a five-element tool, includes guidance for the conversation between dermatologists/nurses and patients, patient information material, telephone/e-mail helpdesks and treatment reminders. It has been developed by patients and dermatologists to help increase adherence to treatment in psoriasis. OBJECTIVES: To compare TTOP with standard of care ('non-TTOP') within a large European investigator-initiated study, PSO-TOP (clinicaltrials.gov NCT01587755). METHODS: Patients with mild-to-moderate psoriasis received Calcipotriol/betamethasone dipropionate gel as standardized study medication and were randomized 1 : 1 to either TTOP or non-TTOP management. Study medication was applied once daily for 8 weeks followed by 'as needed' application for an additional 56 weeks. Response was defined as a Physician's Global Assessment (PGA) of 'clear' or 'almost clear'. RESULTS: In 1790 patients (full analysis set), response rates after 8 weeks (primary objective) were significantly higher for TTOP (36.3%) than for non-TTOP (31.3%, P = 0.0267). Better clinical outcome was accompanied by higher rates of patients feeling well informed about their skin condition, treatment and other factors related to adherence, but the Dermatology Life Quality Index was not statistically different. TTOP patients regarded the structured one-to-one conversations with their dermatologist/nurse as the most important element of TTOP. CONCLUSIONS: Patients randomized to the TTOP intervention had a better clinical response than patients receiving standard of care. Improved communication between the healthcare provider and patient might be an important element in increasing adherence to topical therapy in psoriasis.

Nanoemulsion loaded gel for topical co-delivery of clobitasol propionate and calcipotriol in psoriasis.[Pubmed:28259803]

Nanomedicine. 2017 May;13(4):1473-1482.

Current work reports the development and optimization of clobitasol propionate (CP) and Calcipotriol (CT) loaded nanoemulsion based gel for topical treatment of psoriasis. Components of nanoemulsion viz., oil and surfactant/co-surfactant were selected depending upon solubility and emulsification potential respectively. The optimized ratio of 5:3:2 of Capmul MCM C8 EP, Cremophor RH 40 and Labrafil 1944 CS was selected. Carbopol 980 was used as gelling agent to achieve final drug concentration of 0.05% w/w and 0.005% w/w respectively for CP and CT. HaCaT cell lines showed higher uptake of drug from nanoemulsion in correlation with the enhancement in penetration of both drugs in stratum corneum (SC) and viable layer from nanoemulsion and gel as compared to free drugs. Imiquimod induced psoriatic BALB/c mice revealed significantly higher anti-psoriatic activity of nanoemulsion gel as compared to free drugs and marketed formulation. The developed formulation showed negligible skin irritation despite increased penetration into the skin.

RETRACTED: Ameliorative potential of linagliptin and/or calcipotriol on bleomycin-induced lung fibrosis: In vivo and in vitro study.[Pubmed:28192751]

Environ Toxicol Pharmacol. 2017 Mar;50:216-226.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted due to the authors' plagiarism of text and images from the work of Eman Said Abd-Elkhalek, Hatem Abdel-Rahman Salem, Ghada Mohamed SuddeK, Marwa Ahmed Zaghloul and Ramy Ahmed Abdel-Salam, Faculties of Pharmacy and Medicine, Mansoura University, Mansoura, Egypt.

Calcipotriol Plus Betamethasone Dipropionate Aerosol Foam in Patients with Moderate-to-Severe Psoriasis: Sub-Group Analysis of the PSO-ABLE Study.[Pubmed:28236223]

Am J Clin Dermatol. 2017 Jun;18(3):405-411.

BACKGROUND: Fixed-combination Calcipotriol 50 mug/g plus betamethasone 0.5 mg/g (Cal/BD) aerosol foam is a new topical treatment for psoriasis. Although moderate-to-severe psoriasis is typically treated with systemic/biologic therapies, a topical treatment that is efficacious in these patients may be a significant cost-saving alternative to systemic therapy. OBJECTIVE: The objective of this study was to assess the response to Cal/BD foam and gel in patients with moderate-to-severe psoriasis enrolled in the phase III, 12-week PSO-ABLE study. METHODS: Patients eligible for this analysis had moderate-to-severe psoriasis, defined by the 'Rule of Tens': body surface area >/=10% or Psoriasis Area and Severity Index (PASI) [excluding head; modified PASI (mPASI)] >10 or Dermatology Life-Quality Index >10. Endpoints included: proportion of patients achieving mPASI75 or mPASI90; change in body surface area; proportion of patients clear/almost clear with a >/=2 grade improvement (i.e., treatment success); change in Dermatology Life-Quality Index. RESULTS: Seventy-seven Cal/BD foam patients and 82 gel patients had moderate-to-severe psoriasis. A greater proportion achieved mPASI75 and mPASI90 with Cal/BD foam than gel at weeks 4, 8, and 12 (57.1 vs. 35.4%; p = 0.006 and 15.6 vs. 12.2% at week 12, respectively); overall reduction in mPASI from baseline to week 12 was 64% with the foam vs. 51% with the gel. Overall reduction in body surface area at week 12 was 50% with the foam and 39% with the gel. Treatment success rates were higher with the Cal/BD foam than the gel at weeks 1, 2, 4, 8 (p = 0.0089), and 12, and a greater proportion of foam patients achieved a Dermatology Life-Quality Index score of 0/1 at weeks 4 (p = 0.004), 8, and 12 (p = 0.001). CONCLUSION: Cal/BD foam can be considered as a treatment option in some patients with moderate-to-severe psoriasis who are potential candidates for systemic therapy. CLINICALTRIALS. GOV IDENTIFIER: NCT02132936.

Antitumor properties of diastereomeric and geometric analogs of vitamin D3.[Pubmed:17351397]

Anticancer Drugs. 2007 Apr;18(4):447-57.

Analogs of 1,25-dihydroxyvitamin D3 with a reversed configuration at C-1 or C-24 and E or Z geometry of the double bond at C-22 in the side chain or at C-5 in the triene system were examined for their antiproliferative activity in vitro against a spectrum of various human cancer cell lines. The analogs coded PRI-2201 (Calcipotriol), PRI-2202 and PRI-2205, such as calcitriol and tacalcitol (used as a referential agents), revealed antiproliferative activity against human HL-60, HL-60/MX2, MCF-7, T47D, SCC-25 and mouse WEHI-3 cancer cell lines. The toxicity studies in vivo showed that PRI-2202 and PRI-2205 are less toxic than referential agents. Even at total doses of 2.5-5.0 mg/kg distributed during 5 successive days, no changes in body weight were observed. Calcitriol and tacalcitol showed toxicity in the same protocol at 100 times lower doses. Calcipotriol was lethal to all mice after administration of a total dose of 5.0 mg/kg. The analog PRI-2205 appeared to be more active in mouse Levis lung cancer tumor growth inhibition than calcitriol, Calcipotriol or PRI-2202. This analog did not reveal calcemic activity at doses which inhibit tumor growth in vivo nor at higher doses.

Pharmacokinetics and systemic effect on calcium homeostasis of 1 alpha,24-dihydroxyvitamin D2 in rats. Comparison with 1 alpha,25-dihydroxyvitamin D2, calcitriol, and calcipotriol.[Pubmed:9113104]

Biochem Pharmacol. 1997 Mar 21;53(6):829-37.

1 alpha,24-Dihydroxyvitamin D2 (1 alpha,24(OH)2D2) is a metabolite of 1 alpha-hydroxyvitamin D2 (1 alpha-OH-D2), a prodrug in development as a treatment for secondary hyperparathyroidism occurring in end stage renal disease. This prodrug has a broader therapeutic index than the corresponding vitamin D3 analogue, possibly because hepatic metabolism of 1 alpha-OH-D2 shifts at higher dose levels from 1 alpha,25-dihydroxyvitamin D2 (1 alpha,25(OH)2D2) to 1 alpha,24(OH)2D2. In this report, we present the pharmacokinetics of 1 alpha,24(OH)2D2 and its systemic effects on serum and urine calcium in rats. These properties were compared with those of 1 alpha,25(OH)2D2, calcitriol, the active metabolite of endogenous vitamin D3, and Calcipotriol, a vitamin D analogue noted for its rapid clearance and minimal effect on calcium homeostasis. Comparison of the blood concentration curves from time zero to infinity indicated that 1 alpha,24(OH)2D2 had about one-fifth the systemic exposure of 1 alpha,25(OH)2D2 or calcitriol, but almost 30 times that of Calcipotriol. The oral bioavailabilities and circulating half-lives of 1 alpha,24(OH)2D2 and calcitriol were similar, whereas those of Calcipotriol were much less. In vitamin D-deficient rats, oral doses of 1 alpha,25(OH)2D2 and calcitriol produced similar dose-dependent increases in serum calcium, whereas an oral dose 30 times greater was required for 1 alpha,24(OH)2D2 to produce a similar response. Dose-response curves generated after oral and subcutaneous administration of 1 alpha,24(OH)2D2, calcitriol, and Calcipotriol to normal rats indicated that 1 alpha,24(OH)2D2 increases serum and urine calcium to a much lesser extent than calcitriol, and to a slightly greater extent than Calcipotriol. These properties of 1 alpha,24(OH)2D2 suggest that production of this metabolite from 1 alpha-OH-D2 contributes to the lowered toxicity of 1 alpha-OH-D2 and indicate that 1 alpha,24(OH)2D2 contributes to the lowered toxicity of 1 alpha-OH-D2 and indicate that 1 alpha,24(OH)2D2 itself has therapeutic potential.

Comparison of calcipotriol with selected metabolites and analogues of vitamin D3: effects on cell growth regulation in vitro and calcium metabolism in vivo.[Pubmed:8396769]

Pharmacol Toxicol. 1993 Apr-May;72(4-5):240-4.

Calcipotriol is a novel vitamin D3 analogue developed for topical treatment of psoriasis. Calcipotriol is believed to act via regulation of cell proliferation and differentiation. In this respect Calcipotriol is as potent as 1 alpha, 25(OH)2D3, the physiologically active form of vitamin D3, but its calcaemic activity in vivo is 100 to 200 times lower. In the present investigation, the effects of Calcipotriol on cell growth regulation in vitro and on calcium metabolism in vivo were compared to those exerted by a number of metabolites and analogues of vitamin D3. Besides 1 alpha, 25(OH)2D3, these included the two physiologically occurring metabolites 25(OH)D3 and 24,25(OH)2D3, and the two synthetic analogues 1 alpha (OH)D3 and 1 alpha, 24(OH)2D3. 25(OH)D3 and 24,25(OH)2D3 were shown to be inactive both in vitro and in vivo. 1 alpha (OH)D3 was found to have a low biological activity in vitro, but was highly calcaemic in vivo after biotransformation to 1 alpha, 25(OH)2D3. Calcipotriol, 1 alpha, 24(OH)2D3 and 1 alpha, 25(OH)2D3 were all three potent regulators of cell proliferation and differentiation in vitro. In vivo, only Calcipotriol showed a greatly reduced calcaemic activity after both oral and intravenous administration. It is concluded that Calcipotriol, with a reduced risk of inducing calcaemic side-effects upon absorption from the skin, possesses a favourable therapeutic profile for topical treatment of hyperproliferative diseases.