DRUG EVALUATION
Drugs 43 (3): 415-429, 1992 0012-6667/92/0003-0415/$07.50/0 © Adis International Limited. All rights reserved. ORE!
Calcipotriol A Review of its Pharmacological Properties and Therapeutic Use in Psoriasis Vulgaris David Murdoch and Stephen P. Clissold Adis International Limited, Auckland, New Zealand
Various sections of the manuscript reviewed by: O.E. Araujo, University of Florida, College of Pharmacy, Gainesville, Florida, USA; W.P. Arnold, Research Department of Dermatology, Nijmegen, The Netherlands; I. Berthlones, Department of Dermatology, Leicester Royal Infirmary, Leicester, England; A.J. Brown, Renal Division, Washington University School of Medicine, St Louis, Missouri, USA; C Dwyer, Department of Dermatology, Stobhill General Hospital, Glasgow, Scotland; P.H. Maenpaa, Department of Biochemistry and Biotechnology, University of Kuopio, Kuopio, Finland; H.I. Maibach, UCSF School of Medicine, Department of Dermatology, San Francisco, California, USA; P.I. Marie, H6pital Lariboisiere, Paris, France; T. Menne, Gentofte Hospital, Hellerup, Denmark; E. Ogata, Fourth Department ofInternal Medicine, University of Tokyo School of Medicine, Tokyo, Japan; CA. Ramsay, Diseases of the Skin, Toronto, Ontario, Canada; I-H. Saurat, Dermatology Clinic and Division of Clinical Pathophysiology, H6pital Cantonal Universitaire, Geneva, Switzerland; S. Shuster, Department of Dermatology, Royal Victoria Infirmary, Newcastle-upon-Tyne, England; P.CM. van de Kerkho/, Research Department of Dermatology, Nijmegen, The Netherlands; I. Yip, Dermatology Centre, Lidcombe Hospital, Lidcombe, New South Wales, Australia.
Contents 416 417 418 418 419 420 420 421 422 422 423 423 425 425 425 427 428
Summary 1. Pharmacological Properties 1.1 Effects on Cell Proliferation and Differentiation 1.1.1 In Vitro and Ex Vivo Studies 1.1.2 In Patients with Psoriasis 1.2 Effects on Calcium Absorption and Mobilisation 1.3 Effects on Immunological and Inflammatory Mediators 1.4 Pharmacokinetic Properties 2, Therapeutic Efficacy in Psoriasis Vulgaris 2.1 Placebo-Controlled, Dose-Ranging and Noncomparative Studies 2.2 Comparisons with Other Antipsoriatic Treatments 2.2.1 Betamethasone Valerate 2.2.2 Dithranol (Anthralin) 2.2.3 Calcipotriol Plus Ultraviolet Radiation Therapy 3. Tolerability 4. Administration 5. Place of Calcipotriol in Therapy
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Summary Synopsis Calcipotriol (calcipotriene) is a vitamin D3 analogue which inhibits epidermal cell proliferation and enhances cell differentiation. In patients with chronic plaque psoriasis involved in short term studies of 6 to 8 weeks' duration, calcipotriol ointment applied twice daily was significantly more effective than betamethasone valerate and dithranol (anthralin). Pooled data from clinical trials show that calcipotriol is well tolerated, with the majority of adverse events being mild and transient local reactions. Topically applied calcipotriol has low hypercalcaemic potential and, in contrast to topical corticosteroids, oral retinoids and orally administered calcitriol, methotrexate and cyclosporin, calcipotriol does not appear to be associated with a risk of serious adverse events. Thus, at this early stage in its clinical development, calcipotriol appears to be an effective and well tolerated topical therapy for the management of psoriasis; if promising preliminary clinical findings are confirmed, calcipotriol will represent a major advance in this difficult area of therapeutics. Pharmacological Properties Calcipotriol has pharmacodynamic properties similar to those of calcitriol (1,25-dihydroxycholecalciferol), the active metabolite of vitamin D3. In several in vitro models, calcipotriol and calcitriol markedly inhibit cell proliferation and enhance cell differentiation over a range of concentrations from approximately 10- 10 to 10- 6 molfL. For example, both drugs reduce cell numbers, total DNA content and incorporation of radiolabelled thymidine into DNA, and increase the number of human keratinocytes with cornified envelopes and activity of the enzyme causing protein cross-linking in the envelopes. In patients with psoriasis, calcipotriol also reduces epidermal cell proliferation and enhances differentiation in lesional skin. Calcipotriol binds to intestinal calcitriol receptors with affinity similar to that of calcitriol, but is 100 to 200 times less potent than calcitriol in its effect on in vivo calcium metabolism in rats. Intraperitoneal calcipotriol I and 10 Ilg/kg/day administered to rats for 7 days did not significantly affect serum and urinary calcium levels, or dry weight and calcium content of tibial metaphyses. Conversely, calcitriol 0.5 Ilg/kg/day significantly altered these parameters. Calcipotriol inhibits interleukin-I-induced mouse thymocyte proliferation in vitro and, in patients with psoriasis, reduces the amount and distribution of epidermal interleukin-6 and the number of activated epidermal T-Iymphocytes. However, the relevance of these findings to the mechanism of action and clinical efficacy of calcipotriol in psoriasis remain uncertain. In patients with psoriasis, less than I % of calcipotriol is systemically absorbed after a single application of 0.3 to 1. 7g of radiolabelled calcipotriol ointment 50 Ilg/g. Calcipotriol is thought to undergo rapid hepatic conversion to MC 1046 and MC 1080, metabolites with negligible pharmacological activity, and has an affinity for human vitamin D binding protein 30 times less than that of calcitriol in vitro. Only traces of calcipotriol « I %) are recovered in urine and faeces after topical application.
Therapeutic Efficacy In patients with psoriasis, calcipotriol cream 1200 Ilg/g is significantly superior to cream base alone, and dose-response relationships have been identified for cream (10 to 100 Ilg/g) and ointment (25 to 100 Ilg/g) formulations of the drug. Marked decreases in physician-assessed mean clinical scores for severity of skin erythema, thickness and scaling were observed after cream (about 17 to 49%) and ointment (about 50 to 90%) application, and investigator global assessments of overall clinical response showed significant improvement. After calcipotriol ointment 25, 50 and 100 Ilg/g application, 40, 63 and 88% of patients with psoriasis, respectively, demonstrated 'marked' improvement or total clearance of lesions; the 50 Ilg/g concentration was significantly superior to 25 Ilg/g (n = 20), but not significantly different from 100 Ilg/g (n = 17). Additionally, calcipotriol ointment 50 Ilg/g significantly reduced mean psoriasis area and severity index (PASI) score by 67% in 161 patients with psoriasis treated for up to I year.
Calcipotriol: A Review
417
Calcipotriol ointment 50 p,g/g, compared with betamethasone valerate ointment 1 mg/g, produced significantly greater 6-week subjective clearance rates [% of patients with healed psoriatic lesions plus those showing marked improvement (61 to 82% vs 51 to 69%)], significantly greater 6-week reductions in PASI scores (approximately 70 vs 60%), and significantly lower physicianassessed mean scores for severity of skin erythema, thickness and scaling. Calcipotriol ointment 50 p.g/g was significantly more effective and had significantly greater cosmetic acceptability than dithranol cream 11 to 2.0% in a total of 478 patients with psoriasis.
Tolerability The most frequently occurring calcipotriol-induced adverse events are lesional/perilesional skin irritation (incidence approximately 9 to 20%), nonlesional erythema/infiltration/desquamation ('" 4%), facial/scalp irritation (2%), and miscellaneous skin disorders ('" 2 to 5%). Although lesional/perilesional skin irritation is more common in calcipotriol than betamethasone valerate recipients, all of the above events are generally mild and transient in nature and rarely require calcipotriol withdrawal. In large-scale, 6-week direct comparative trials, both calcipotriol and betamethasone were well tolerated. However, it is important to remember that, with longer term use (> 6 weeks) topical corticosteroids may have tolerability disadvantages in relation to calcipotriol: i.e. corticosteroids have the potential to cause complications such as adrenal-pituitary suppression, skin atrophy, masked tinea infection and pustular psoriasis. Interestingly, calcipotriol ointment 50 p.g/g applied twice daily for 6 months appeared not to be associated with skin atrophy in 8 patients with psoriasis; this certainly requires confirmation in larger numbers of patients. Calcipotriol is rarely associated with facial dermatitis, the reported cases probably resulting from inadvertent ointment transfer from hands to face, or allergic contact dermatitis. Hypercalcaemia has occurred in only a small number of patients treated with calcipotriol, usually involving large amounts or higher concentrations of the ointment; and appears to be more of a problem in patients receiving oral calcitriol. Importantly, none of more than 900 psoriatic patients treated with calcipotriol ointment 50 Jl.g/g twice daily (no more than lOOg applied per week) developed hypercalcaemia.
Administration For treatment of. psoriasis vulgaris calcipotriol ointment 50 p.g/g (no more than lOOg per week) should be applied to affected areas twice daily. Because of the risk offacial dermatitis, calcipotriol should not be applied to the face, and patients should wash their hands thoroughly after ointment application to prevent inadvertent transfer from hands to face.
1. Pharmacological Properties Calcipotriol (Me 903; calcipotriene) is a vitamin D3 analogue with a structure similar to that of calcitriol (1 ,25-dihydroxy-cholecalciferol; 1,25dihydroxy-vitamin D3), the most active metabolite of vitamin D3 (fig. 1). Vitamin D3, together with parathyroid hormone and calcitonin, plays an integral role in calcium and phosphorus homeostasis - controlling the absorption, distribution and excretion of these essential minerals. Analogues of
vitamin D3 have been used in the management of osteoporosis and, in 1986, Japanese researchers administered a vitamin D3 prodrug to a patient with osteoporosis and discovered, by chance, that the patient's psoriasis improved; this serendipitous finding led to evaluation of vitamin D3 analogues in patients with psoriasis. In several pharmacodynamic studies, calcipotriol has been compared with the 'experimental standard' calcitriol and, as outlined below, the 2 drugs appear to have similar pharmacodynamic properties.
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OH
Calcipotriol (MC 903)
Calcitriol (1 a,25-dihydroxyvitamin 03; 1a,25-dihydroxycholecalciferol)
differentiation, and therefore therapeutic value in the treatment of psoriasis (Binderup 1988; Binderup et al. 1988b; Valaja et a1. 1990). 1.1.1 In Vitro and Ex Vivo Studies Calcipotriol demonstrated effects on cell proliferation and differentiation similar to those of calcitriol in many in vitro experiments (Kissmeyer & Binderup 1991; table I). Reduced cellular proliferation, at drug concentrations of 10-8 mol/L in various cell cultures, was indicated by reduction of cell numbers (calcipotriol 5 to 58% vs calcitriol 41 to 61%) [Kragballe & Wildfang 1990; Valaja et a1. 1990], decreased total cellular DNA content relative to control values (22 vs 3%; Binderup 1988), and reduced incorporation of [3H]thymidine into DNA (fig. 3). In human cell lines, concentrations of calcipotriol and calcitriol required to inhibit cellular proliferation by 50%, or to inhibit incorporation of [3H]thymidine into DNA by 50%, ranged from 1.4 X 10-8 to > 10-7 mol/L (table I). Additionally, calcipotriol and calcitriol inhibited human osteoblast-like cell proliferation across the concentration range 10- 10 to 10-6 mol/L in a con-
o
Fig. 1. Structural formulae of calcipotriol and calcitriol.
1.1 Effects on Cell Proliferation and Differentiation Although the aetiology of psoriasis vulgaris remains unclear, characteristic features of the disease include hyperproliferation and incomplete differentiation of the epidermis (Araujo et al. 1991; Binderup 1988; Holick 1989). Recent studies have shown that calcitriol receptors are present in a number of cell types, including skin cells, and that calcitriol markedly suppresses proliferation and enhances differentiation of epidermal keratinocytes (Araujo et a1. 1991; Binderup 1988; Binderup & Bramm 1988). Because calcipotriol and calcitriol displayed similar affinity for calcitriol receptors in several in vitro models (fig. 2), it was logical to expect that calcipotriol also possessed antiproliferative activity, the ability to induce epidermal cell
............ Calcitriol
t:
20
~0
40
~
~
e----e Calcipotriol
6 weeks) topical corticosteroids, unlike calcipotriol, may be associated with a risk of adrenal-pituitary suppression, skin thinning, masked tinea infection and possible development of pustular psoriasis (Cunliffe et al. 1992; Kragballe et aI. 1991a; Long & Marks 1991; Ramsay 1991). Interestingly, in a 6-month nonblind study of 15 patients with psoriasis, twice daily application of calcipotriol ointment 50 J,Lg/g (up to 100g per week) appeared not to be associated with skin atrophy. Although skin biopsies from 8 ofthe 15 patients showed that thickness of the epidermis and papillary dermis was similar in calcipotrioltreated perilesional skin compared with untreated lesional skin (Kragballe et al. 1991 b), these findings obviously require confirmation in larger numbers of patients. Calcipotriol ointment was applied to facial psoriatic lesions in only 1 clinical trial: 5 of 46 patients 10 9 8 7 ~ 0 6 0 If) 5 Cii 4 « a. 3 2 1 0
a
(10.9%) developed facial dermatitis (3 patients were applying calcipotriol to the face, 2 were not) and 2 patients stopped calcipotriol treatment because of this reaction (Kragballe 1989). However, other studies showed that facial dermatitis, probably resulting from inadvertent transfer of calcipotriol ointment from hands to face, was a rare occurrence (Ramsay 1991), or was generally mild and transient in nature (Kragballe 1990; Kragballe et al. 1991 b). Calcipotriol has been associated with only a small number of cases of allergic contact dermatitis (Ramsay 1991; Yip & Goodfield 1991), and isolated reports of hypercalcaemia (Cunliffe et al. 1992; Dwyer & Chapman 1991). In the latter cases, large amounts of calcipotriol were applied: a 77-year-old woman applied 400g of calcipotriol ointment (50 J,Lgfg) over a lO-day period (Cunliffe et al. 1992); and a 67-year-old woman with a moderate degree of renal impairment applied approximately 200g of calcipotriol ointment 50 J,Lg/g twice daily over a 7day period (Dwyer & Chapman 1991). Importantly, calcipotriol is known to have a far lesser effect on in vivo calcium metabolism than oral or parenteral calcitriol (section 1.2) and, in over 900 psoriatic patients treated with calcipotriol ointment 50 J,Lg/g twice daily (no more than lOOg applied per week) for 6 to 52 weeks, mean serum levels of total calcium were not significantly altered (Cunliffe et al. 1992; Jurgensen 1991; Kragballe et
o Calcipotriol • Betamethasone valerate
o Calcipotriol
12
D Dithranol
10 ~
8 ~ «
a.
8
6
4 2
o
O~.----,---.---,----r
2
4
o
6
Treatment duration (weeks)
b
2
6
4
8
Treatment duration (weeks)
Fig. 7. Reductions in psoriasis area and severity index (PAS!) scores in: (a) 342 patients treated with calcipotriol 50 p.gjg and betamethasone valerate I mgjg ointments applied twice daily for 6 weeks in a right-left comparison (Kragballe et al. 199Ia); and (b) in 478 patients treated with calcipotriol ointment 50 p.gjg or dithranol cream (0.1 to 2.0%) for 8 weeks in a parallel study (Jiirgensen 1991). Statistically significant difference between treatments: t = p < 0.01; = p < 0.001.
*
Calcipotriol: A Review
427
Table III. Number (and percentage) of patients experiencing adverse events in studies in which calcipotriol (CPL) ointment SO I"g/g was applied to psoriatic lesions twice daily for 6 to 8 weeks (Cunliffe et al. 1992; Jurgensen 1991; Kragballe et al. 1991 a) Adverse event
Cunliffe et al. (1992)
Kragballe etal. (1991 a)
Jurgensen (1991)
CPL
BET
CPL
DIT
CPL
(n = 20S)
(n = 204)
(n = 239)
(n = 239)
(n = 342)
43 (18.0%)8'
110 (46%)8
26 4b
21
30 (8.8%)
22 (6.4%)
1 (0.3%) 6 (1.8%)
10 (2.9%)
2 (0.6%)
1 (0.3%)
BET (n = 342)
Lesional/perilesional irritation Burning/itching/stinging
23
Erythema/scaling/peeling/ exfoliation
12
Other (e.g. dry skin, slight
S
'prickling sensation' Total
40 (19.S%)'
Nonlesional erythema/ infiltration/desquamation
8 (3.9%)
Facial/scalp irritation
4 (2.0%)
Skin infection Miscellaneous skin problems Treatment withdrawals
8 (3.9%) 3 (1.S%)
1 (O.S%)
S (2.S%)
11 (S.4%)
2 (1.0%)
S (2.4%)
S (2.S%)
a
Data about other events not provided.
b
One patient had 'increased exfoliation'.
4 (1.7%)C
12 (S.O%)C
3 (0.9%)
c Adverse reactions (I.e. considered possibly or probably related to calcipotriol). Abbreviations and symbols: BET = bethamethasone valerate; DIT = dithranol; • statistically significant difference between calcipotriol and comparator regimen.
al. 1991a; Ramsay 1991). Further, in 12 to 33 patients with psoriasis, calcipotrio1 ointment (50 J.tg/g) had no significant effects on calcium metabolism compared with placebo (Mortensen et al. 1991), and at a total daily dose of 150J.tg, had no significant effect on serum calcium levels and daily or fasting urinary calcium excretion, whereas an equivalent dose of oral calcitriol (1.5 J.tgjday) caused significant hypercalcaemia and hypercalciuria (Gumowski-Sunek et al. 1991; Saurat et al. 1991). Thus, hypercalcaemia may occur if large amounts of calcipotriol ointments are used indiscriminately, but elevated serum calcium levels would seem to be an unlikely occurrence with prudent application (i.e. the recommended maximum of 100 g/week) of calcipotriol ointment 50 J.tg/g (Saurat et al. 1991). Overall, these preliminary data suggest that calcipotriol ointment 50 J.tg/g applied twice daily is a well tolerated regimen for the treatment of psoriasis. However, clinical experience with the drug has been limited and much larger numbers of patients need to be assessed before the tolerability
profile of calcipotriol, particularly in relation to other antipsoriatic agents (e.g. topically applied calcitriol, betamethasone valerate' and dithranol), can be clearly defined.
4. Administration In the UK, the currently recommended application regimen for calcipotriol ointment in the treatment of patients with psoriasis vulgaris affecting up to 40% of the skin area is 50 J.tg/g twice daily to affected areas. Importantly, no more than 100g of calcipotriol ointment 50 J.tg/g should be applied per week, as this may be associated with iln increased risk of hypercalcaemia. Further, the course of calcipotriol treatment should not exceed 5 weeks. Because of the possibility of facial dermatitis, calcipotriol should not be applied to the face. Patients should be advised to thoroughly wash their hands after use of the ointment, thus preventing inadvertent ointment transfer from hands to face.
428
5. Place of Calcipotriol in Therapy Psoriasis vulgaris is a common, very distressing skin disorder of unknown aetiology. Historically, the condition has proved difficult to treat, and commonly used antipsoriatic agents have had poor tolerability profiles (e.g. oral retinoids, methotrexate and topical corticosteroids) or have been unacceptable to patients because of unpleasant aromas and messy application (e.g. coal tar and dithranol). Rather fortuitously, oral and topical vitamin D3 and its analogues were recently found to be effective in the treatment of psoriasis. Orally administered calcitriol may have limited therapeutic value because of hypercalcaemic potential and, although no direct efficacy and tolerability comparisons have been made between topical formulations of calcitriol and calcipotriol, topical calcipotriol seems to have a promising future as an anti psoriatic. Large-scale trials showed calcipotriol ointment to be significantly more effective than betamethasone valerate and dithranol in patients with chronic plaque psoriasis; calcipotriol was also significantly more acceptable to patients than dithranol. Whether the antipsoriatic efficacy of calcipotriol is enhanced by ultraviolet (UV) radiation therapy (UVB or PUVA) remains unclear. Ongoing, large-scale, comparative trials assessing the efficacy of calcipotriol alone, and in combination with UVB or PUVA therapy, should clarify this. Thus, although further clinical experience with calcipotriol is required before its place in therapy can be more clearly defined, early indications are that it is an effective and well tolerated agent which represents a worthwhile therapeutic advance in the management of psoriasis, a traditionally distressing and difficult-to-treat skin disorder.
References Araujo OE, Flowers FP, Brown KD. Vitamin D therapy in psoriasis. DICP: Annals of Pharmacotherapy 25: 835-839, 1991 Arnold WP, van de Kerkhof PCM. The induction of epidermal ornithine decarboxylase following tape stripping is inhibited by a topical vitamin D3 analogue (MC 903). British Journal of Dermatology 125: 6-8, 1991 Berth-Jones J, Fletcher A, Hutchinson PE. Epidermal cytokeratin and immunocyte responses during treatment of psoriasis with
Drugs 43 (3) 1992
caIcipotriol and betamethasone valerate. British Journal of Dermatology, in press, 1992 Binderup L, Bramm E. Effects of a novel vitamin D analogue MC903 on cell proliferation and differentiation in vitro and on calcium metabolism in vivo. Biochemical Pharmacology 37: 889-895, 1988 Binderup L. MC 903 - A novel vitamin D analogue with potent effects on cell proliferation and cell differentiation. In Vitamin D: molecular, cellular and clinical endocrinology, pp. 300-309, Walter de Gruyter & Co., Berlin, 1988 Bouillon R, Allewaert K, Xiang DZ, Vandewalle M, De Oerq P. Structure-function analysis of vitamin D analogs: difference in binding to the vitamin D receptor and vitamin-D binding serum protein. Abstract. Journal of Bone and Mineral Research 4 (Suppl. I): 301, 1989 Cunliffe WJ, Berth-Jones J, Oaudy A, Fairiss G, Goldin D, et a1. Comparative study ofCalcipotriol (MC 903) ointment and betamethasone 17-valerate ointment in patients with psoriasis vulgaris. Journal of the American Academy of Dermatology, in press, 1992 de Mare S, de Jong EGJM, van de Kerkhof PCM. DNA content and Kg8.12 binding of the psoriatic lesion during treatment with the vitamin D3 analogue MC903 and betamethasone. British Journal of Dermatology 123: 291-295, 1990 Dubertret L. Calcipotriol (MC 903) versus placebo in psoriasis: a multicenter double-blind study. Abstract. Presented at symposium: Daivonex® (calcipotriol). A totally new treatment in psoriasis; Athens, Greece, October 1991 Dwyer C, Chapman RS. CaIcipotriol and hypercalcaemia. Lancet 338: 764-765, 1991 Evans DB, Thavarajah M, Binderup L, Kanis JA. Comparison of the actions of MC903 and 1,25(OHhD3 on human osteoblast-like cells in vitro. Abstract. Journal of Bone and Mineral Research 4: S334, 1989 Evans DB, Thavarajah M, Binderup L, Kanis JA. The regulatory actions of MC903, a novel vitamin D3 analogue on human osteoblast-like cells in culture. Abstract. Bone II: 223, 1990 Griffiths WAD. Comparison of calcipotriol ointment and betamethasone ointment in the treatment of psoriasis vulgaris (parallel group). Abstract. Presented at symposium: Daivonex® (calcipotriol). A totally new treatment in psoriasis; Athens, Greece, October 1991 Gumowski-Sunek D, Rizzoli R, Saurat J-H. Effects of topical calcipotriol on calcium metabolism in psoriatic patients: comparison with oral calcitriol. Dermatologica 183: 275-279, 1991 Holick MF. Will 1,25-dihydroxyvitamin D3, MC 903, and their analogues herald a new pharmacologic era for the treatment of psoriasis? Archives of Dermatology 125: 1692-1697, 1989 Holland DB, Roberts SG, Russell A, Wood EJ, Cunliffe WJ. Changes in epidermal keratin levels during treatment of psoriasis with topical vitamin D3 analogue MC903. Abstract. British Journal of Dermatology 122: 284, 1990 Jiirgensen HJ. A comparative study of calcipotriol ointment and Dithrocream® in treating psoriasis vulgaris. Abstract. Presented at symposium: Daivonex® (calcipotriol). A totally new treatment in psoriasis; Athens, October, 1991 Kissmeyer A-M, Binderup L. Calcipotriol (MC 903): Pharmacokinetics in rats and biological activities of metabolites. A comparative study with 1,25(OHhD3. Biochemical Pharmacology 41, NO. 11: 1601-1606, 1991 KragbaIle K. Treatment of psoriasis by the topical application of the novel cholecalciferol analogue calcipotriol (MC 903). Archives of Dermatology 125: 1647-1652, 1989 Kragballe K, Beck HI, Sogaard H. Improvement of psoriasis by a topical vitamin D3 analogue (Me 903) in a double-blind study. British Journal of Dermatology 119: 223-230, 1988 Kragballe K, Fogh K, SIlgaard H. Long-term efficacy and tolerability of topical calcipotriol in psoriasis. Results of an open study. Acta Dermato-Venerologica 71: 475-478, 1991b
CaJcipotrioi: A Review
Kragballe K, Gjertsen BT, De Hoop D, Karlsmark T, Van De Kerkhof PCM, et al. Double-blind, right/left comparison of calcipotriol and betamethasone valerate in treatment of psoriasis vulgaris. Lancet 337: 193-196, 1991a Kragballe K, Wildfang IL. Calcipotriol (MC 903), a novel vitamin D3 analogue stimulates terminal differentiation and inhibits proliferation of cultured human keratinocytes. Archives of Dermatological Research 282: 164-167, 1990 Kragballe K. Combination of topical calcipotriol (MC 903) and UVB radiation for psoriasis vulgaris. Dermatologica 181: 211214, 1990 Kragballe K. Vitamin D3 analogues in psoriasis. Letters to the Editor. Dermatologica 180: 110, 1990 Long CC, Marks R. Calcipotriol and betamethasone valerate for psoriasis. Lancet 337: 921-922, 1991 Marie PJ, Connes D, Hott M, Miravet L. Comparative effects of a novel vitamin D analogue MC-903 and 1,25-dihydroxyvitam in D3 on alkaline phosphatase activity, osteocalcin and DNA synthesis by human osteoblastic cells in culture. Bone II: 171-179, 1990 Milde P, Hauser U, Simon T, Mall G, Ernst V, et al. Expression of 1,25-dihydroxyvitamin D3 receptors in normal and psoriatic skin. Journal of Investigative Dermatology 97: 230-239, 1991 Mortensen LS, Kragballe K, Schifter S, Charles P. A double-blind placebo-controlled study on calcipotriol (MC903) and Ca-metabolism. Abstract. Presented at symposium entitled Vitamin D Analogues, San Francisco, California, USA, July 12, 1991 Muller K, Svenson M, Bendtzen K. I alpha,25-dihydroxyvitamin D3 and a novel vitamin D analogue MC 903 are potent inhibitors of human interleukin I in vitro. Immunology Letters 17: 361-366,1988 Oxholm A, Oxholm P, Staberg B, Bendtzen K. Expression of interleukin-6-like molecules and tumour necrosis factor after topical treatment of psoriasis with a new vitamin D analogue (MC903). Acta Dermato-Venerologica 69: 385-390, 1989 Ramsay CA. Long-term experience with calcipotriol in the treatment of psoriasis. Abstract. Presented at Symposium [Dai-
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vonex (calcipotriol) - a totally new treatment in psoriasis), Athens, Greece, October 1991 Roenigk Jr. HH, Maibach HI (Eds). Psoriasis, 2nd ed., Dekker, New York, 1991 Saurat J-H, Sunek DG, Rizzoli R. Topical calcipotriol and hypercalcaemia. Lancet 337: 1287-1287, 1991 Sorensen H, Binderup L, Calverley MJ, Hoffmeyer L, Andersen NR. In vitro metabolism of calcipotriol (MC 903), a vitamin D analogue. Biochemical Pharmacology 39, 391-393, 1990 Staberg B, Roed-Petersen J, Menne T. Efficacy of topical treatment in psoriasis with MC903, a new vitamin D analogue. Acta Dermato-Venerologica 69: 147-150, 1989 Thavarajah M, Evans DB, Binderup L, Kanis JA. 1,25(OHJ2D3 and calcipotriol (MC903) have similar effects on the induction of osteoclast-like cell formation in human bone marrow cultures. Biochemical and Biophysical Research Communications 171: 1056-1063, 1990 Valaja T, Mahonen A, Pirskanen A, Maenpaa PH. Affinity ofMC 903 for 1,25-dihydroxyvitamin D receptor and its effects on the synthesis of osteocalcin in human osteosarcoma cells. Biochemical Pharmacology 40: 1827-1832, 1990 van de Kerkhof PCM, de Jong EGJM, de Mare S. DNA content and Ks8.12 binding of the psoriatic lesion during treatment with the vitamin D3 analogue MC903 and betamethasone. Abstract. Journal ofinvestigative Dermatology 95: 493-493, 1990 Verburgh CA, Nieboer C. Local application of vitamin D3 derivative MC903 in psoriasis: influence on cellular infiltrate, Langerhans cells and keratinocyte (KC) markers. Abstract. Journal of Investigative Dermatology 93: 310, 1989 Yip J, Goodfield M. Contact dermatitis from MC 903, a topical vitamin D3 analogue. Contact Dermatitis 25: 139-140, 1991
Correspondence: David Murdoch, Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand
Drugs 43 (3): 415-429, 1992 0012-6667/92/0003-0415/$07.50/0 © Adis International Limited. All rights reserved. ORE!
Calcipotriol A Review of its Pharmacological Properties and Therapeutic Use in Psoriasis Vulgaris David Murdoch and Stephen P. Clissold Adis International Limited, Auckland, New Zealand
Various sections of the manuscript reviewed by: O.E. Araujo, University of Florida, College of Pharmacy, Gainesville, Florida, USA; W.P. Arnold, Research Department of Dermatology, Nijmegen, The Netherlands; I. Berthlones, Department of Dermatology, Leicester Royal Infirmary, Leicester, England; A.J. Brown, Renal Division, Washington University School of Medicine, St Louis, Missouri, USA; C Dwyer, Department of Dermatology, Stobhill General Hospital, Glasgow, Scotland; P.H. Maenpaa, Department of Biochemistry and Biotechnology, University of Kuopio, Kuopio, Finland; H.I. Maibach, UCSF School of Medicine, Department of Dermatology, San Francisco, California, USA; P.I. Marie, H6pital Lariboisiere, Paris, France; T. Menne, Gentofte Hospital, Hellerup, Denmark; E. Ogata, Fourth Department ofInternal Medicine, University of Tokyo School of Medicine, Tokyo, Japan; CA. Ramsay, Diseases of the Skin, Toronto, Ontario, Canada; I-H. Saurat, Dermatology Clinic and Division of Clinical Pathophysiology, H6pital Cantonal Universitaire, Geneva, Switzerland; S. Shuster, Department of Dermatology, Royal Victoria Infirmary, Newcastle-upon-Tyne, England; P.CM. van de Kerkho/, Research Department of Dermatology, Nijmegen, The Netherlands; I. Yip, Dermatology Centre, Lidcombe Hospital, Lidcombe, New South Wales, Australia.
Contents 416 417 418 418 419 420 420 421 422 422 423 423 425 425 425 427 428
Summary 1. Pharmacological Properties 1.1 Effects on Cell Proliferation and Differentiation 1.1.1 In Vitro and Ex Vivo Studies 1.1.2 In Patients with Psoriasis 1.2 Effects on Calcium Absorption and Mobilisation 1.3 Effects on Immunological and Inflammatory Mediators 1.4 Pharmacokinetic Properties 2, Therapeutic Efficacy in Psoriasis Vulgaris 2.1 Placebo-Controlled, Dose-Ranging and Noncomparative Studies 2.2 Comparisons with Other Antipsoriatic Treatments 2.2.1 Betamethasone Valerate 2.2.2 Dithranol (Anthralin) 2.2.3 Calcipotriol Plus Ultraviolet Radiation Therapy 3. Tolerability 4. Administration 5. Place of Calcipotriol in Therapy
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Summary Synopsis Calcipotriol (calcipotriene) is a vitamin D3 analogue which inhibits epidermal cell proliferation and enhances cell differentiation. In patients with chronic plaque psoriasis involved in short term studies of 6 to 8 weeks' duration, calcipotriol ointment applied twice daily was significantly more effective than betamethasone valerate and dithranol (anthralin). Pooled data from clinical trials show that calcipotriol is well tolerated, with the majority of adverse events being mild and transient local reactions. Topically applied calcipotriol has low hypercalcaemic potential and, in contrast to topical corticosteroids, oral retinoids and orally administered calcitriol, methotrexate and cyclosporin, calcipotriol does not appear to be associated with a risk of serious adverse events. Thus, at this early stage in its clinical development, calcipotriol appears to be an effective and well tolerated topical therapy for the management of psoriasis; if promising preliminary clinical findings are confirmed, calcipotriol will represent a major advance in this difficult area of therapeutics. Pharmacological Properties Calcipotriol has pharmacodynamic properties similar to those of calcitriol (1,25-dihydroxycholecalciferol), the active metabolite of vitamin D3. In several in vitro models, calcipotriol and calcitriol markedly inhibit cell proliferation and enhance cell differentiation over a range of concentrations from approximately 10- 10 to 10- 6 molfL. For example, both drugs reduce cell numbers, total DNA content and incorporation of radiolabelled thymidine into DNA, and increase the number of human keratinocytes with cornified envelopes and activity of the enzyme causing protein cross-linking in the envelopes. In patients with psoriasis, calcipotriol also reduces epidermal cell proliferation and enhances differentiation in lesional skin. Calcipotriol binds to intestinal calcitriol receptors with affinity similar to that of calcitriol, but is 100 to 200 times less potent than calcitriol in its effect on in vivo calcium metabolism in rats. Intraperitoneal calcipotriol I and 10 Ilg/kg/day administered to rats for 7 days did not significantly affect serum and urinary calcium levels, or dry weight and calcium content of tibial metaphyses. Conversely, calcitriol 0.5 Ilg/kg/day significantly altered these parameters. Calcipotriol inhibits interleukin-I-induced mouse thymocyte proliferation in vitro and, in patients with psoriasis, reduces the amount and distribution of epidermal interleukin-6 and the number of activated epidermal T-Iymphocytes. However, the relevance of these findings to the mechanism of action and clinical efficacy of calcipotriol in psoriasis remain uncertain. In patients with psoriasis, less than I % of calcipotriol is systemically absorbed after a single application of 0.3 to 1. 7g of radiolabelled calcipotriol ointment 50 Ilg/g. Calcipotriol is thought to undergo rapid hepatic conversion to MC 1046 and MC 1080, metabolites with negligible pharmacological activity, and has an affinity for human vitamin D binding protein 30 times less than that of calcitriol in vitro. Only traces of calcipotriol « I %) are recovered in urine and faeces after topical application.
Therapeutic Efficacy In patients with psoriasis, calcipotriol cream 1200 Ilg/g is significantly superior to cream base alone, and dose-response relationships have been identified for cream (10 to 100 Ilg/g) and ointment (25 to 100 Ilg/g) formulations of the drug. Marked decreases in physician-assessed mean clinical scores for severity of skin erythema, thickness and scaling were observed after cream (about 17 to 49%) and ointment (about 50 to 90%) application, and investigator global assessments of overall clinical response showed significant improvement. After calcipotriol ointment 25, 50 and 100 Ilg/g application, 40, 63 and 88% of patients with psoriasis, respectively, demonstrated 'marked' improvement or total clearance of lesions; the 50 Ilg/g concentration was significantly superior to 25 Ilg/g (n = 20), but not significantly different from 100 Ilg/g (n = 17). Additionally, calcipotriol ointment 50 Ilg/g significantly reduced mean psoriasis area and severity index (PASI) score by 67% in 161 patients with psoriasis treated for up to I year.
Calcipotriol: A Review
417
Calcipotriol ointment 50 p,g/g, compared with betamethasone valerate ointment 1 mg/g, produced significantly greater 6-week subjective clearance rates [% of patients with healed psoriatic lesions plus those showing marked improvement (61 to 82% vs 51 to 69%)], significantly greater 6-week reductions in PASI scores (approximately 70 vs 60%), and significantly lower physicianassessed mean scores for severity of skin erythema, thickness and scaling. Calcipotriol ointment 50 p.g/g was significantly more effective and had significantly greater cosmetic acceptability than dithranol cream 11 to 2.0% in a total of 478 patients with psoriasis.
Tolerability The most frequently occurring calcipotriol-induced adverse events are lesional/perilesional skin irritation (incidence approximately 9 to 20%), nonlesional erythema/infiltration/desquamation ('" 4%), facial/scalp irritation (2%), and miscellaneous skin disorders ('" 2 to 5%). Although lesional/perilesional skin irritation is more common in calcipotriol than betamethasone valerate recipients, all of the above events are generally mild and transient in nature and rarely require calcipotriol withdrawal. In large-scale, 6-week direct comparative trials, both calcipotriol and betamethasone were well tolerated. However, it is important to remember that, with longer term use (> 6 weeks) topical corticosteroids may have tolerability disadvantages in relation to calcipotriol: i.e. corticosteroids have the potential to cause complications such as adrenal-pituitary suppression, skin atrophy, masked tinea infection and pustular psoriasis. Interestingly, calcipotriol ointment 50 p.g/g applied twice daily for 6 months appeared not to be associated with skin atrophy in 8 patients with psoriasis; this certainly requires confirmation in larger numbers of patients. Calcipotriol is rarely associated with facial dermatitis, the reported cases probably resulting from inadvertent ointment transfer from hands to face, or allergic contact dermatitis. Hypercalcaemia has occurred in only a small number of patients treated with calcipotriol, usually involving large amounts or higher concentrations of the ointment; and appears to be more of a problem in patients receiving oral calcitriol. Importantly, none of more than 900 psoriatic patients treated with calcipotriol ointment 50 Jl.g/g twice daily (no more than lOOg applied per week) developed hypercalcaemia.
Administration For treatment of. psoriasis vulgaris calcipotriol ointment 50 p.g/g (no more than lOOg per week) should be applied to affected areas twice daily. Because of the risk offacial dermatitis, calcipotriol should not be applied to the face, and patients should wash their hands thoroughly after ointment application to prevent inadvertent transfer from hands to face.
1. Pharmacological Properties Calcipotriol (Me 903; calcipotriene) is a vitamin D3 analogue with a structure similar to that of calcitriol (1 ,25-dihydroxy-cholecalciferol; 1,25dihydroxy-vitamin D3), the most active metabolite of vitamin D3 (fig. 1). Vitamin D3, together with parathyroid hormone and calcitonin, plays an integral role in calcium and phosphorus homeostasis - controlling the absorption, distribution and excretion of these essential minerals. Analogues of
vitamin D3 have been used in the management of osteoporosis and, in 1986, Japanese researchers administered a vitamin D3 prodrug to a patient with osteoporosis and discovered, by chance, that the patient's psoriasis improved; this serendipitous finding led to evaluation of vitamin D3 analogues in patients with psoriasis. In several pharmacodynamic studies, calcipotriol has been compared with the 'experimental standard' calcitriol and, as outlined below, the 2 drugs appear to have similar pharmacodynamic properties.
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418
OH
Calcipotriol (MC 903)
Calcitriol (1 a,25-dihydroxyvitamin 03; 1a,25-dihydroxycholecalciferol)
differentiation, and therefore therapeutic value in the treatment of psoriasis (Binderup 1988; Binderup et al. 1988b; Valaja et a1. 1990). 1.1.1 In Vitro and Ex Vivo Studies Calcipotriol demonstrated effects on cell proliferation and differentiation similar to those of calcitriol in many in vitro experiments (Kissmeyer & Binderup 1991; table I). Reduced cellular proliferation, at drug concentrations of 10-8 mol/L in various cell cultures, was indicated by reduction of cell numbers (calcipotriol 5 to 58% vs calcitriol 41 to 61%) [Kragballe & Wildfang 1990; Valaja et a1. 1990], decreased total cellular DNA content relative to control values (22 vs 3%; Binderup 1988), and reduced incorporation of [3H]thymidine into DNA (fig. 3). In human cell lines, concentrations of calcipotriol and calcitriol required to inhibit cellular proliferation by 50%, or to inhibit incorporation of [3H]thymidine into DNA by 50%, ranged from 1.4 X 10-8 to > 10-7 mol/L (table I). Additionally, calcipotriol and calcitriol inhibited human osteoblast-like cell proliferation across the concentration range 10- 10 to 10-6 mol/L in a con-
o
Fig. 1. Structural formulae of calcipotriol and calcitriol.
1.1 Effects on Cell Proliferation and Differentiation Although the aetiology of psoriasis vulgaris remains unclear, characteristic features of the disease include hyperproliferation and incomplete differentiation of the epidermis (Araujo et al. 1991; Binderup 1988; Holick 1989). Recent studies have shown that calcitriol receptors are present in a number of cell types, including skin cells, and that calcitriol markedly suppresses proliferation and enhances differentiation of epidermal keratinocytes (Araujo et a1. 1991; Binderup 1988; Binderup & Bramm 1988). Because calcipotriol and calcitriol displayed similar affinity for calcitriol receptors in several in vitro models (fig. 2), it was logical to expect that calcipotriol also possessed antiproliferative activity, the ability to induce epidermal cell
............ Calcitriol
t:
20
~0
40
~
~
e----e Calcipotriol
6 weeks) topical corticosteroids, unlike calcipotriol, may be associated with a risk of adrenal-pituitary suppression, skin thinning, masked tinea infection and possible development of pustular psoriasis (Cunliffe et al. 1992; Kragballe et aI. 1991a; Long & Marks 1991; Ramsay 1991). Interestingly, in a 6-month nonblind study of 15 patients with psoriasis, twice daily application of calcipotriol ointment 50 J,Lg/g (up to 100g per week) appeared not to be associated with skin atrophy. Although skin biopsies from 8 ofthe 15 patients showed that thickness of the epidermis and papillary dermis was similar in calcipotrioltreated perilesional skin compared with untreated lesional skin (Kragballe et al. 1991 b), these findings obviously require confirmation in larger numbers of patients. Calcipotriol ointment was applied to facial psoriatic lesions in only 1 clinical trial: 5 of 46 patients 10 9 8 7 ~ 0 6 0 If) 5 Cii 4 « a. 3 2 1 0
a
(10.9%) developed facial dermatitis (3 patients were applying calcipotriol to the face, 2 were not) and 2 patients stopped calcipotriol treatment because of this reaction (Kragballe 1989). However, other studies showed that facial dermatitis, probably resulting from inadvertent transfer of calcipotriol ointment from hands to face, was a rare occurrence (Ramsay 1991), or was generally mild and transient in nature (Kragballe 1990; Kragballe et al. 1991 b). Calcipotriol has been associated with only a small number of cases of allergic contact dermatitis (Ramsay 1991; Yip & Goodfield 1991), and isolated reports of hypercalcaemia (Cunliffe et al. 1992; Dwyer & Chapman 1991). In the latter cases, large amounts of calcipotriol were applied: a 77-year-old woman applied 400g of calcipotriol ointment (50 J,Lgfg) over a lO-day period (Cunliffe et al. 1992); and a 67-year-old woman with a moderate degree of renal impairment applied approximately 200g of calcipotriol ointment 50 J,Lg/g twice daily over a 7day period (Dwyer & Chapman 1991). Importantly, calcipotriol is known to have a far lesser effect on in vivo calcium metabolism than oral or parenteral calcitriol (section 1.2) and, in over 900 psoriatic patients treated with calcipotriol ointment 50 J,Lg/g twice daily (no more than lOOg applied per week) for 6 to 52 weeks, mean serum levels of total calcium were not significantly altered (Cunliffe et al. 1992; Jurgensen 1991; Kragballe et
o Calcipotriol • Betamethasone valerate
o Calcipotriol
12
D Dithranol
10 ~
8 ~ «
a.
8
6
4 2
o
O~.----,---.---,----r
2
4
o
6
Treatment duration (weeks)
b
2
6
4
8
Treatment duration (weeks)
Fig. 7. Reductions in psoriasis area and severity index (PAS!) scores in: (a) 342 patients treated with calcipotriol 50 p.gjg and betamethasone valerate I mgjg ointments applied twice daily for 6 weeks in a right-left comparison (Kragballe et al. 199Ia); and (b) in 478 patients treated with calcipotriol ointment 50 p.gjg or dithranol cream (0.1 to 2.0%) for 8 weeks in a parallel study (Jiirgensen 1991). Statistically significant difference between treatments: t = p < 0.01; = p < 0.001.
*
Calcipotriol: A Review
427
Table III. Number (and percentage) of patients experiencing adverse events in studies in which calcipotriol (CPL) ointment SO I"g/g was applied to psoriatic lesions twice daily for 6 to 8 weeks (Cunliffe et al. 1992; Jurgensen 1991; Kragballe et al. 1991 a) Adverse event
Cunliffe et al. (1992)
Kragballe etal. (1991 a)
Jurgensen (1991)
CPL
BET
CPL
DIT
CPL
(n = 20S)
(n = 204)
(n = 239)
(n = 239)
(n = 342)
43 (18.0%)8'
110 (46%)8
26 4b
21
30 (8.8%)
22 (6.4%)
1 (0.3%) 6 (1.8%)
10 (2.9%)
2 (0.6%)
1 (0.3%)
BET (n = 342)
Lesional/perilesional irritation Burning/itching/stinging
23
Erythema/scaling/peeling/ exfoliation
12
Other (e.g. dry skin, slight
S
'prickling sensation' Total
40 (19.S%)'
Nonlesional erythema/ infiltration/desquamation
8 (3.9%)
Facial/scalp irritation
4 (2.0%)
Skin infection Miscellaneous skin problems Treatment withdrawals
8 (3.9%) 3 (1.S%)
1 (O.S%)
S (2.S%)
11 (S.4%)
2 (1.0%)
S (2.4%)
S (2.S%)
a
Data about other events not provided.
b
One patient had 'increased exfoliation'.
4 (1.7%)C
12 (S.O%)C
3 (0.9%)
c Adverse reactions (I.e. considered possibly or probably related to calcipotriol). Abbreviations and symbols: BET = bethamethasone valerate; DIT = dithranol; • statistically significant difference between calcipotriol and comparator regimen.
al. 1991a; Ramsay 1991). Further, in 12 to 33 patients with psoriasis, calcipotrio1 ointment (50 J.tg/g) had no significant effects on calcium metabolism compared with placebo (Mortensen et al. 1991), and at a total daily dose of 150J.tg, had no significant effect on serum calcium levels and daily or fasting urinary calcium excretion, whereas an equivalent dose of oral calcitriol (1.5 J.tgjday) caused significant hypercalcaemia and hypercalciuria (Gumowski-Sunek et al. 1991; Saurat et al. 1991). Thus, hypercalcaemia may occur if large amounts of calcipotriol ointments are used indiscriminately, but elevated serum calcium levels would seem to be an unlikely occurrence with prudent application (i.e. the recommended maximum of 100 g/week) of calcipotriol ointment 50 J.tg/g (Saurat et al. 1991). Overall, these preliminary data suggest that calcipotriol ointment 50 J.tg/g applied twice daily is a well tolerated regimen for the treatment of psoriasis. However, clinical experience with the drug has been limited and much larger numbers of patients need to be assessed before the tolerability
profile of calcipotriol, particularly in relation to other antipsoriatic agents (e.g. topically applied calcitriol, betamethasone valerate' and dithranol), can be clearly defined.
4. Administration In the UK, the currently recommended application regimen for calcipotriol ointment in the treatment of patients with psoriasis vulgaris affecting up to 40% of the skin area is 50 J.tg/g twice daily to affected areas. Importantly, no more than 100g of calcipotriol ointment 50 J.tg/g should be applied per week, as this may be associated with iln increased risk of hypercalcaemia. Further, the course of calcipotriol treatment should not exceed 5 weeks. Because of the possibility of facial dermatitis, calcipotriol should not be applied to the face. Patients should be advised to thoroughly wash their hands after use of the ointment, thus preventing inadvertent ointment transfer from hands to face.
428
5. Place of Calcipotriol in Therapy Psoriasis vulgaris is a common, very distressing skin disorder of unknown aetiology. Historically, the condition has proved difficult to treat, and commonly used antipsoriatic agents have had poor tolerability profiles (e.g. oral retinoids, methotrexate and topical corticosteroids) or have been unacceptable to patients because of unpleasant aromas and messy application (e.g. coal tar and dithranol). Rather fortuitously, oral and topical vitamin D3 and its analogues were recently found to be effective in the treatment of psoriasis. Orally administered calcitriol may have limited therapeutic value because of hypercalcaemic potential and, although no direct efficacy and tolerability comparisons have been made between topical formulations of calcitriol and calcipotriol, topical calcipotriol seems to have a promising future as an anti psoriatic. Large-scale trials showed calcipotriol ointment to be significantly more effective than betamethasone valerate and dithranol in patients with chronic plaque psoriasis; calcipotriol was also significantly more acceptable to patients than dithranol. Whether the antipsoriatic efficacy of calcipotriol is enhanced by ultraviolet (UV) radiation therapy (UVB or PUVA) remains unclear. Ongoing, large-scale, comparative trials assessing the efficacy of calcipotriol alone, and in combination with UVB or PUVA therapy, should clarify this. Thus, although further clinical experience with calcipotriol is required before its place in therapy can be more clearly defined, early indications are that it is an effective and well tolerated agent which represents a worthwhile therapeutic advance in the management of psoriasis, a traditionally distressing and difficult-to-treat skin disorder.
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Drugs 43 (3) 1992
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CaJcipotrioi: A Review
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vonex (calcipotriol) - a totally new treatment in psoriasis), Athens, Greece, October 1991 Roenigk Jr. HH, Maibach HI (Eds). Psoriasis, 2nd ed., Dekker, New York, 1991 Saurat J-H, Sunek DG, Rizzoli R. Topical calcipotriol and hypercalcaemia. Lancet 337: 1287-1287, 1991 Sorensen H, Binderup L, Calverley MJ, Hoffmeyer L, Andersen NR. In vitro metabolism of calcipotriol (MC 903), a vitamin D analogue. Biochemical Pharmacology 39, 391-393, 1990 Staberg B, Roed-Petersen J, Menne T. Efficacy of topical treatment in psoriasis with MC903, a new vitamin D analogue. Acta Dermato-Venerologica 69: 147-150, 1989 Thavarajah M, Evans DB, Binderup L, Kanis JA. 1,25(OHJ2D3 and calcipotriol (MC903) have similar effects on the induction of osteoclast-like cell formation in human bone marrow cultures. Biochemical and Biophysical Research Communications 171: 1056-1063, 1990 Valaja T, Mahonen A, Pirskanen A, Maenpaa PH. Affinity ofMC 903 for 1,25-dihydroxyvitamin D receptor and its effects on the synthesis of osteocalcin in human osteosarcoma cells. Biochemical Pharmacology 40: 1827-1832, 1990 van de Kerkhof PCM, de Jong EGJM, de Mare S. DNA content and Ks8.12 binding of the psoriatic lesion during treatment with the vitamin D3 analogue MC903 and betamethasone. Abstract. Journal ofinvestigative Dermatology 95: 493-493, 1990 Verburgh CA, Nieboer C. Local application of vitamin D3 derivative MC903 in psoriasis: influence on cellular infiltrate, Langerhans cells and keratinocyte (KC) markers. Abstract. Journal of Investigative Dermatology 93: 310, 1989 Yip J, Goodfield M. Contact dermatitis from MC 903, a topical vitamin D3 analogue. Contact Dermatitis 25: 139-140, 1991
Correspondence: David Murdoch, Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand
