Recent developments in vitamin D analogs

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.     

Calcipotriol/betamethasone dipropionate: a review of its use in the treatment of psoriasis vulgaris of the trunk, limbs and scalp

Calcipotriol/betamethasone dipropionate (calcipotriol 50?μg/g and betamethasone 0.5?mg/g) is a fixed-dose combination of a vitamin D(3) analogue and a corticosteroid indicated for the once-daily, topical treatment of psoriasis vulgaris of the trunk, limbs and scalp in adults. Both the ointment (Daivobet?; Dovobet?) and gel (Xamiol?; Daivobet? Gel; Dovobet? Gel) formulations of calcipotriol/betamethasone dipropionate can be used to treat psoriasis vulgaris of the trunk and/or limbs, although the gel formulation was specifically developed for the treatment of scalp psoriasis. This article reviews the efficacy and tolerability of calcipotriol/betamethasone dipropionate in patients with psoriasis vulgaris, as well as summarizing its pharmacological properties. Calcipotriol/betamethasone dipropionate has low systemic absorption and displays local anti-inflammatory and immunoregulatory properties. It reduces the hyperproliferation of keratinocytes and helps normalize keratinocyte differentiation. In large, well designed clinical trials, calcipotriol/betamethasone dipropionate, either as the ointment or the gel formulation, applied once daily for 4-8 weeks, was more effective than placebo, calcipotriol and tacalcitol, as well as betamethasone dipropionate in most instances, for the topical, symptomatic treatment of psoriasis vulgaris of the trunk/limbs. Likewise, calcipotriol/betamethasone dipropionate gel applied once daily for 8 weeks was more effective than placebo or either component alone in the topical, symptomatic treatment of psoriasis vulgaris of the scalp. Long-term, once-daily, when required therapy with calcipotriol/betamethasone dipropionate for 52 weeks was more effective than calcipotriol alone for the treatment of scalp psoriasis, and was at least as effective as switching to calcipotriol for 48 weeks after 4 weeks of calcipotriol/betamethasone dipropionate or alternating between calcipotriol/betamethasone dipropionate and calcipotriol every 4 weeks for 52 weeks in the treatment of psoriasis vulgaris of the trunk/limbs. Calcipotriol/betamethasone dipropionate also improved health-related quality of life. Calcipotriol/betamethasone dipropionate was generally well tolerated, with most adverse drug reactions being lesional or perilesional effects of mild or moderate severity. Calcipotriol/betamethasone dipropionate was often associated with fewer lesional/perilesional adverse reactions than calcipotriol or tacalcitol and did not appear to be associated with a higher incidence of corticosteroid-related adverse events during long-term therapy. Pharmacoeconomic analyses predicted calcipotriol/betamethasone dipropionate to be more cost effective than other topical therapies. Thus, calcipotriol/betamethasone dipropionate is an important, effective, once-daily, topical therapy for the symptomatic treatment of psoriasis vulgaris of the trunk, limbs and scalp.     

The therapeutic effects of vitamin D3 and its analogues in psoriasis

Psoriasis is a common skin disease which is characterised by the proliferation and abnormal differentiation of keratinocytes, coupled with complex immune disturbances. The beneficial effects of vitamin D derivatives in this disease are due to their capacity to inhibit proliferation, their ability to induce normal differentiation and their immunomodulatory properties. Since the systemic administration of these compounds is limited by their effect on calcium metabolism, topical preparations have become available in most countries. Topical calcipotriol and/or tacalcitol are now considered as first-line treatment for mild-to-moderate psoriasis and can be taken in combination with other systemic therapies in more severe cases of the disease. Novel orally active vitamin D analogues, with minimal calcitropic effercts, are, however, required for more effective treatment.     

Calcipotriol. A review of its pharmacological properties and therapeutic use in psoriasis vulgaris.

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.     

Management of scalp psoriasis: guidelines for corticosteroid use in combination treatment

Scalp psoriasis is a frequent expression of the common skin disease psoriasis, and scaling and itching are the two major complaints. Topical treatments are the mainstay of the treatment of psoriasis of the scalp, with the vehicle as well as the active ingredient relevant to efficacy, tolerability and compliance. Vehicles can be shampoos, lotions, gels, foams, creams and more greasy ointments. Active ingredients are keratolytics, coal tar (liquor carbonis detergens), dithranol, corticosteroids and vitamin D3 analogues. Some effect has also been described from topical or systemic imidazole derivatives. Topical corticosteroids remain the mainstay in the treatment of scalp psoriasis. The effects are rapid, the formulations are patient friendly and the adverse effects seem limited, although no data are available to support safety during prolonged use (more than 4 weeks). Topical vitamin D3 analogues have been available for the treatment of psoriasis since 1992. In the lotion formulation in particular, vitamin D3 analogues are a patient friendly, tolerable and effective alternative to corticosteroids, although the effects are optimal after 8 weeks, in contrast to 2-3 weeks for topical corticosteroids. Facial irritation (often temporary) can also be a disadvantage of vitamin D3 analogues, although only a small proportion of patients stop treatment for this reason. All other treatment options for psoriasis, such as tazarotene, phototherapy and systemic treatment with methotrexate, acitretin and cyclosporin are often not indicated or not suitable for treatment of the scalp. In daily practice, to make a choice from the available therapeutic arsenal for psoriasis, each patient should be examined individually. Deteriorating factors have to be excluded. For scaling, keratolysis is the first step. Subsequently, active treatment can be chosen depending on the clinical picture. When the psoriatic lesions are mainly characterised by inflammation, anti-inflammatory drugs such as topical corticosteroids are indicated. When scaling is the more important clinical feature, vitamin D3 analogues are indicated. Generally, intermittently used topical corticosteroids alternating with vitamin D3 derivatives either combined or not with liquor carbonis detergens containing shampoo is the most suitable treatment for most patients. Because psoriasis capitis is a chronic disease, long term treatment should, in addition to medical advice, also provide patient support and motivation.     

Calcipotriol: A New Drug for Topical Psoriasis Treatment

Abstract: Vitamin D is best known for its role in the regulation of calcium and bone metabolism. The effects of the biologically active form of vitamin D, 1,25-dihydroxyvitamin D₃ (1,25 (OH)₂D₃), are mediated by binding to a specific intracellular vitamin D receptor, which is present in most tissues including the skin where it regulates the growth of epidermal cells. Calcipotriol is a synthetic analogue of 1,25(OH)₂D₃. In vitro the activity of calcipotriol is comparable to that of 1,25(OH)₂D₃. In vivo, however, the risk of calcipotriol changing calcium metabolism is greatly reduced. Animal studies have established that calcipotriol is 100–200 times less calcaemic than 1,25 (OH)₂-D₃. This low calcaemic activity is mainly due to the rapid metabolism of calcipotriol. This pharmacological profile makes calcipotriol an ideal candidate for topical treatment of hyperproliferative skin disorders, such as psoriasis. This paper reviews the clinical experience with calcipotriol in psoriasis patients.     

Calcipotriol ointment versus cream in psoriasis vulgaris

Psoriasis is a multifactorial, chronically relapsing, inflammatory skin disease occurring in 1-3% of the world's population. Vitamin D3 analogs have effects on proliferation and differentiation, as well as on the infiltration and activation of neutrophils and immunocytes in psoriatic skin lesions. This study aims to assess the efficacy and safety of topical calcipotriol and to compare ointment and cream formulations in the treatment of psoriasis vulgaris. A total of 41 patients with mild to moderate psoriasis vulgaris (18 men and 23 women aged between 5 and 63 years) were enrolled in the study. Each patient was instructed to apply the treatment twice daily over the psoriatic lesions. Routine blood tests and serum calcium were performed prior to and at the end of treatment. Treatment assessment was carried out on weeks 2, 4 and 6 and was based on the Psoriasis Area and Severity Index (PASI) score. Of the 41 patients included in our study, only 29 completed the treatment course. Their PASI before treatment ranged from 1.2 to 43 (mean: 12.1). Both groups, calcipotriol 50 microg/g ointment (11 patients) and calcipotriol 50 microg/g cream (18 patients) showed time-dependent improvement and after 6 weeks there was excellent improvement with a marked reduction in the total mean PASI from 12.1 to 1.02. There was a significant reduction of PASI in the ointment group in comparison with the cream group (mean PASI from 12.7 to 0.8 and 11.1 to 1.15, respectively). No significant adverse effects were observed in either group, except for mild irritation in a few patients in the calcipotriol cream group. In conclusion, calcipotriol was effective, safe and well tolerated in the treatment of psoriasis vulgaris and better results were observed with the ointment formulation. Longer treatment courses could be advised.     

Combination topical therapy for the treatment of psoriasis

Dermatological research continues to move toward the goal of developing an effective psoriasis treatment that would rapidly clear lesions and provide long-term freedom from visible signs and symptoms. Currently, topical corticosteroids remain a pivotal treatment due to their effective anti-inflammatory properties; however, potential adverse effects associated with chronic application limit long-term continuous therapy. Vitamin D analogues provide another mechanism of action, reducing lesions through effects on both keratinocytes and on the cytokine environment. A topical combination of corticosteroid and vitamin D derivative appears to provide a balanced approach to psoriasis treatment. The development of clobetasol propionate foam 0.05% (clobetasol propionate foam/Olux) offers a convenient topical corticosteroid that can be used concomitantly, that is, immediately followed by application of calcipotriene ointment 0.005% (Dovonex). This regimen has been shown to offer an increased short-term efficacy compared with either agent alone. Continued application of calcipotriene ointment on weekdays supplemented by long-term clobetasol propionate foam pulse therapy on weekends appears to provide an enhanced maintenance of remission compared with calcipotriene monotherapy.     

Vitamin D<Subscript>3</Subscript>–Based Conjugates for Topical Treatment of Psoriasis: Synthesis,Antiproliferative Activity,and Cutaneous Penetration Studies

No HeadingPurpose. The goals of the experiments reported in this paper were to explore skin bioavailability and cell growth inhibitory activity of new vitamin D₃–based conjugates studied as a potential drug complex for psoriasis.Methods. Conjugation was made between polyunsaturated fatty acids (PUFAs), such as linolenic acid or -linolenic acid, and calcipotriol—a vitamin D₃ analogue clinically used for topical treatment of psoriasis. These complexes were prepared by coupling the corresponding fatty acid with calcipotriol in the presence of dicyclohexyl-carbodiimide (DCC) and 4-(dimethylamino)-pyridine (DMAP) to obtain an ester bond.Results. The conjugates were capable of enhancing the penetration of the vitamin into the skin as well as inhibiting proliferation of keratinocytes in cultures. The antiproliferative activity even increased after simulating the full hydrolysis of the conjugates. In vitro skin penetration studies revealed that the conjugates penetrated into the skin at higher levels relative to calcipotriol alone. It was also demonstrated that the conjugate containing n-3 fatty acid penetrated into the skin at higher levels as compared to the conjugate containing n-6 PUFA. High-performance liquid chromatography analysis has shown that after penetration, a major portion of calcipotriol-PUFA conjugate was first converted mainly into another isomer form, presumably by transesterification, and only then it was hydrolyzed to form apparently high local concentrations of both calcipotriol and PUFA.Conclusions. The unique biotransformation that occurred after penetration into the skin indicates that these conjugates are mutual prodrugs that are able to be bioprocessed in the skin and fully converted to the parent therapeutic agents.     

Psoriasis

Psoriasis is an inflammatory disorder of the skin that involves complex interactions between the dermis and epidermis. There are several forms of psoriasis, the most common being plaque type psoriasis. Other forms include guttate, pustular and erythrodermic psoriasis. Both the skin and joints are affected in this disease. Psoriasis ranges in severity from a few small plaques to involvement of the entire cutaneous surface. Therapy of psoriasis depends on the location, type and severity of the disease. Treatments include a wide array of topical medications including tars, anthralin, topical corticosteroids, vitamin D(3) analogs, retinoids and over-the-counter preparations. Phototherapy with ultraviolet B and PUVA are used for more widespread involvement. Common systemic therapies include methotrexate, retinoids and cyclosporin. This article will review the pathogenesis and clinical features of psoriasis, as well as current and future therapies.     

Emerging topical treatments for psoriasis

Introduction: Psoriasis is an immune-mediated chronic inflammatory skin disease which classically presents as erythematous, scaly plaques affecting extensor surfaces of the limbs, scalp and trunk. Approximately 80% of patients have a mild-to-moderate form routinely treated with topical medications, whereas phototherapy, systemic and biological therapies are typically reserved for treatment of moderate-to-severe psoriasis.

Areas covered: The major advances in psoriasis therapy in the past 15 years have been in new immunomodulatory and biological molecules, with a significant unmet need to have new, efficient and safe topical treatment options for the large percentage of patients for whom systemic therapy is not indicated. The available topical therapies (corticosteroids and vitamin D3 analogs) have remained relatively unchanged over the past several decades. This article reviews emerging topical drugs and formulations currently under evaluation in clinical trials.

Expert opinion: The time is right for a revolution in our topical therapy armamentarium. It has lagged significantly behind the systemic biological evolution of new drug development. Our large psoriasis population with mild-to-moderate psoriasis certainly deserves potent but safe and innovative topical agents with a new mode of action as well as with long-lasting clinical efficacy.     

Topical treatments for scalp psoriasis

Psoriasis is a common, chronic inflammatory skin disease that affects the scalp more commonly than any other site. Scalp psoriasis causes significant psychosocial disability as it is highly visible and can, on occasion, extend onto the face. Furthermore, current treatment regimens are messy, time consuming and, in some instances, ineffective, leading to a high level of non-compliance. The majority of current evidence for topical treatments for this condition comes from open-label, uncontrolled studies. From such studies, there are data to support the use of topical corticosteroids in a number of different formulations and topical vitamin D analogues. However, these studies have not addressed issues such as the need for keratolytics, which may be required to remove adherent scale before a topical corticosteroid or vitamin D analogue may prove efficacious. There is an urgent need for well designed, controlled trials to assess the efficacy of existing and new treatment regimens for scalp psoriasis. The aim of this review is to critically assess the relative effectiveness and tolerability of available topical therapies for this problematic condition and provide recommendations for selection of treatment.     

Calcipotriene/betamethasone in the treatment of psoriasis: a review article

Plaque-type psoriasis is a chronic and immune-mediated skin disease affecting ～ 1 – 3% of the Caucasian population. Most cases are of mild or moderate severity and benefit from local treatment that represents the mainstay therapy. Topical corticosteroids and vitamin D₃ analogues remain the option of choice. Optimization of these treatments is made by the combination of calcipotriene and betamethasone dipropionate. This formulation combines the keratinocyte differentiation and antiproliferative action of the vitamin D₃ analogues with the anti-inflammatory effect of steroids enhancing effectiveness while reducing the side-effect profile of the single topical agent. In this article, we highlight the advantages of the association of calcipotriene and betamethasone in the treatment of localized plaque-type, scalp and nail psoriasis.     

Calcipotriol Affects Keratinocyte Proliferation by Decreasing Expression of Early Growth Response-1 and Polo-like Kinase-2

Purpose Calcipotriol is a potent drug for topical treatment of psoriasis because it manages to inhibit keratinocyte proliferation. In the present study we investigated the effects of calcipotriol on gene expression in human keratinocytes in terms of mechanism of how calcipotriol decreases proliferation. Materials and methods Cell proliferation was analyzed by MTT assay. The differential display approach together with qPCR was used to assess the gene expression after treatment. In addition, Western immunoblotting revealed differences on the protein level. Finally, transfection of the KCs with specific small interfering RNA determined the genes necessary to inhibit proliferation. Results KCs proliferation was decreased in a concentration-dependent manner. Moreover, calcipotriol dowregulated the expression of two proliferation factors: early growth response-1 (EGR1) and polo-like kinase-2 (PLK2). The protein levels of EGR1 and PLK2 were also decreased. Specific siRNA against EGR1 and PLK2 in KCs resulted in marked reduction of EGR1 and PLK2 expression. In both cases, the reduction resolved in the decreased proliferation of KCs. Conclusion This study provides a new insight into how calcipotriol affects proliferation of keratinocytes by decreasing the expression of EGR1 and PLK2. Furthermore, the results offer groundwork for developing novel compounds for the treatment of hiperproliferative skin disorders like psoriasis.     

Vitamin D Analogues Tacalcitol and Calcipotriol Inhibit Proliferation and Migration of T98G Human Glioblastoma Cells

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.     

Clobetasol propionate foam in the treatment of psoriasis

Psoriasis is a common, chronic, distressing skin disorder that frequently affects the scalp, skin, nails and joints. Despite treatment, many patients suffer from unremitting disease and decreased quality of life. Scalp-type psoriasis is particularly difficult to treat. Although topical corticosteroids are the mainstay of therapy for moderate-to-severe disease, patients frequently object to the messiness and unfavourable cosmetic appearance of topical treatments. In this context, foam vehicles, which have the advantage of minimal residue and increased ease of application, have emerged as novel alternatives to traditional creams, ointments and solutions. Clobetasol propionate foam 0.05% (OLUX, Connetics Corporation), a high potency topical steroid, has been shown to alleviate symptoms of several dermatological conditions, including scalp and body psoriasis, improve disease severity and increase quality of life. Dose should be limited to 50 g/week, given the risk of adrenal suppression. Because patient preference is an important determinant of medication efficacy in clinical practice, clobetasol foam is a useful new formulation in the treatment of psoriasis and other skin conditions.     

Tolerance to calcitriol and tacalcitol in three patients with allergic contact dermatitis to calcipotriol

We describe 3 cases of psoriatic patients who developed a severe eczematous eruption after the use of calcipotriol ointment. For all of them, the dermatitis recovered after the suspension of the calcipotriol ointment and topical application of corticosteroids. We performed patch tests with the standard series of SIDAPA (Italian Society of Environmental, Occupational and Allergological Dermatology), with an integrative series of vehicles and preservatives, with the commercial ointment containing calcipotriol, with its excipients and, finally, with a series of diluted calcipotriol in isopropanol and petrolatum. They all revealed a strong allergic reaction to calcipotriol and also to its dilution in isopropanol (for all patients) and in petrolatum (only one patient). It is interesting to underline that the reactions always occurred on the legs, even if the patients had applied the ointment elsewhere. We can hypothesize that the venom stasis dermatitis of the legs, associated with xerosis, may have favored the penetration of the drug through the skin, increasing the risk of allergic contact sensitization. Finally, cross-reactivity to other vitamin D3 analogue, tacalcitol, and calcitriol was excluded.     

Clobetasol propionate foam in the treatment of psoriasis

Psoriasis is a common, chronic, distressing skin disorder that frequently affects the scalp, skin, nails and joints. Despite treatment, many patients suffer from unremitting disease and decreased quality of life. Scalp-type psoriasis is particularly difficult to treat. Although topical corticosteroids are the mainstay of therapy for moderate-to-severe disease, patients frequently object to the messiness and unfavourable cosmetic appearance of topical treatments. In this context, foam vehicles, which have the advantage of minimal residue and increased ease of application, have emerged as novel alternatives to traditional creams, ointments and solutions. Clobetasol propionate foam 0.05% (OLUX^?, Connetics Corporation), a high potency topical steroid, has been shown to alleviate symptoms of several dermatological conditions, including scalp and body psoriasis, improve disease severity and increase quality of life. Dose should be limited to 50 g/week, given the risk of adrenal suppression. Because patient preference is an important determinant of medication efficacy in clinical practice, clobetasol foam is a useful new formulation in the treatment of psoriasis and other skin conditions.