BACKGROUND:There continues to be a need to develop new pharmacological approaches for treating psoriasis. Topical active vitamin D compounds have proven to be both safe and effective for treating psoriasis. Paricalcitol (19-nor-1 alpha,25-dihydroxyvitamin D(2)) is a novel vitamin D analogue which has been developed for the prevention of secondary hyperparathyroidism in patients with chronic renal failure.OBJECTIVES:To investigate the efficacy and safety of 12 weeks' therapy with a once-daily application of paricalcitol ointment (15 microg g(-1)) in comparison with placebo ointment.METHODS:This pilot double-blinded self-controlled study was initiated in 11 patients with moderate plaque psoriasis. To characterize the biological effects further and to evaluate the efficacy of topical paricalcitol treatment in psoriasis, we have analysed immunohistochemically the expression of one of the markers for epidermal differentiation (transglutaminase K) in paricalcitol-treated skin as compared with placebo treatment.RESULTS:Treatment with paricalcitol was superior to placebo treatment beginning at week 1. The global severity score for erythema, plaque elevation and scaling was improved significantly more by paricalcitol ointment than by placebo (P < 0.001). Similar results were obtained for assessments of scaling, erythema and plaque elevation. No symptoms of local skin irritation were noted. Laboratory parameters including serum calcium, phosphorus, parathyroid hormone and urinary calcium/creatinine ratio did not reveal any changes of clinical relevance during treatment. The immunoreactivity of transglutaminase K changed after 12 weeks of paricalcitol treatment almost completely to the pattern characteristic for nonlesional psoriatic skin.CONCLUSIONS:Once-daily application of paricalcitol ointment was safe and effective for the treatment of plaque psoriasis.

Background There continues to be a need to develop new pharmacological approaches for treating the common skin disease psoriasis. Human skin produces parathyroid hormone related peptide. This peptide is a potent inhibitor of epidermal cell growth.Objectives A programme was initiated to determine whether an agonist of this peptide's receptor, PTH (1-34), could be developed as a drug to treat psoriasis.Methods PTH (1-34) was formulated in Novasome A(R) cream. Fifteen adult patients with chronic plaque psoriasis who had failed to respond to at least one standard treatment were enrolled in a randomized double-blinded placebo self-controlled trial. The patients topically applied to a 25-cm(2) psoriatic lesion 0.1 g of either Novasome A(R) cream or Novasome A(R) cream that contained 20 mug of PTH (1-34) twice a day for 2 months. At the end of the double-blind study, patients were enrolled in an open large area study. Ten patients applied PTH (1-34) (50 mug per 0.1 g) once daily to their psoriatic lesions. The patients were evaluated for their global improvement and calcium metabolism.Results Novasome A(R) cream enhanced the percutaneous absorption of PTH (1-34) in human skin in comparison with formulations in propylene glycol or normal saline. Psoriatic lesions treated with PTH (1-34) showed marked improvement in scaling, erythema and induration. There was a 67.3% improvement in the global severity score for the lesion treated with PTH (1-34) compared with the placebo-treated lesion, which only showed a 17.8% improvement. Ten patients topically applied PTH (1-34) on all of their lesions in a stepwise manner. A Psoriasis Area and Severity Index score analysis of all the patients revealed improvement of 42.6% (P < 0.02). None of the patients experienced hypercalcaemia or hypercalciuria or developed any side-effect to the medication.Conclusions Patients who were resistant to at least one standard therapy for psoriasis had a remarkable improvement in their psoriasis when they applied PTH (1-34) to their lesion(s). No untoward toxicity was observed in any of the subjects. This pilot study suggests that topical PTH (1-34) is a safe and effective novel therapy for psoriasis.

Parathyroid hormone (PTH) related peptide (PTHrP) and the PTH/PTHrP receptor (PTH/PTHrP-R) show prominent cutaneous expression, where this signaling system may exert important paracrine and/or autocrine functions, such as in hair growth control. Chemotherapy-induced alopecia - one of the fundamental unsolved problems of clinical oncology - is driven in part by defined abnormalities in hair follicle cycling. We have therefore explored the therapeutic potential of a PTH/PTHrP-R agonist and two PTH/PTHrP-R antagonists in a mouse model of cyclophosphamide-induced alopecia. Intraperitoneal administration of the agonist PTH(1-34) or the antagonists PTH(7-34) and PTHrP(7-34) significantly altered the follicular response to cyclophosphamide in vivo. PTH(7-34) and PTHrP(7-34) shifted it towards a mild form of "dystrophic anagen", associated with a significant reduction in apoptotic (TUNEL+) hair bulb cells, thus mitigating the degree of follicle damage and retarding the onset of cyclophosphamide-induced alopecia. PTH(1-34), in contrast, forced hair follicles into "dystrophic catagen", associated with enhanced intrafollicular apoptosis. We had previously shown that an induced shift in the follicular damage-response towards "dystrophic catagen" mitigates cyclophosphamide-induced alopecia, whereas a shift towards "dystrophic catagen" initially enhanced the hair loss, yet subsequently promoted accelerated hair follicle recovery. Therefore, this study in an established animal model of chemotherapy-induced alopecia, which closely mimics human chemotherapy-induced alopecia, strongly encourages the exploration of PTH/PTHrP-R agonists and antagonists as novel therapeutic agents in chemotherapy-induced alopecia.

Parathyroid hormone (PTH) related peptide (PTHrP) is thought to influence the proliferation and differentiation of the epidermis and hair follicle. As a means of elucidating the biologic function of PTHrP on the hair follicle, a PTHrP analog PTH (7-34), which is a PTH/PTHrP receptor antagonist, was given intraperitoneally twice daily to C57 BL/6 mice at different stages of the hair cycle. PTH (7-34) induced 99 +/- 4.5% (mean +/- SEM) of resting telogen hair follicles into a proliferative (anagen) state, whereas 100% of the hair follicles in the control group remained in telogen. To determine whether this peptide influenced the progression of the hair follicles from anagen to catagen (hair follicle maturation and regression), groups of mice that were either spontaneously in or induced to anagen received either PTH (7-34) or placebo. Morphometric analysis of the hair follicles from the middle back region of the spontaneous anagen mice that received PTH (7-34) revealed that 19 +/- 4% (mean +/- SEM) of the follicles were in anagen VI, whereas none (0%) were in anagen in the control group. Similarly, in induced anagen mice treated with PTH (7-34), 22.3 +/- 1.4 (mean +/- SEM) of the follicles were in anagen VI compared to only 1.3 +/- 0.7% in the control mice. Together these observations suggest that PTHrP is a hair follicle morphogen that may be a major factor responsible for controlling the hair cycle. These studies provide a new insight for development of PTHrP analogs for a wide variety of disorders related to disturbances of hair cycling.

In this communication we describe the synthesis of 1α,25-dihydroxyvitamin D3-3β-bromoacetate [1,25(OH)2-BE], an analog of 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], as a part of our ongoing interest in characterizing the hormone-binding domain of the 1α,25-dihydroxyvitamin D3 receptor (VDR). We carried out several binding studies of 1,25(OH)2-BE with chick intestinal VDR preparations to demonstrate that 1,25(OH)2-BE is capable of blocking the entry of 1,25(OH)2D3 into its binding pocket and possibly covalently linking to the VDR molcule.

The biologic action of parathyroid hormone (PTH)-related peptide (PTHrP) in normal skin was investigated in cultured human keratinocytes and in SKH-1 hairless mice. The results indicate that the PTHrP agonists human PTHrP-(1-34) and PTH(1-34) are potent inhibitors of epidermal cell proliferation. [Nle8,18,Tyr34]bovine PTH-(7-34)-amide, an antagonist of the PTH/PTHrP receptor, blocked the inhibitory effect of PTH-(1-34) in cultured keratinocytes. In the SKH-1 mice, PTH-(7-34) caused a 244% increase of [3H]thymidine incorporation into isolated epidermal DNA and 246% and 180% increases in the number and length of hair shafts, respectively. Thus, PTH and PTHrP may play an important role in the normal physiology of skin, and their agonists and antagonists have potentially wide therapeutic applications in the treatment of hyperproliferative skin disorders and aging skin and could also be effective in stimulating and maintaining hair growth.

The photoaffinity labeling of chick intestinal 1α,25-dihydroxyvitamin D3 receptor with 1α,25-dihydroxyvitamin D3-3β-{N-(-4-azido-2-nitro[3,5-3H]phenyl)}glycinate has been determined under a variety of conditions.

Exposure of the skin to sunlight results in both tanning and vitamin D3 production. It has therefore been suggested that vitamin D3 or its active metabolite 1,25-dihydroxyvitamin D3 may be the mediator of UV-induced melanogenesis. To test this hypothesis, newborn foreskin-derived melanocytes were cultured in paired dishes in hormone-supplemented medium with 2% serum containing no detectable vitamin D3 or in the same medium containing 10(-8) or 10(-10) M of either provitamin D3, lumisterol, previtamin D3, vitamin D3, 25-hydroxyvitamin D3, or 1,25-dihydroxyvitamin D3. After 10 days, cell number in cultures containing vitamin D compounds was 93%-140% of unsupplemented controls and melanin content was 60%-120% of control, with no significant difference in either parameter for any compound tested. In separate experiments, human melanocytes and Cloudman S91 melanoma cells were repeatedly irradiated with physiologic doses of simulated sunlight and incubated between irradiations with provitamin D3, previtamin D3, vitamin D3, or 1,25-dihydroxyvitamin D3. Irradiated cultures had a 90%-95% inhibition of cell growth associated with a 200%-800% increase in melanin content per cell relative to controls, but there was no effect of any vitamin D compound on either cell type. Neither cultured human melanocytes nor S91 cells showed evidence of the cytosolic 1,25-dihydroxy-vitamin D3 receptor binding by sucrose density gradient analysis using radiolabeled 1,25-dihydroxyvitamin D3. The combined data strongly suggest that neither vitamin D3 nor its precursors or metabolites directly mediate melanogenesis in these cells.