Ruth Thieroff-Ekerdt

Do Urea/Ammonium Lactate Combinations Achieve Better Skin Protection and Hydration than Either Component Alone?

Twenty subjects with healthy skin were treated with the following formulations for two weeks: drug-free W/O vehicle, 5% ammonium lactate (CAS 52003-58-4) in W/O vehicle, 5% urea (CAS 57-13-6) in W/O vehicle, 3% ammonium lactate + 3% urea in W/O vehicle, 5% ammonium lactate + 5% urea in W/O vehicle. These formulations were applied in randomized order to 6 test areas on the forearms; one area was left untreated. Repetitive washings were additionally performed in the second treatment week. TEWL, stratum corneum water content (corneometry-determined electrical capacitance), and cutaneous blood flow (laser Doppler) were measured at baseline, day 7, and day 14. 5% urea and both ammonium lactate/urea combinations produced significant stratum corneum hydration and improved stratum corneum barrier function; there were no significant differences between these three treatments.

Potent gene regulatory and antiproliferative activities of 20-methyl analogues of 1,25 dihydroxyvitamin D3.

The biological active form of vitamin D3, 1,25‐dihydroxyvitamin D3 (VD), regulates cellular growth and differentiation. This provides the hormone with an interesting therapeutic potential. However, hypercalcemia is a side effect, which is caused by VDs classical action, the regulation of calcium homeostasis. This made the need for VD analogues with selectively increased cell regulatory properties. Studies with 20‐epi analogues pointed out the importance of the carbon‐20 position and led to the development of 20‐methyl derivatives of VD. In this report the biological properties of the compounds ZK161422 and ZK157202, which are 20‐methyl‐ and 20‐methyl‐23‐eneanalogues, respectively, have been analyzed in comparison with VD. Both compounds show about 2‐fold lower affinity to the VD receptor (VDR) than VD. However, compared to VD, their antiproliferative effect is up to 30‐fold higher on human peripheral blood mononuclear cells and even up to 300‐fold higher on human breast cancer MCF‐7 cells. Whereas the hypercalcemic effect for ZK157202 is also increased 10‐fold, ZK161422 has the same calcium‐mobilizing potency as VD. Moreover, ZK161422, but not ZK157202, showed preference for gene activation from a promoter carrying a VD response element with a palindromic arrangement of two hexameric receptor binding sites spaced by 9 nucleotides (IP9) rather than for activation from a response element formed by a direct repeat spaced by 3 nucleotides (DR3). This observation supports a model, in which promoter selectivity reflects the selectively increased antiproliferative effect of VD analogues.

Synthesis and biological activities of 8(14)a-homocalcitriol

8(14)a-Homocalcitriol was synthesized and tested for its biologic activities. It exhibited a vitamin D agonist activity profile. The compound was bound to the pig intestinal receptor with an affinity slightly less than calcitriol, showed the same potency in inducing HL 60 cell differentiation and inhibition of keratinocyte proliferation as calcitriol, and was found to be approximately 10-fold less potent in inducing hypercalcemia and hypercalciuria after a single injection in normal rats.

Effects of Calcipotriol (MC 903) and Calcitriol after Topical Application on the Skin of Hairless Rats

Topical application of calcitriol or its analogs is a new approach for treating psoriasis, but may be limited by systemic calcitropic effects. Calcipotriol (MC 903) is a novel calcitriol analog with low calcitropic potency after systemic application. To compare the topical potency of calcitriol and calcipotriol we applied the two drugs on the right flanks of hairless rats for 10 days. In concentrations of 0.001-0.01 g/100 ml (ethanol) the two drugs are equally effective in inducing changes in the horny layer of the skin (increase in the amount of horny material that is able to be desquamated). This can be interpreted as a stimulation of terminal keratinocyte differentiation. However, only calcitriol caused a significant rise in the serum calcium concentration. In conclusion, calcitriol and calcipotriol seem to be equally effective after topical application on the skin of hairless rats, but calcipotriol has a much lower systemic calcium liability.