3.1.2.4 PSK-3841: Phase II
A topical, non-steroidal androgen antagonist, PSK-3841 (formerly HMR-3841 and RU-58841), is being investigated in France by Proskelia for possible therapeutic value in Androgenetic Alopecia and acne. The compound was is Phase II clinical trials as of January 2004, and was originally researched by Roussel-Uclaf and Hoechst Marion Roussel. When compared with the antiandrogenic compound cyproterone acetate, PSK-3841 exhibited a 20% increase in AR binding. This compound binds to both the ligand and regulatory domains of the androgen receptor. PSK-3841 exerts allosteric binding effects and may provide a unique mechanism of action in the treatment of alopecia.
Imamura et al. noted that this compound prevents androgenetic follicular regression in bald stumptailed macaques; however, it does not promote follicular cell growth directly. Photographic and folliculogram evaluations of combined PSK-3841 5% plus minoxidil 2%, or minoxidil 5% versus previous results from each compound’s performance alone were compared. The most rapid hair regrowth in 1 month was observed in the PSK-3841 5% plus minoxidil 5% group, followed by 2 months for the PSK-3841 5% plus minoxidil 2% group. At 3 months, hair regrowth was comparable for both PSK-3841 5% and minoxidil 5% alone. At the 3-month interval, the researchers noted that both combined groups had regrowth of long-terminal hairs that persisted for 6 – 12 months. The combined groups also boasted greater anagen conversion and follicular enlargement over the individual compounds alone. It was concluded that the combined treatment groups experienced the greatest impact early on; however, after 1 year had elapsed, no difference was observed in the combined treatment groups versus PSK-3841 or minoxidil used alone.
Pan et al. compared the antiandrogen effects of RU-58841 with other known antiantrogens, hydroxyflutamide, Casodexâ„¢ (bicalutamide) and genisten in human prostate cells. PSK-3841 demonstrated suppression of DHT activation of the androgen receptor competitively, and in a dose-dependent manner similar to the other antiandrogens. Pan et al. applied topical RU-58851 5% to the bald scalp of stumptailed macaques. Researchers evaluated folliculogram results and noted an increase in the number of anagen follicles and a decrease in telogen follicles as compared with baseline. The PSK-3841-treated group displayed progression from telogen to anagen and an increase in follicle size as opposed to the control group. No systemic side effects were reported. PSK-3841, dosed at 100-fold the therapeutic tested range, showed no signs of systemic antiandrogenic effects. Pan et al. described results from RU-58841 as inducing “remarkable effects on hair and folliclar regrowth in the bald frontal scalp of macaques.â€
Brouwer et al. studied the effects of PSK-3841 (1%) in human scalp grafts on testosterone-conditioned nude mice. The PSK-3841-treated grafts were compared with controltreated grafts. The PSK-3841 grafts showed increased recycling. A second hair cycle was noted in 28% of the active follicles of the PSK-3841 grafts versus 7% in the placebo-treated group. PSK-3841 treated mice also had greater linear hair growth rates (LHGR). However, PSK-3841 had no effect on hair diameter.
Battmann et al. investigated PSK-3841 in the intact hamster model in which the flank organ area is evaluated; this organ consists mainly of androgen-dependent sebaceous tissue. PSK-3841 1 – 100 ?g/animal resulted in both a dose- and time-related reduction in flank organ area. No effects on T levels were noted at this dose range or mode of delivery. In contrast, the androgen-dependent sebaceous tissue of the flank organ area of the controltreated hamsters increased. When PSK-3841 was administered via the subcutaneous route, the higher doses of 300 and 1000 ?g/animal were required to yield the antiandrogen effects. Battmann et al. also tested PSK-3841 via percutaneous, subcutaneous and oral routes of administration in the rat model. Results reported that systemic antiandrogenic effects were only seen at the highest titrated dose of 10 mg. Results from the previously described experiments led researchers to conclude that PSK-3841 is a ‘potent local antiandrogen’ with a favourable safety margin.
