Androgens are well known for their many functions in promoting sexual differentiation and the induction of the male phenotype. In the male, the two endogenous androgens most active in promoting these effects are testosterone and nonaromatizable 5a-dihydrotestosterone (DHT). They also play important roles in the regulation of bone metabolism. The direct effects of androgen on bone cells is suggested by the presence of androgen receptors (AR) on several human and rat established osteoblast cell lines as well as normal human osteoblast cells (HOB).1) Androgens increase rates of cellular proliferation and differentiation of osteoblasts, increase TGF-b levels, increase production of matrix proteins and inhibit osteoclast function.2,3) A role of androgens in skeletal regulation is substantiated by numerous studies in human and rodents, demonstrating that chemical or surgical castration, as well as untreated hypogonadism in men and androgen deficiency in women with hypopituitarism, lead to accelerated bone loss.2,4-7) Importantly, the deleterious effects of these conditions on bone can be reversed by treatment with androgens.One apparently unique effect of androgens is to increase periosteal bone formation in cortical bone, while estrogens depress it.8) This reflects a major gender difference in bone size, which is one of important factors determining the bone strength. A number of studies provide the proof of principle that androgens are osteoanabolic in rodents, women and men. Nonaromatizable DHT increased cortical bone volume and periosteal bone formation rates when administrated to ovariectomized rats.9) The synthetic anabolic steroids, such as nandrolone decanoate or stanozolol, have been shown to increase bone mass in postmenopausal women, possibly via stimulation of bone formation.10,11) Beneficial anabolic effects of androgens on bone in postmenopausal osteoporosis are well-documented in recent studies using combined testosterone and estrogen administration.12,13) On the other hand, bone resorption inhibitors such as estrogens, bisphosphonates, selective estrogen receptor modulators (SERMs) and calcitonin, which are still first line of treatment/prevention of osteoporosis, are not sufficient to restore bone mass for patients who have already lost a significant amount of bone. In addition, bone turnover rate differs from site to site; higher in the cancellous bone of vertebrae than in the cortical bone of the long bones. Therefore, osteoanabolic agents, which increase cortical/periosteal bone formation and bone mass of long bones, would address unmet need in the treatment of osteoporosis especially for patients with high risk of fractures. The osteoanabolic agents also complement the bone resorption inhibitors that target the cancellous bones, leading to a biomechanically favorable bone structure. 14)Despite the beneficial effects of androgens in therapies for osteoporosis, hypogonadism and other androgen deficient diseases, clinical use of them has been limited because of the undesirable virilizing (acne, hirsu...

The control of inflammation, which arises from complex biological responses to harmful stimuli, is an important determinant of both clinical outcomes and patient comfort. However, the side effects of many current therapies such as non-steroidal anti-inflammatory drugs mean that new safe treatments are required. We previously reported that 12.5 µg/ml hydroxytyrosol (HT) suppressed gene expression of the inducible nitric oxide (NO) synthase (iNOS) isoform and NO production, in mouse peritoneal macrophages treated with lipopolysaccharide (LPS), where nuclear factor-κB (NF-κB) gene expression was not altered. The present study evaluated the anti-inflammatory effects of various concentrations of HT in LPS-induced RAW264.7 mouse macrophages. HT suppressed NF-κB signaling and downregulated LPS-mediated expression of iNOS, cyclooxygenase-2, tumor necrosis factor alpha, and interleukin-1β at 12.5 µg/ml, resulting in reduced production of NO and prostaglandin E2. At lower concentrations, HT seemed to act via another signaling pathway to regulate the inflammatory response. In contrast, HT did not suppress LPS-induced expression of phosphorylated p44/42 mitogen-activated protein kinase. This study showed that HT had anti-inflammatory effects on LPS-stimulated RAW264.7 cells. HT is already available as a nutritional supplement and no toxic effects have been reported. Hence, HT represents a potential novel anti-inflammatory agent.

-Guinea pigs are the most frequently used animals in phototoxicity studies. However, general toxicity studies most often use Sprague-Dawley (SD) rats. To reduce the number of animals needed for drug development, we examined whether skin phototoxicity studies could be performed using SD rats. A total of 19 drugs that had previously been shown to have phototoxic potential and 3 known phototoxic compounds were administered transdermally to guinea pigs and SD rats. Eleven of the potentially phototoxic drugs and 2 of the known phototoxic compounds were also administered orally to guinea pigs and SD rats. After administration, the animals were irradiated with UV-A (10 J/cm 2 ) and UV-B (0.25 J/cm 2 in guinea pigs and 0.031 J/cm 2 in SD rats) with doses based on standard phototoxicity study guidelines and the results of a minimum erythema dose test, respectively. In the transdermal administration study, all of the known phototoxic compounds and 7 of the drugs induced phototoxic reactions. In the oral administration study, both known phototoxic compounds and 5 drugs induced phototoxic reactions in both species; one compound each was found to be toxic only in SD rats or guinea pigs. The concordance rate of guinea pigs and SD rats was 100% in the transdermal administration study and 85% in the oral administration study. This study demonstrated that phototoxicity studies using SD rats have the same potential to detect phototoxic compounds as studies using guinea pigs.

The current results indicate that S-40542 possesses the prostate-selective SARM activity, suggestive of clinical benefit against benign prostate hyperplasia. THQ compounds may be useful for the research of mode of action of SARMs and for the development of safe SARM antagonists.