Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein-protein interaction profile.

Glucocorticoids are commonly used antiinflammatory agents whose use is limited by side effects. We have developed a series of glucocorticoid receptor (GR) ligands that retain the strong antiinflammatory activity of conventional glucocorticoids with reduced side effects. We present a compound, LGD5552, that binds the receptor efficiently and strongly represses inflammatory gene expression. LGD5552 bound to GR activates gene expression somewhat differently than glucocorticoids. It activates some genes with an efficacy similar to that of the glucocorticoids. However, other glucocorticoid-activated genes are not regulated by LGD5552. These differences may be because of the more efficient binding of corepressor in the presence of LGD5552, compared with glucocorticoid agonists. This class of nonsteroidal, GR-dependent antiinflammatory drugs may offer a safer alternative to steroidal glucocorticoids in the treatment of inflammatory disease.

Combination treatment with a selective androgen receptor modulator q(SARM) and a bisphosphonate has additive effects in osteopenic female rats.

Recent clinical trials with bisphosphonates and PTH have not supported the hypothesis that combination treatments with antiresorptive and anabolic agents would lead to synergistic activity. We hypothesized that combination treatment with a selective androgen receptor modulator (SARM), LGD-3303, and a bisphosphonate would be beneficial. In vitro competitive binding and transcriptional activity assays were used to characterize LGD-3303. LGD-3303 is a potent nonsteroidal androgen that shows little or no cross-reactivity with related nuclear receptors. Tissue selective activity of LGD-3303 was assessed in orchidectomized male rats orally administered LGD-3303 for 14 days. LGD-3303 increased the levator ani muscle weight above eugonadal levels but had greatly reduced activity on the prostate, never increasing the ventral prostate weight to >50% of eugonadal levels even at high doses. Ovariectomized female rats were treated with LGD-3303, alendronate, or combination treatment to study the effects on bone. DXA scans, histomorphometry, and biomechanics were performed. LGD-3303 increased muscle weight in females rats. In addition, LGD-3303 increased BMD and BMC at both cortical and cancellous bone sites. At cortical sites, the effects were caused in part by anabolic activity on the periosteal surface. At every measured site, combination treatment was as effective as either single agent and in some cases showed significant added benefit. LGD-3303 is a novel SARM with anabolic effects on muscle and cortical bone not observed with bisphosphonates. Combination therapy with LGD-3303 and alendronate had additive effects and may potentially be a useful therapy for osteoporosis and frailty.

Colorado workers' compensation: medical vs chiropractic costs for the treatment of low back pain.

OBJECTIVE: Low back disorders (LBDs) are the most common complaint among workers; therefore, many questions arise about cost-effective treatment approaches. This investigation evaluated the differences in cost-related factors among a population of patients selecting chiropractic vs allopathic care for the treatment of nonspecific LBDs. The study hypothesis was that chiropractic care would be more cost-effective or equivalent to allopathic care for the noncomplicated LBDs. METHODS: Cases were extracted from an insurance company database of patients reporting work-related low back injuries who were treated with either chiropractic or allopathic approaches. Cases were matched using the International Classification of Diseases, Ninth Revision, codes 722 (intervertebral disk disorders), 724 (other and unspecified disorders of the back), and 847 (sprains and strains of other and unspecified parts). The data set included 76 chiropractic cases and 2386 medical cases. RESULTS: The total amount paid by the insurance company was 1.7 times higher for patients treated by doctors of chiropractic (DCs) compared with those treated by medical doctors (MDs), and the cost of clinical treatment was 3.3 times higher for the DCs than MDs. CONCLUSION: The cost for treatment by DCs was greater than that of MDs for similarly classified conditions affecting the low back. The amount paid by the insurance company was primarily related to the number of services given by each provider.