Improvement in immune parameters and human immunodeficiency virus-1 viral response in individuals treated with 16α-bromoepiandrosterone (HE2000)

ABSTRACTA randomised, double-blind, placebo-controlled study examined the safety, tolerance, immunological effect and anti-human immunodeficiency virus (HIV) activity of sub-cutaneously administered HE2000 (16α-bromoepiandrosterone) as monotherapy in treatment-naïve patients with HIV-1. Twenty-four patients received five sequential daily doses of 50 or 100 mg of HE2000 or placebo every 6 weeks for up to three courses, and were followed thereafter for 3 months. HE2000 was safe, with transient injection site reactions being the main side-effect. Peripheral blood samples, collected serially, were analysed for changes in immune cell phenotypes. Significant increases were observed in the numbers of circulating dendritic cells, early activated (CD69+CD25–) CD8 T-cells and T-NK cells after administration of 50-mg doses of HE2000 (p <0.05). Gene expression in peripheral blood mononuclear cells was analysed by real-time RT-PCR. Before treatment, HIV-1-infected patients had significantly elevated transcripts for a number of inflammatory mediators (p <0.012). After 50 mg or 100 mg HE2000, but not after placebo, there were significant sustained decreases in IL-1β, TNF-α, IL-6 and Cox-2 transcripts (p <0.05). There were no significant differences in CD4 cell numbers, although patients receiving 50-mg doses demonstrated a significant decrease in viral load (– 0.6 log; p <0.01). Anti-HIV-1 T-cell responses were analysed serially using GAG-peptides to stimulate cytoplasmic IFN-γ responses. After three courses, the 50-mg dose group demonstrated a significant increase in CD8 T-cell response against two distinct GAG peptide pools (p <0.03). These findings suggest that immune-based therapies may be able to impact viral load by decreasing inflammation and/or stimulating CD8 T-cells

An orally bioavailable synthetic analog of an active dehydroepiandrosterone metabolite reduces established disease in rodent models of rheumatoid arthritis.

Dehydroepiandrosterone (DHEA) treatment provides diverse anti-inflammatory benefits in rodent models of diseases, including rheumatoid arthritis (RA), but only limited benefits to patients. In rodents, DHEA is metabolized to (among others) androstene-3beta,7beta,17beta-triol (AET), which retains potent anti-inflammatory activity. 17Alpha-ethynyl-5-androstene-3beta,7beta,17beta-triol (HE3286) is a novel, metabolically stabilized, orally bioavailable derivative of AET. In the DBA mouse model of collagen-induced arthritis (CIA), once-daily oral treatments (gavage) with HE3286 (40 mg/kg), beginning at onset of disease, significantly decreased disease. Benefit was associated with reduction in joint inflammation, erosion, and synovial proliferation as measured by histological analysis and mRNA of proinflammatory cytokines, including tumor necrosis factor-alpha, interleukin (IL)-6, IL-1beta, and IL-23. Significant benefit was also observed in the CIA model even when treatments were delayed until 7 days after the onset of arthritis. Furthermore, dose-dependent benefit was observed in the DBA mouse model of collagen antibody-induced arthritis, as well as reductions in IL-6 and matrix metalloproteinase-3 mRNA levels in joints at the peak of disease and at the end of the study. HE3286, in contrast to dexamethasone, was not immune-suppressive in several classic animal models of immune function. Instead, HE3286 treatment was associated with reduced nuclear factor-kappaB activation and in our previous studies, with increased regulatory T cells. We hypothesize that HE3286 may represent a novel, perhaps first-in-class, anti-inflammatory agent and may more fully translate the benefits of DHEA, heretofore largely limited to rodents, into treatments for human diseases, including autoimmune disorders such as RA