A novel rapid test for detecting antibody responses to Loa loa infections.

Ivermectin-based mass drug administration (MDA) programs have achieved remarkable success towards the elimination of onchocerciasis and lymphatic filariasis. However, their full implementation has been hindered in Central Africa by the occurrence of ivermectin-related severe adverse events (SAEs) in a subset of individuals with high circulating levels of Loa loa microfilariae. Extending MDA to areas with coincident L. loa infection is problematic, and inexpensive point-of-care tests for L. loa are acutely needed. Herein, we present a lateral flow assay (LFA) to identify subjects with a serological response to Ll-SXP-1, a specific and validated marker of L. loa. The test was evaluated on serum samples from patients infected with L. loa (n = 109) and other helminths (n = 204), as well as on uninfected controls (n = 77). When read with the naked eye, the test was 94% sensitive for L. loa infection and was 100% specific when sera from healthy endemic and non-endemic controls or from those with S. stercoralis infections were used as the comparators. When sera of patients with O. volvulus, W. bancrofti, or M. perstans were used as the comparators, the specificity of the LFA was 82%, 87%, and 88%, respectively. A companion smartphone reader allowed measurement of the test line intensities and establishment of cutoff values. With a cutoff of 600 Units, the assay sensitivity decreased to 71%, but the specificity increased to 96% for O. volvulus, 100% for W. bancrofti, and 100% for M. perstans-infected individuals. The LFA may find applications in refining the current maps of L. loa prevalence, which are needed to eliminate onchocerciasis and lymphatic filariasis from the African continent.

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.

A tissue-selective nonsteroidal progesterone receptor modulator: 7,9-difluoro-5-(3-methylcyclohex-2-enyl)-2,2,4-trimethyl-1,2-dihydrochromeno[3,4-f]quinoline.

The progesterone receptor plays an important role in the female reproductive system. Here we describe the discovery of a new selective progesterone receptor modulator (SPRM). In rats, the lead compound, 7,9-difluoro-5-(3-methylcyclohex-2-enyl)-2,2,4-trimethyl-1,2-dihydrochromeno[3,4- f]quinoline ( 5c), inhibited ovulation and showed full efficacy in uterine and vaginal tissue but was a mixed partial agonist/antagonist in breast tissue. The compound also suppressed ovulation in monkeys, but in contrast to currently approved steroidal PR agonists, it did not suppress estradiol levels.