1. GSK2140944 is a novel bacterial topoisomerase inhibitor in development for the treatment of bacterial infections. The metabolism and disposition in healthy human subjects was investigated. 2. Six male subjects received [(14)C] GSK2140944 orally (2000 mg) and as a single 2-hour i.v. infusion (1000 mg). Urinary elimination (59%) was major by the i.v. route, whereas fecal elimination (53%) pre-dominated via the oral route. Accelerator mass spectrometry (AMS) was used for the analysis of plasma and bile samples due to the low level of radioactivity in samples (low specific activity of the doses). Unchanged GSK2140944 was the predominant circulating component (>60% DRM), with the main circulating metabolite M4 formed by oxidation of the triazaacenaphthylene moiety representing 10.8% (considered major) and 8.6% drug-related material by the oral and i.v. route, respectively. Approximately 50% of the oral dose was absorbed and eliminated mainly as unchanged GSK2140944 in urine (∼20% of dose). Elimination via metabolism (∼13% of dose) was relatively minor. The facile oxidation of GSK2140944 to metabolite M4 was believed to be a result of activation by adjacent electron withdrawing groups. 3. This study demonstrates the use of AMS to overcome radioprofiling challenges presented by low specific activity resulted from high doses administration.

Up to ∼20% of HIV-infected individuals eventually develop broadly neutralizing antibodies (bnAbs), and many of these antibodies (∼40%) target a region of dense high-mannose glycosylation on gp120 of the HIV envelope protein, known as the “high-mannose patch” (HMP). Thus, there have been numerous attempts to develop glycoconjugate vaccine immunogens that structurally mimic the HMP and might elicit bnAbs targeting this conserved neutralization epitope. Herein, we report on the immunogenicity of glycopeptides, designed by in vitro selection, that bind tightly to anti-HMP antibody 2G12. By analyzing the fine carbohydrate specificity of rabbit antibodies elicited by these immunogens, we found that they differ from some natural human bnAbs, such as 2G12 and PGT128, in that they bind primarily to the core structures within the glycan, rather than to the Manα1 → 2Man termini (2G12) or to the whole glycan (PGT128). Antibody specificity for the glycan core may result from extensive serum mannosidase trimming of the immunogen in the vaccinated animals. This finding has broad implications for vaccine design aiming to target glycan-dependent HIV neutralizing antibodies.

Renal failure is the primary cause of death in obese Zucker rats (OZR). We previously found that renal injury occurred earlier and with greater severity in female OZR; also, prevention of hyperphagia decreased renal damage in females more than males. To examine the relationship between estrogen (E), hyperphagia, hyperlipidemia, and renal injury in female OZR, we studied four groups from 5 to 10 or 21 weeks of age: Sham-operated (Sham), ovariectomized (Ovx), Ovx with estrogen treatment (Ovx + E), and since Ovx increases food intake, Ovx pair-fed to sham (Ovx-PF). By only six weeks of age, albumin excretion (UAE) increased significantly in Ovx + E (9.9 +/- 4.1 mg/day). Ovx + E also ate least and gained the least weight, but had the highest plasma lipid levels. In contrast, UAE in Ovx did not increase by 10 weeks of age, despite a significantly greater food consumption. The hyperlipidemia of Ovx + E was due primarily to triglycerides. Both plasma triglycerides and renal injury, judged from either histology or UAE, were greatest in the Ovx + E group Fasting plasma glucose was lower and insulin was higher in Ovx + E compared to Ovx rats at 15 weeks of age. Estrogen may promote renal injury in female OZR by increasing the plasma concentration of triglyceride-rich lipoproteins.