Background Ghrelin stimulates growth hormone (GH) secretion and regulates energy and glucose metabolism. The two circulating isoforms, acyl (AG) and desacyl (DAG) ghrelin, have distinct metabolic effects and are under active investigation for their therapeutic potentials. However, there is only limited data on the pharmacokinetics of AG and DAG. Objectives To evaluate key pharmacokinetic parameters of AG, DAG, and total ghrelin in healthy men and women. Methods In study 1 AG (1, 3 and 5 μg/kg/h) was infused over 65 min in 12 healthy (8F/4M) subjects in randomized order in. In study 2 AG (1 μg/kg/h), DAG (4 μg/kg/h), or both were infused over 210 min in 10 healthy individuals (5 F/5 M). Plasma AG and DAG were measured using specific two-site ELISAs (study1 and 2), and total ghrelin with a commercial RIA (study 1). Pharmacokinetic parameters were estimated by non-compartmental analysis. Results After the 1, 3 and 5 μg/kg/h doses of AG there was a dose-dependent increase in the maximum concentration (Cmax) and area under the curve [AUC(0-last)] of AG and total ghrelin. Among the different AG doses there was no difference in the elimination half-life, systemic clearance (CL), and volume of distribution. DAG had decreased CL relative to AG. The plasma DAG:AG ratio approximates 2:1 during steady state infusion of AG. Infusion of AG caused an increase of DAG, but DAG administration did not change plasma AG. Ghrelin administration did not affect plasma acylase activity. Conclusions The pharmacokinetics of AG and total ghrelin appear to be linear and proportional in the dose range tested. AG and DAG have very distinct metabolic fates in the circulation. There is deacylation of AG in the plasma but no evidence of acylation.

To investigate the effects of venetoclax on the anti-tumor activity of anti-PD-1/PD-L1 treatment, we performed tumor efficacy studies in immunocompetent C57BL/6 mice bearing MC38 tumors. Analysis from eight independent studies indicated that, as expected, anti-PD-1 led to significant tumor growth inhibition compared to isotype control (p-value = 0.0001) and this was, unexpectedly, further enhanced by co-treatment with venetoclax (venetoclax / anti-PD-1 cotreatment vs. anti-PD-1 alone, p-value = 0.005) (Fig. 1A, Supplementary Fig. 1A-I). Venetoclax also increased tumor growth inhibition when combined with anti-PD-L1 (Supplementary Fig. 2).Research.

Hospital systems increasingly utilize pharmacogenomic testing to inform clinical prescribing. Successful implementation efforts have been modeled at many academic centers. In contrast, this report provides insights into the formation of a pharmacogenomics consultation service at a safety-net hospital, which predominantly serves low-income, uninsured, and vulnerable populations. The report describes the INdiana GENomics Implementation: an Opportunity for the UnderServed (INGENIOUS) trial and addresses concerns of adjudication, credentialing, and funding.

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