Effect of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Intravenous Rivipansel.

Two studies evaluated the effects of renal and hepatic impairment on pharmacokinetics and safety of rivipansel (NCT02813798, NCT02871570). A single intravenous 840-mg rivipansel dose was administered to subjects with renal impairment or normal renal function in study 1005 and subjects with moderate hepatic impairment or normal hepatic function in study 1006. Plasma (both studies) and urine (study 1005) samples were collected for 96 hours postdose. All subjects in studies 1005 (n = 28) and 1006 (n = 16) completed all study procedures. Rivipansel exposure (AUCinf ) was 47%, 124%, and 437% higher and total clearance 30%, 57%, and 82% lower in the mild, moderate, and severe renal impairment groups, respectively, than in the normal renal function group. Overall rivipansel exposure was 20% lower and total clearance 31% higher in the moderate hepatic impairment group than in the normal hepatic function group. Ten treatment-emergent adverse events occurred in studies 1005 and 1006; no event was considered treatment related. As expected, clearance of rivipansel decreased with increasing renal impairment. The difference observed between rivipansel pharmacokinetics in subjects with moderate hepatic impairment and subjects with normal hepatic function was not considered clinically significant. Single doses of rivipansel were well tolerated in subjects with either renal or hepatic impairment.

Inhibition of Pro-Inflammatory Functions of Human Neutrophils by Constituents of Melodorum fruticosum Leaves.

In an initial screening, the dichloromethane extract from the leaves of Melodorum fruticosum showed distinct inhibitory effects on the release of interleukin-8 (IL-8) in human neutrophils. Therefore, the aim of the present study was the phytochemical and pharmacological investigation of this extract, to better understand which compounds might be responsible for the anti-inflammatory effect. Phytochemical analysis led to the isolation of 12 known compounds and two new natural products, 5-hydroxy-6-(2-hydroxybenzyl)-4',7-dimethoxyflavanone (13) and 2',4'-dihydroxy-3'-(2-hydroxybenzyl)-4,6'-dimethoxychalcone (14). The influence of the isolated compounds on the production and release of the pro-inflammatory factors IL-8, tumor necrosis factor alpha (TNF-α), reactive oxygen species (ROS), and adhesion molecules (CD62L and CD11b) in human neutrophils was evaluated. Three constituents, melodamide A, 2',4'-dihydroxy-4,6'-dimethoxychalcone, and 2',6'-dihydroxy-4'-methoxychalcone, showed significant inhibition of IL-8 release (IC50 =6.6, 8.6, and 11.6 µm, respectively) and TNF-α production (IC50 =4.5, 13.3, and 6.2 µm, respectively).

HIV-1 targets L-selectin for adhesion and induces its shedding for viral release.

CD4 and chemokine receptors mediate HIV-1 attachment and entry. They are, however, insufficient to explain the preferential viral infection of central memory T cells. Here, we identify L-selectin (CD62L) as a viral adhesion receptor on CD4+ T cells. The binding of viral envelope glycans to L-selectin facilitates HIV entry and infection, and L-selectin expression on central memory CD4+ T cells supports their preferential infection by HIV. Upon infection, the virus downregulates L-selectin expression through shedding, resulting in an apparent loss of central memory CD4+ T cells. Infected effector memory CD4+ T cells, however, remain competent in cytokine production. Surprisingly, inhibition of L-selectin shedding markedly reduces HIV-1 infection and suppresses viral release, suggesting that L-selectin shedding is required for HIV-1 release. These findings highlight a critical role for cell surface sheddase in HIV-1 pathogenesis and reveal new antiretroviral strategies based on small molecular inhibitors targeted at metalloproteinases for viral release.