Heme oxygenase-1 deficiency accelerates formation of arterial thrombosis through oxidative damage to the endothelium, which is rescued by inhaled carbon monoxide.

Heme oxygenase (HO)-1 (encoded by Hmox1) catalyzes the oxidative degradation of heme to biliverdin and carbon monoxide. HO-1 is induced during inflammation and oxidative stress to protect tissues from oxidative damage. Because intravascular thrombosis forms at sites of tissue inflammation, we hypothesized that HO-1 protects against arterial thrombosis during oxidant stress.

Quality of life and tolerability after administration of enfuvirtide with a thin-walled needle: QUALITE Study.

Purpose: Use of enfuvirtide-containing regimens leads to virologic and immunologic benefits and quality of life (QoL) improvements. This study (QUALITE) was designed to primarily identify baseline predictors of QoL improvements and characterize injection site reaction (ISR) signs/symptoms using a thinner/shorter needle.

Method: Enfuvirtide-naïve, antiretroviral (ARV)-experienced patients with CD4 counts >50 cells/mm3 enrolled in this prospective, 12-week, multisite, open-label study.

A prospective clinical and pathological examination of injection site reactions with the HIV-1 fusion inhibitor enfuvirtide.

Objective: Antiretroviral regimens containing the fusion inhibitor enfuvirtide (ENF) are associated with sustained viral suppression and immunological benefit. However, local injection site reactions (ISR) occur in the majority of patients. The aim of this study was to determine the pathogenesis of ISRs.

Pharmacokinetic bioequivalence of enfuvirtide using a needle-free device versus standard needle administration.

Study Objectives: To compare the relative bioavailability of enfuvirtide, a human immunodeficiency virus type 1 (HIV-1) fusion inhibitor, injected with the Biojector 2000 (B2000) needle-free device versus a 27-gauge half-inch needle-syringe; and to assess safety, tolerability, and patient preference for the two devices.

Design: Open-label, randomized, two-period crossover bioequivalence evaluation.

Setting: Clinical research center.

Pharmacokinetics, pharmacodynamics and safety of once-daily versus twice-daily dosing with enfuvirtide in HIV-infected subjects.

Objective: To investigate the pharmacokinetics, safety/tolerability and antiviral activity of enfuvirtide administered once-daily (QD) versus twice-daily (BID).

Design: An open-label, randomized, multiple dose, two-period crossover study comparing 180 mg enfuvirtide, two injections QD versus 90 mg enfuvirtide, two injections, BID.

Methods: Steady-state intensive pharmacokinetic samples were obtained on days 7 and 14.

Bone marrow-derived immune cells regulate vascular disease through a p27(Kip1)-dependent mechanism.

The cyclin-dependent kinase inhibitors are key regulators of cell cycle progression. Although implicated in carcinogenesis, they inhibit the proliferation of a variety of normal cell types, and their role in diverse human diseases is not fully understood. Here, we report that p27(Kip1) plays a major role in cardiovascular disease through its effects on the proliferation of bone marrow-derived (BM-derived) immune cells that migrate into vascular lesions.

cAMP targeting of p38 MAP kinase inhibits thrombin-induced NF-kappaB activation and ICAM-1 expression in endothelial cells.

We investigated the mechanisms by which elevated intracellular cAMP concentration inhibits the thrombin-induced ICAM-1 expression in endothelial cells. Exposure of human umbilical vein endothelial cells to forskolin or dibutyryl cAMP, which increase intracellular cAMP by separate mechanisms, inhibited the thrombin-induced ICAM-1 expression. This effect of cAMP was secondary to inhibition of NF-kappaB activity, the key regulator of thrombin-induced ICAM-1 expression in endothelial cells.

Galpha(q) and Gbetagamma regulate PAR-1 signaling of thrombin-induced NF-kappaB activation and ICAM-1 transcription in endothelial cells.

As thrombin binding to the G protein-coupled proteinase activated receptor-1 (PAR-1) induces endothelial adhesivity to leukocytes through NF-kappaB activation and intercellular adhesion molecule-1 (ICAM-1) expression, we determined the signaling pathways mediating the response. Studies showed that the heterotrimeric G proteins, Galpha(q), and the Gbetagamma dimer were key determinants of the PAR-1 agonist peptide (TFLLRNPNDK)-induced NF-kappaB activation and ICAM-1 expression in endothelial cells. Cotransfection of RGS3T, a regulator of G-protein signaling that inhibits Galpha(q), or alpha-transducin (Galpha(t)), a scavenger of the Gbetagamma, markedly decreased NF-kappaB activity induced by PAR-1 activation.

A growth factor-dependent nuclear kinase phosphorylates p27(Kip1) and regulates cell cycle progression.

The cyclin-dependent kinase inhibitor, p27(Kip1), which regulates cell cycle progression, is controlled by its subcellular localization and subsequent degradation. p27(Kip1) is phosphorylated on serine 10 (S10) and threonine 187 (T187). Although the role of T187 and its phosphorylation by Cdks is well-known, the kinase that phosphorylates S10 and its effect on cell proliferation has not been defined.