Impact of Tesamorelin, a Growth Hormone-Releasing Factor (GRF) Analogue, on the Pharmacokinetics of Simvastatin and Ritonavir in Healthy Volunteers.

The potential impact of tesamorelin on CYP3A activity was investigated by examining its effect on the pharmacokinetics of simvastatin and ritonavir. In two randomized, two-way crossover studies, subjects were administered 2 mg tesamorelin on Days 1-7 with 80 mg simvastatin or 100 mg ritonavir co-administered on Day 6 (Treatment A), and a single dose of simvastatin or ritonavir alone on Day 6 (Treatment B). Pharmacokinetic samples were collected on Day 6 to measure simvastatin, ritonavir and tesamorelin plasma concentrations.

Effects of tesamorelin, a growth hormone-releasing factor, in HIV-infected patients with abdominal fat accumulation: a randomized placebo-controlled trial with a safety extension.

Background: HIV-infected patients receiving antiretroviral therapy often demonstrate excess visceral fat. A growth hormone-releasing factor, tesamorelin, may selectively reduce visceral fat in this population. We investigated the effects of tesamorelin (GHRH(1-44)) in HIV-infected patients with central fat accumulation.

Sildenafil increases endothelial progenitor cell function and improves ischemia-induced neovascularization in hypercholesterolemic apolipoprotein E-deficient mice.

Hypercholesterolemia is associated with impaired neovascularization in response to ischemia. Potential mechanisms include defective NO bioactivity and a reduction in the number/function of endothelial progenitor cells (EPCs). Here we tested the hypothesis that sildenafil, a phosphodiesterase 5 inhibitor that increases NO-driven cGMP levels, could stimulate EPC function and improve ischemia-induced neovascularization in hypercholesterolemic conditions.

Probucol and antioxidant vitamins rescue ischemia-induced neovascularization in mice exposed to cigarette smoke: potential role of endothelial progenitor cells.

Objective: Cigarette smoking is associated with impaired neovascularization in response to ischemia. Potential mechanisms include increased generation of reactive oxygen species (ROS) and a reduction in the function of endothelial progenitor cells (EPCs). Here we tested the hypothesis that antioxidant therapies could stimulate EPC function and improve ischemia-induced neovascularization following cigarette smoke exposure.

Nox2-containing NADPH oxidase deficiency confers protection from hindlimb ischemia in conditions of increased oxidative stress.

Objective: Because Nox2-containing NADPH oxidase is a major source of ROS in the vasculature, we investigated its potential role for the modulation of ischemia-induced neovascularization in conditions of increased oxidative stress.

Methods And Results: To mimic a clinical situation of increased oxidative stress, mice were exposed to cigarette smoke before and after the surgical induction of hindlimb ischemia. Nox2 expression and oxidative stress in ischemic tissues were significantly increased in wild-type mice, but not in mice deficient for the Nox2-containing NADPH oxidase (Nox2(-/-)).

Moderate consumption of red wine (cabernet sauvignon) improves ischemia-induced neovascularization in ApoE-deficient mice: effect on endothelial progenitor cells and nitric oxide.

Moderate consumption of red wine is associated with a decreased incidence of cardiovascular diseases in populations with relatively high amount of fat in the diet. However, the mechanisms involved in this protective effect are not completely understood. Here we show that moderate consumption of red wine (equivalent to 2 glasses/day in humans) but not ethanol only, improves blood flow recovery by 32% after hindlimb ischemia in hypercholesterolemic ApoE-deficient mice.

Cigarette smoke exposure impairs VEGF-induced endothelial cell migration: role of NO and reactive oxygen species.

Endothelial dysfunction is one of the earliest pathological effects of cigarette smoking. Vascular endothelial growth factor (VEGF) has been shown to be an important regulator of endothelial healing and growth. Accordingly, we tested the hypothesis that cigarette smoke exposure impairs VEGF actions in endothelial cells.

Circulating endothelial progenitor cells from healthy smokers exhibit impaired functional activities.

Objective: Endothelial dysfunction is one of the earliest pathological effects of cigarette smoking. It has recently been suggested that endothelial progenitor cells (EPCs) could contribute to ongoing endothelial maintenance and repair. Accordingly, we tested the hypothesis that cigarette smoking is associated with EPC dysfunction.

Inhibition of vascular smooth muscle cell proliferation and neointimal formation in injured arteries by a novel, oral mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor.

Background: Mitogen-activated protein kinases (MAPKs) are rapidly induced after arterial injury in different animal models. However, their precise role in vascular smooth muscle cell (VSMC) proliferation and neointimal formation in vivo remains to be determined.

Methods And Results: We investigated the properties of a novel, selective inhibitor of the upstream kinase, MAPK/extracellular signal-regulated kinase, that is orally active (PD0185625).

Advanced glycation end products potentiate the stimulatory effect of glucose on macrophage lipoprotein lipase expression.

Lipoprotein lipase (LPL) secreted by macrophages in the arterial wall promotes atherosclerosis. We have shown that macrophages of patients with type 2 diabetes overproduce LPL and that metabolic factors, including glucose, stimulate macrophage LPL secretion. In this study, we determined the effect of advanced glycation end products (AGEs) on LPL expression by macrophages cultured in a high-glucose environment and the molecular mechanisms underlying this effect.

Inhibition of hypoxia-induced angiogenesis by cigarette smoke exposure: impairment of the HIF-1alpha/VEGF pathway.

Smoking is a major risk factor for atherosclerotic diseases. However, the impact of cigarette smoke exposure on neovascularization that develops in response to tissue ischemia is unknown. Here we demonstrate that cigarette smoke extracts inhibit hypoxia-induced in vitro angiogenesis (matrigel assay) in human umbilical vascular endothelial cells.

Role of p44/p42 MAP kinase in the age-dependent increase in vascular smooth muscle cell proliferation and neointimal formation.

Objective: Age-dependent increase in vascular smooth muscle cell (VSMC) proliferation is thought to contribute to the pathology of atherosclerotic diseases. In this study, we investigated the role of mitogen-activated protein kinases (MAPKs) on VSMC proliferation and neointimal formation in the context of aging.

Methods And Results: VSMCs were isolated from the aorta of young and old rabbits.

Age-dependent impairment of reendothelialization after arterial injury: role of vascular endothelial growth factor.

Background: The mechanisms responsible for the association between advanced age and atherosclerotic diseases are not clear. Because atherosclerosis develops in response to local endothelial injuries, we investigated the effect of aging on vascular healing and reendothelialization.

Methods And Results: Endothelium denudation was performed by balloon angioplasty of the iliac arteries in young and old New Zealand White rabbits.