Highly active antiretroviral therapy (HAART) has significantly improved the prognosis of HIV-1-infected patients but is associated with significant side effects such as diabetes, atherosclerosis, and cardiovascular complications. Oxidative stress can disrupt endothelial homeostasis by dysregulating the balance between pro- and antiatherogenic factors. We hypothesized that chronic exposure to HAART results in endothelial oxidative stress and activation of mononuclear cell recruitment, an early event in atherosclerosis. We studied the effects of HAART drug combinations, consisting of zidovudine, a nucleoside reverse transcriptase inhibitor; efavirenz, a nonnucleoside reverse transcriptase inhibitor; and either of the two protease inhibitors (PIs), indinavir or nelfinavir, on human aortic endothelial cells (HAECs) by monitoring the following parameters: (1) generation of reactive oxygen species (ROS), (2) mono-nuclear cell (Jurkat or U-937) adhesion, and (3) expression of cell adhesion molecules (CAMs). HAART exposure increased ROS formation in HAECs. Exposure to PIs alone and in HAART combinations increased mononuclear cell adhesion to HAECs in a concentration-dependent manner. Mononuclear cell adhesion to HAART-exposed HAECs was significantly enhanced following acute (24-h) exposure to the inflammatory cytokines, tumor necrosis factor (TNF)-alpha or interleukin (IL)-1beta and was suppressed by the antioxidants N-ace-tylcysteine and glutathione. Exposure to HAART increased intercellular adhesion molecule-1 (ICAM-1) gene expression and concomitant exposure to TNF-alpha further increased ICAM-1, vascular cell adhesion molecule-1 (VCAM-1), and endothelial-leukocyte adhesion molecule cell surface protein levels. These studies indicate that chronic HAART exposure increases oxidative stress in endothelial cells and induces mononuclear cell recruitment, which may eventually precipitate the cardiovascular diseases observed in HIV-1+ individuals on antiretroviral therapy.

Aim: In combination therapy using interferon (IFN) and ribavirin for chronic hepatitis C, reduced doses should be used due to ribavirin-induced hemolytic anemia. The present study aimed to elucidate whether high-dose vitamins E and C supplementation attenuated ribavirin-induced hemolytic anemia. Methods: Twenty-one consecutive patients with chronic hepatitis C were enrolled in this study between July 2003 and December 2004, and received high-dose vitamins E (2000 mg) and C (2000 mg) supplementation, daily, in addition to IFN alfa-2b and ribavirin combination therapy (vitamins E/C group). Twenty-one sex- and age-matched patients who received a standard regimen of IFN alfa-2b and ribavirin for chronic hepatitis C between January 2001 and June 2003 were evaluated as the control group. Results: Decrease in hemoglobin level was significantly prevented in the vitamins E and C group compared to that in the control group (P = 0.029). Three (14.3%) patients in the control group discontinued treatment because of anemia, while no treated patient dropped out of the study due to anemia. Sustained virological response was not significantly different between the two groups. Conclusion: High-dose vitamins E and C supplementation prevented ribavirin-induced hemolytic anemia during combination therapy with ribavirin and IFN alfa-2b in patients with chronic hepatitis C.

The toxicities associated with 5-fluorouracil (5-FU), a potent broad-spectrum chemotherapeutic agent, can not only affect the morbidity and the efficacy of chemotherapy but also limit its clinical use. The objective of this study is to investigate the effects of a commercial anthocyanin-rich extract from bilberry (AREB) against 5-FU-induced myelotoxicity in vivo, and against chemosensitivity to 5-FU in vitro. A single injection of 5-FU at 200 mg/kg induced severe peripheral erythrocytopenia, thrombocytopenia and leucopenia as well as hypocellularity of the spleen and bone marrow in C57BL/6 mice. Oral administration of 500 mg/kg of AREB for 10 days significantly increased the number of red blood cells, neutrophils, and monocytes in peripheral blood to 1.2-fold, 9-fold, and 6-fold, respectively, compared with those seen after treatment with 5-FU alone (p< 0.05-0.001). The hypocellularity of the spleen and bone marrow caused by 5-FU was also distinctly alleviated in the AREB-treated group. Furthermore, AREB treatment with 50 and 100 microg/ml as a monomeric anthocyanin did not interfere with, but rather enhanced the chemotherapeutic efficacy of 5-FU in vitro. These results suggest that AREB may have protective potential against 5-FU-induced myelotoxiciy and/or the ability to enhance the chemotherapeutic effectiveness of 5-FU.