Background-Human immunodeficiency virus protease inhibitors (HIV PIs) are associated with hyperlipidemia, hyperglycemia, and obesity; however, it is not known whether they increase risk of atherosclerotic vascular disease. The purposes of this study were to characterize the lipoprotein abnormalities associated with use of HIV PIs in individuals with HIV infection and to determine the pathophysiological significance of these changes by assessing their effect on endothelial dysfunction. Methods and Results-This was a cross-sectional study of 37 adults with HIV-1 infection who were receiving antiretroviral therapy. Twenty-two were taking HIV PIs (group 1); 15 were not (group 2). Lipids and lipoproteins were measured by enzymatic techniques and nuclear magnetic resonance spectroscopic analysis. Flow-mediated vasodilation (FMD) of the brachial artery was measured by high-resolution ultrasound. Subjects in both groups were similar in regard to age, time since diagnosis of HIV infection, and CD4 cell count.
Ascorbate deficiency is common in HIV-positive patients and is associated with impaired detoxification of sulfamethoxazole-nitroso, the suspected proximate toxin in sulfonamide hypersensitivity. Patients taking daily ascorbate supplements (500-1000 mg) achieved high plasma ascorbate concentrations and did not show this detoxification defect. Ascorbate deficiency (or supplementation) was not associated with changes in glutathione or cysteine concentrations. These data suggest that ascorbate deficiency, independent of thiol status, may be an important determinant of impaired drug detoxification in HIV infection.
Sulfamethoxazole (SMX) hypersensitivity affects 20–50% of treated HIV patients. SMX‐nitroso (SMX‐NO), the cytotoxic metabolite thought to mediate these reactions, is non‐enzymatically reduced by ascorbate (AA). The purpose of these studies was to determine the relationship between intracellular AA deficiency (reported in HIV‐infection) and in vitro cytotoxicity in the presence of SMX metabolites (which has been used as a marker for sulfonamide hypersensitivity). Peripheral blood mononuclear cells (PBMC) were obtained from HIV‐positive patients and healthy controls. PBMC AA concentrations and SMX‐NO reduction were determined by HPLC. PBMC from each subject were also exposed to 0.1‐1.0 mM SMX‐NO for 2 h., followed by overnight incubation in media. Cytotoxicity was quantified using YO‐PRO‐1® fluorescence. In preliminary results from 22 subjects, intracellular AA was strongly correlated with PBMC reduction of SMX‐NO (r=0.73; P=0.0001). In addition, AA was depleted during exposure to SMX‐NO, with a strong linear correlation between nmoles SMX‐NO reduced and nmoles AA depleted (r=0.75; P<0.0001). There was a trend toward an inverse relationship between intracellular AA and cytotoxicity (r= ‐0.31; P=0.18), and between SMX‐NO reduction and cytotoxicity (r= ‐0.36; P=0.14), but the association was not significant in this preliminary sample. Additional patient recruitment is underway to further characterize the relationship between ascorbate deficiency and sulfonamide toxicity.
Clinical Pharmacology & Therapeutics (2004) 75, P15–P15; doi:
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