Nathaniel A. Page

Rapid Desensitization Protocols for Patients with Cardiovascular Disease and Aspirin Hypersensitivity in an Era of Dual Antiplatelet Therapy

Objective: To review the available protocols for rapid desensitization of patients with aspirin hypersensitivity and apply the data for use in patients with cardiovascular disease who would benefit from the dual antiplatelet therapy. Data Sources: A literature search was conducted via MEDLINE from 1966 to December 2006. Main search terms included: aspirin sensitivity, aspirin allergy, aspirin desensitization, aspirin-induced asthma, aspirin therapy, and aspirin intolerance syndrome. Study Selection And Data Extraction: Articles describing rapid aspirin desensitization protocols were selected for review. Literature pertaining to aspirin hypersensitivity, drug desensitization, and the use of aspirin and dual antiplatelet therapy was also examined. Three rapid desensitization protocols were identified and evaluated. Data Synthesis: While landmark studies demonstrated that dual antiplatelet therapy with aspirin and clopidogrel significantly reduces mortality and morbidity in acute coronary syndromes and coronary stenting, patients with aspirin hypersensitivity are frequently managed with clopidogrel alone with no supporting data. Approximately 10% of the population experiences hypersensitivity to aspirin, which can manifest as asthma exacerbations, rhinorrhea, angioedema, urticaria, and anaphylaxis. The hypersensitivity reaction is mediated through aspirin-directed antibodies or by excessive leukotriene production. The desensitization process involved depletion of these mediators, as well as down-regulation of leukotriene receptors. Two groups of investigators developed rapid protocols to desensitize patients with aspirin hypersensitivity safely and effectively. The rapid protocol developed by Wong provides benefits over other protocols with its low starting dose and completion in less than 3 hours, low incidence of adverse effects, and high success rate in aspirin desensitization. Conclusions: The Wong protocol is an attractive option for the rapid desensitization of patients requiring dual antiplatelet therapy with aspirin and clopidogrel in the perimyocardial infarction period.

Role of Glutaredoxin-Mediated Protein S -Glutathionylation in Cellular Nitroglycerin Tolerance

We hypothesize that nitroglycerin (NTG) causes direct oxidation of multiple cellular sulfhydryl (SH) proteins and that manipulation of SH redox status affects NTG tolerance. In LLC-PK1 cells, we found that nitrate tolerance, as indicated by cGMP accumulation toward NTG, was accompanied by increased protein [35S]cysteine incorporation, significant S-glutathionylation of multiple proteins, and decreased metabolic activity of several SH-sensitive enzymes, including creatine kinase, xanthine oxidoreductase, and glutaredoxin (GRX). Cells overexpressing GRX exhibited reduced cellular protein S-glutathionylation (PSSG) and absence of NTG tolerance, whereas those with silenced GRX showed increased extent of NTG-induced tolerance. Incubation of LLC-PK1 cells with oxidized glutathione led to several major observations associated with nitrate tolerance, namely, reduced cGMP accumulation, PSSG formation, superoxide accumulation, and the attenuation of these events by vitamin C. Aortic S-glutathionylated proteins increased approximately 3-fold in rats made tolerant in vivo to NTG and showed significant negative correlation with vascular responsiveness ex vivo. NTG incubation in EA.hy926 endothelial cells and LLC-PK1 cells led to increased S-glutathionylation and activity of p21ras, a known mediator of cellular signaling. These results indicate that the hallmark events of NTG tolerance, such as reduced bioactivation and redox signaling, are associated with GRX-dependent protein deglutathionylation.

Pharmacology of Nitrovasodilators

There are two classes of nitrovasodilators used clinically: the organic nitrates (nitroglycerin, isosorbide dinitrate, and isosorbide-5-mononitrate) and the metal nitrosyls (sodium nitroprusside). Nitrovasodilators themselves are inactive and must release vasoactive nitric oxide (NO) or its related species to exert their pharmacological effects. The metabolic end-products of nitrovasodilators are nitrite and nitrate, and increased exposure to these ions can be significant especially when nitrovasodilators are used on a chronic basis. In addition to their effects on vasotone, nitrovasodilators are also potent anti-platelet agents. Nitrovasodilators are used for the management of several cardiovascular pathologies including stable and unstable angina, congestive heart failure, and myocardial infarction. Metabolism of organic nitrates can be categorized as mechanism-based (releasing NO) or clearance-based (releasing nitrite). Various enzymes, including mitochondrial aldehyde dehydrogenase and glutathione-S-transferase, play key roles in these processes. Tolerance to the vasodilatory effects of organic nitrates is mediated via oxidation of multiple protein cysteine groups, producing a myriad of downstream events. A nitrate-free period is used clinically to circumvent this loss of efficacy. Organic nitrates can induce endothelial dysfunction through increased oxidative stress and several studies have questioned the long-term safety of these agents. Cyanide radical release from the nitroprusside complex and its rapid elimination precludes the use of sodium nitroprusside on a chronic basis.