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Phosphorothioate oligonucleotides (S-ODNs) have the ability to modulate gene expression selectively and thus have potential therapeutic capabilities. This potential led us to investigate the protein binding characteristics of selected S-ODNs. We evaluated S-ODN interactions with bovine serum albumin (BSA) and human serum albumin (HSA) in vitro. The equilibrium dissociation constants Km for the binding of a 20 mer S-ODN with BSA and HSA range between 1.1-5.2 x 10(-5) and 2.4-3.1 x 10(-4) M, respectively. The Km for an unrelated 15 mer S-ODN binding with HSA ranges between 3.7 and 4.8 x 10(-5) M. Studies with a fluorescently labeled 27 mer S-ODN suggest cooperative binding (Hill slope = 1.67) and/or the presence of secondary binding sites on the S-ODN. HSA or BSA linked to Sepharose was incubated with a 15, 20, or 24 mer S-ODN followed by the addition of selected drugs known to be highly protein bound (nifedipine, warfarin, midazolam, probenecid, indomethacin, and mitoxantrone). Up to 30% of S-ODN was displaced by warfarin in competition binding assays. Conversely, HSA-bound warfarin was incubated with a variety of oligonucleotides, including RNA and genomic dsDNA. Maximum displacement of warfarin-bound HSA was observed following incubation with 5'-cholesterol-conjugated 20 mer S-ODN. In summary, S-ODNs are likely to interact and displace other therapeutic agents that bind to albumin, particularly those binding at site I.

Antiphospholipid antibody syndrome (APAS) commonly presents with cutaneous infarctions mimicking thromboembolic vaso-occlusive disease. Systemic anticoagulation is the standard of care for this disorder, but treatment failures can occur. The authors report the first successful treatment of cutaneous infarctions due to APAS with low-dose, intravenous tissue plasminogen activator (rTPA) in a patient who failed to improve with high-dose anticoagulation. Wound healing was associated with a marked improvement in blood flow as assessed by scanning laser Doppler. The authors recommend that patients presenting with cutaneous infarctions in the absence of atherosclerosis be evaluated for APAS, and that fibrinolytic therapy be considered if cutaneous infarction persists despite anticoagulant therapy.