The aim of this study is to determine whether drug-specific Fab antibody fragments can reverse toxicity of the tricyclic antidepressant desipramine (DMI) in the rat, and to study the mechanism of this therapeutic effect. Drug-specific antibodies can redistribute drugs with large volumes of distribution from tissues to serum and extracellular fluid, reduce the unbound drug concentration and reverse drug toxicity. This approach has been successfully applied to the potent toxin digoxin. The toxic dose of the TCAs is, however, about 200 times higher than digoxin and the treatment of TCA toxicity may require correspondingly large doses of antibody. The proposed study is intended to develop methods of using antibodies to reverse the toxicity of drugs with large toxic doses such as the TCAs. Attention will be focused on obtaining a better understanding of factors determining the efficacy of this technique, and minimizing the dose of Fab required to reverse toxicity. The study will address 5 principal areas: 1) The mechanism of action of DMI-specific Fab will be studied in rats by determining its affect on the distribution of DMI to tissues and the binding of DMI in serum. 2) The efficacy and dose-response relationship of DMI-specific Fab for reversing DMI toxicity will be studied to anticipate the dose of DMI-Fab needed for clinical use. 3) Anti-DMI Fab's with a wide range of Ka's will be used to study the influence of Ka on the rate and completeness of DMI redistribution. 4) Efficacy of DMI-specific Fab will be compared to the current standard clinical therapy, hypertonic sodium bicarbonate. The combined use of these therapies will be evaluated to determine whether their current use will allow a lower dose of DMI-specific Fab to be effective. 5) The potential toxicity of large doses of non-specific Fab will be studied in dogs to supplement previous studies of toxicity in the rat. These data should be useful in extending the therapeutic use of drug-specific Fab to wide variety of drugs and chemicals.
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