REDUCTION OF DESIPRAMINE CARDIOTOXICITY AND PROLONGATION OF SURVIVAL IN RATS WITH THE USE OF POLYCLONAL DRUG-SPECIFIC ANTIBODY FAB FRAGMENTS

Study objective: Tricyclic antidepressants (TCAs) are a leading cause of death from intentional drug overdose. Available therapies are often unsatisfactory. In this study we evaluated the use of a high-affinity drug-specific polyclonal Fab fragment (TFab) as an antidote to desipr amine toxicity. Design: We gave anesthetized rats under mechanical ven tilation IV desipramine so that we might study the effect of TFab on s urvival or IP desipramine to facilitate study of the interaction of TF ab and hypertonic sodium bicarbonate (NaHCO3), the standard clinical t reatment for TCA overdose. Interventions: For the study of the effects of TFab and NaHCO3 on survival, each rat was given a constant IV infu sion of desipramine until it died, together with TFab 2 g/kg, bovine s erum albumin, or.9% NaCl starting 5 minutes after the desipramine infu sion. In the study of the interaction of TFab and NaHCO3, each rat rec eived 30 mg/kg IP desipramine followed by TFab (molar TFab:desipramine ratio,.1 1), NaHCO3, TFab+NaHCO3, or NaCl at the time of maximal toxi city (15 minutes). Results: In the survival protocol, QRS-interval dur ation, systolic blood pressure, and heart rate were significantly impr oved by TFab, and survival was prolonged by 58% compared with that in the albumin and NaCI groups (P<.001). The molar ratio of TFab to admin istered desipramine was .21. The unbound fraction of desipramine in se rum at the time of death was reduced by TFab, but the unbound desipram ine concentration was not, suggesting that TFab prolonged survival by delaying the increase in the unbound serum desipramine concentration. In the interaction protocol, neither TFab nor NaHCO3 was effective alo ne, but the combination significantly reduced QRS-interval prolongatio n (P=.001). Conclusion: These data demonstrate the efficacy of TFab in reducing desipramine-induced cardiovascular toxicity and prolonging s urvival. The pharmacokinetic effects of TFab in rats with severe desip ramine toxicity were similar to those observed in sublethal desipramin e toxicity. Therapeutic benefit is enhanced by the concurrent use of N aHCO3 and may be achieved despite binding only a fraction of the desip ramine dose.