REVERSAL OF DESIPRAMINE TOXICITY IN RATS WITH POLYCLONAL DRUG-SPECIFIC ANTIBODY FAB FRAGMENTS

Drug-specific antibodies, or fragments containing their binding site(s ), are a potential means of treating drug overdose. Affinity purified polyclonal ovine Fab (TFab) with a high average affinity constant (K-a = 1.4 x 10(10) M(-1)) for the common tricyclic antidepressants was ev aluated as a possible treatment for tricyclic antidepressant toxicity. Groups of eight anesthetized rats received 30 mg/kg body weight of de sipramine (DMI) intraperitoneally, followed after 15 minutes by a In-m inute intravenous injection of 3 ml normal saline solution, 2 gm/kg no nspecific Fab as a control (CFab), or 1 or 2 gm/kg TFab (representing a molar ratio of TFab to DMI of 0.11 and 0.22, respectively). The anim als were observed for 3 hours. During the initial 15 minutes, serum DM I levels in the four groups reached 2.3 to 2.9 mu g/ml, the QRS durati on increased by 67.5% to 77.9%, and the systolic pressure fell to betw een 65% and 85% of its initial value. The group given saline solution showed a gradual return of all these parameters toward normal, whereas CFab caused a transient further QRS prolongation. CFab also caused an initial rise in blood pressure, which then fell progressively, and tw o of the rats died 2 to 3 hours later with hypotension and bradycardia . Serum DMI concentration did not change significantly in either the s aline or CFab groups. Conversely, the groups given 1 gm/kg or 2 gm/kg of TFab showed an immediate 13-fold and 17-fold rise in their serum DM I concentrations, a prompt and marked fall in the QRS duration when co mpared with the saline and CFab groups (p < 0.01) that was sustained t hroughout the study period, and improved blood pressure. However, one of the rats receiving the larger dose of TFab died. These findings dem onstrate that TFab rapidly reduces DMI cardiotoxicity and support the potential value of this therapeutic approach. The cause of the three d eaths is uncertain but may relate to the rapid rate of infusion of rel atively large amounts of Fab.