Reversal of desipramine toxicity in rats with polyclonal drug-specific antibody Fab fragments
Pentel, P.R.; Ross, C.A.; Landon, J.; Sidki, A.; Shelver, W.L.; Keyler, D.E.
Journal of Laboratory and Clinical Medicine 123(3): 387-393
1994
ISSN/ISBN: 0022-2143 PMID: 8133150 Document Number: 423645
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 times 10-10 M-1) for the common tricyclic antidepressants was evaluated as a possible treatment for tricyclic antidepressant toxicity. Groups of eight anesthetized rats received 30 mg/kg body weight of desipramine (DMI) intraperitoneally, followed after 15 minutes by a 10-minute intravenous injection of 3 ml normal saline solution, 2 gm/kg nonspecific 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 animals were observed for 3 hours. During the initial 15 minutes, serum DMI levels In the four groups reached 2.3 to 2.9 mu-g/ml, the QRS duration increased by 67.5% to 77.9%, and the systolic pressure fell to between 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 two of the rats died 2 to 3 hours later with hypotension and bradycardia. Serum DMI concentration did not change significantly in either the saline 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 DMI concentrations, a prompt and marked fall in the QRS duration when compared with the saline and CFab groups (p lt 0.01) that was sustained throughout the study period, and improved blood pressure. However, one of the rats receiving the larger dose of TFab died. These findings demonstrate that TFab rapidly reduces DMI cardiotoxicity and support the potential value of this therapeutic approach. The cause of the three deaths is uncertain but may relate to the rapid rate of infusion of relatively large amounts of Fab.