TOXICITY OF HIGH-DOSES OF POLYCLONAL DRUG-SPECIFIC ANTIBODY FAB FRAGMENTS

Drug-specific antibody Fab fragments have been used as a treatment for acute drug overdose. For some drugs, the required Fab dose may be ver y high (up to several g/kg) and may have adverse effects of its own. T he current study evaluated the potential toxicity of an affinity purif ied sheep polyclonal Fab (TFab) directed at the two antidepressants de sipramine (DMI) and nortriptyline. TFab 4 g/kg was administered to ane sthetized rats i.v. over 10, 25 or 60 min, with or without a toxic dos e of DMI. This high dose of TFab, which is in excess of that needed to reduce DMI toxicity, was used in order to exaggerate any adverse effe cts. In the absence of DMI, TFab produced minimal changes in the elect rocardiographic QRS duration, systolic blood pressure and heart rate c ompared with control animals and was well tolerated. In the presence o f DMI, groups receiving TFab as a 10 or 25 min infusion showed a thera peutic effect (lessening of DMI toxicity) over the first 60 min compar ed with the control group, but one of the six animals in each of the T Fab groups died prior to the end of the 180 min experiment. No control animals died, but progressive QRS prolongation and decreasing blood p ressure toward the end of the experiment suggested that DMI toxicity w as increasing over time. These data suggest that, when administered al one, very high doses of rapidly infused TFab are well tolerated. When administered with DMI, TFab is effective in initially reducing DMI tox icity. However, this dose of TFab may later aggravate DMI toxicity and /or the effects of prolonged anesthesia. The faster infusion rates wer e more effective in reducing DMI toxicity, but the rate of TFab infusi on did not influence toxicity. Although the TFab dose used in this stu dy is probably higher than would be required for use in humans, these data suggest that strategies to reduce and optimize the dose of TFab a dministered should be pursued.