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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH042799-02
Application #
3382092
Study Section
Neurosciences Research Review Committee (BPN)
Project Start
1988-04-01
Project End
1991-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
2
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Hennepin County Medical Center (Minneapolis)
Department
Type
DUNS #
City
Minneapolis
State
MN
Country
United States
Zip Code
55415
Eldin, P; Pauza, M E; Hieda, Y et al. (1997) High-level secretion of two antibody single chain Fv fragments by Pichia pastoris. J Immunol Methods 201:67-75
Wananukul, W; Keyler, D E; Pentel, P R (1996) Effect of calcium chloride and 4-aminopyridine therapy on desipramine toxicity in rats. J Toxicol Clin Toxicol 34:499-506
Pentel, P R; Wananukul, W; Scarlett, W et al. (1996) Nitric oxide contributes to desipramine-induced hypotension in rats. Hum Exp Toxicol 15:320-8
Shelver, W L; Keyler, D E; Lin, G et al. (1996) Effects of recombinant drug-specific single chain antibody Fv fragment on [3H]-desipramine distribution in rats. Biochem Pharmacol 51:531-7
Lin, G; Pentel, P R; Shelver, W L et al. (1996) Bacterial expression and characterization of an anti-desipramine single-chain antibody fragment. Int J Immunopharmacol 18:729-38
Keyler, D E; Le Couteur, D G; Pond, S M et al. (1995) Effects of specific antibody Fab fragments on desipramine pharmacokinetics in the rat in vivo and in the isolated, perfused liver. J Pharmacol Exp Ther 272:1117-23
Pentel, P R; Keyler, D E (1995) Drug-specific antibodies as antidotes for tricyclic antidepressant overdose. Toxicol Lett 82-83:801-6
Pentel, P R; Scarlett, W; Ross, C A et al. (1995) Reduction of desipramine cardiotoxicity and prolongation of survival in rats with the use of polyclonal drug-specific antibody Fab fragments. Ann Emerg Med 26:334-41
Kitchin, K; Lin, G; Shelver, W L et al. (1995) Cloning, expression, and purification of an anti-desipramine single chain antibody in NS/O myeloma cells. J Pharm Sci 84:1184-9
Pentel, P R; Ross, C A; Landon, J et al. (1994) Reversal of desipramine toxicity in rats with polyclonal drug-specific antibody Fab fragments. J Lab Clin Med 123:387-93

Showing the most recent 10 out of 20 publications