Ovine Desipramine Antibody Fragments Reverse Desipramine Cardiovascular Toxicity in the Rat

doi:10.1016/S0196-0644(96)70265-2

Annals of Emergency Medicine

Volume 27, Issue 3, March 1996, Pages 309-315

Presented at the Annual Scientific Meeting of the American Academy of Clinical Toxicology, Toronto, September, 1992.

https://doi.org/10.1016/S0196-0644(96)70265-2 Get rights and content

Abstract

Study objective: To develop a model of severe desipramine cardiovascular toxicity and to determine whether partial neutralization of the antigen by desipramine-specific Fab antibody fragments ameliorates its cardiovascular effects. Methods: We administered desipramine to rats until the QRS interval tripled in duration and mean arterial pressure (MAP) was less than 100 mm Hg. Animals were then assigned to one of six groups: (1) no treatment, (2) normal saline solution control treatment (.9% NaCl infusion equal to the volume of Fab infusion), (3) nonimmune Fab control treatment (infusion of Fab equal to that in the 9.6% neutralization treatment), (4) 9.6% desipramine Fab (infusion of ovine desipramine Fab equal to 9.6% of an equimolar neutralization), (5) 19.2% desipramine Fab, and (6) 30.0% desipramine Fab. Results: QRS-interval duration, heart rate, and MAP were recorded for 60 minutes. Animals in groups 1 through 3 demonstrated slow and incomplete improvement. Animals in groups 4 through 6 showed improvement in QRS-interval duration and heart rate within 4 minutes (P<.05) compared with untreated animals. A dose-response relationship was evident; animals given the highest dose of desipramine-specific Fab showed the greatest improvement. Conclusion: Partial neutralization of desipramine by specific Fab fragments produces rapid improvement of QRS-interval duration and heart rate in a rat model of severe desipramine toxicity. [Dart RC, Sidki A, Sullivan JB Jr, Egen NB, Garcia RA: Ovine desipramine antibody fragments reverse desipramine cardiovascular toxicity in the rat. Ann Emerg Med March 1996;27:309-315.]

Section snippets

INTRODUCTION

Heterologous antibodies have been developed for analytic, diagnostic, and therapeutic use. Therapeutic uses of antibodies include the production of passive immunity against infectious agents including tetanus and viral hepatitis and the treatment of digoxin intoxication. A strategy common to these applications is equimolar neutralization of the antigen, in which the amount of antibody administered is sufficient to bind every molecule of the antigen. In theory, incomplete neutralization leaves

MATERIALS AND METHODS

Fab was provided by Therapeutic Antibodies, Incorporated (London, England). Desipramine antibodies were produced in sheep immunized with a drug-protein conjugate in accordance with an established immunization protocol.³ The desipramine Fab used in this study was obtained from the fourth-month bleeds of 50 sheep. The sheep were reimmunized monthly, and pooled bleeds were subjected to 18% sodium sulfate fractionation to isolate the immunoglobulin serum fraction. The immunoglobulin fraction was

RESULTS

More than 70% of the 50 immunized sheep produced specific antibody levels of more than 3.0 g/L plasma. Fab affinity for desipramine was 9.2×10⁹ mol^-1 with a binding capacity of .60 mol of desipramine per mole of Fab. Affinities for other cyclic antidepressants were imipramine, 8.0×10⁹ mol^-1; amitriptyline, 8.0×10⁹ mol^-1; and nortriptyline, 5.0×10⁹ mol^-1, with binding capabilities of .70, .96, and .63 mol of antidepressant per mole of Fab, respectively. Fab was homogeneous, as determined with

DISCUSSION

The only therapeutic antibody commercially available for the treatment of drug intoxication is digoxin Fab (Digibind). The guiding principle used in the development of this drug is equimolar neutralization; enough Fab is administered to bind every molecule of digoxin.⁸ This approach produces rapid and complete reversal of digoxin effects. It has been subsequently demonstrated, however, that partial neutralization is also often effective. Infusion of a partial dose of digoxin Fab may ameliorate

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Intravenous lipid infusions in experimental models of tricyclic toxicity have suggested benefit but there are few human data.64,65 Anti-tricyclic antibodies have also been beneficial in experimental models of tricyclic cardiotoxicity.66–71 One small human study72 provided evidence of safety but clinical benefit has not been shown.
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Subsequently, Fab fragments have been used in various degrees to effectively treat intoxication from other agents, including colchicine,16 desipramine,17 and several species of poisonous snake venoms.7,18 This experience has suggested that less than 100% neutralization may still result in effective reversal of clinical toxicity.17 Smaller doses of Fab may result in a lower incidence of adverse events.17
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^☆: From the Department of Surgery, Section of Emergency Medicne*, and the Department of Veterinary Sciences^‡, University of Arizona, Tucson, Arizona; and Therapeutic Antibodies, Incorporated, London, England.^§

^☆☆: Supported in part by Burroughs-Wellcome Laboratories, Research Triangle Park, North Carolina.

^★: Address for reprints: Richard C Dart, MD, PhD, Rocky Mountain Poison Center, 8802 East Ninth Avenue, Denver, Colorado 80220-6800, 303-739-1100, Fax 303-739-1119

^★★: Reprint no. 47/1/70882

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Ovine Desipramine Antibody Fragments Reverse Desipramine Cardiovascular Toxicity in the Rat☆,☆☆,★,★★

Abstract

Section snippets

INTRODUCTION

MATERIALS AND METHODS

RESULTS

DISCUSSION

J Pharm Sci

Ann Emerg Med

Immunotherapy in the poisoned patient

Med Toxicol

Reversal of desipramine toxicity in rats using drug-specific antibody Fab' fragment: Effects on hypotension and interaction with sodium bicarbonate

J Pharmacol Exp Ther

Quinine directly determined in serum or urine by separation fluoroimmunoassay

Clin Chem

The hydrolysis of rabbit gamma globulin and antibodies with crystalline papain

Biochem J