Ovine Desipramine Antibody Fragments Reverse Desipramine Cardiovascular Toxicity in the Rat☆,☆☆,★,★★
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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Cited by (25)
European Resuscitation Council Guidelines for Resuscitation 2010 Section 8. Cardiac arrest in special circumstances: Electrolyte abnormalities, poisoning, drowning, accidental hypothermia, hyperthermia, asthma, anaphylaxis, cardiac surgery, trauma, pregnancy, electrocution
2010, ResuscitationCitation Excerpt :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.
Part 8: Advanced life support: 2010 International consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations
2010, ResuscitationCitation Excerpt :Limited animal research demonstrates a benefit for intravenous lipid infusions in models of tricyclic toxicity (LOE 5).631,632 Antitricyclic Fab has been beneficial in animal models of varying degrees of tricyclic cardiotoxicity (LOE 5),633–638 and one small human study (LOE 5)639 provided evidence of safety and pharmacokinetic advantage; however, clinical benefit has yet to be demonstrated clearly. There is insufficient clinical evidence to suggest any change to cardiac arrest resuscitation treatment algorithms for patients with cardiac arrest or cardiotoxicity caused by tricyclic antidepressants.
Tricyclic and Other Cyclic Antidepressants
2007, Haddad and Winchester's Clinical Management of Poisoning and Drug Overdose, Fourth EditionChapter 12 Immunotherapy of human poisonings
2004, Immunotoxicology of Drugs and Chemicals: an Experimental and Clinical ApproachImmediate and delayed allergic reactions to Crotalidae polyvalent immune Fab (ovine) antivenom
2002, Annals of Emergency MedicineCitation Excerpt :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.§
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Supported in part by Burroughs-Wellcome Laboratories, Research Triangle Park, North Carolina.
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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
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Reprint no. 47/1/70882