Antidotes in De..

Digoxin-specific antibody fragments (DSFab) are indicated for the management of patients with toxicity related to digoxin and digitoxin, as well as oleander, squill, and toad venom which contain other cardioactive steroids. DSFab have an excellent record of efficacy and safety, and should be administered early in both established and suspected cardioactive steroid poisoning.

The production of antibody fragments to treat patients poisoned with digoxin followed the development of digoxin antibodies for measuring serum digoxin concentrations by radioimmunoassay (RIA).11 This RIA technique permitted the correlation between serum digoxin concentration and clinical digoxin toxicity.

In 1967, Butler and Chen suggested that purified antidigoxin antibodies with a high affinity and specificity should be developed to treat digoxin toxicity in humans.11 The digoxin molecule alone, with a molecular weight of 780 daltons, was too small to be immunogenic. But digoxin could function as a hapten when joined to an immunogenic protein carrier such as albumin. These investigators immunized sheep with this conjugate to generate antibodies. The immunized sheep subsequently produced a mixture of antibodies that included antialbumin antibodies and antidigoxin antibodies. The antibodies were separated and highly purified to retain the digoxin antibodies, while removing the antibodies to the albumin and all other extraneous proteins. The antibodies that were developed have a high affinity for digoxin, and sufficient cross-reactivity with digitoxin and other cardioactive steroids to be clinically useful for the treatment of all cardioactive steroid poisonings.

Intact IgG antidigoxin antibodies reversed digoxin toxicity in dogs.12 Unfortunately, the urinary excretion of digoxin was delayed, and free digoxin was released after antibody degradation occurred. Furthermore, there was significant concern for developing hypersensitivity reactions. To make such antibodies both safe and effective in humans, whole IgG antidigoxin antibodies were cleaved with papain, yielding two antigen-binding fragments (Fab), with a molecular weight of 50,000 daltons each, and one Fc fragment of 50,000 daltons.12 Affinity chromatography is used to isolate and purify the DSFab following papain digestion. Since the Fc fragment does not bind antigen and increases the potential for hypersensitivity reactions, it was eliminated. When compared with whole IgG antibodies the advantages of DSFab include a larger volume of distribution, more rapid onset of action, smaller risk of adverse immunologic effects, and more rapid elimination.12,45,48,50 Ultimately, in 1976 Digibind was first used successfully,78 and in 1986—it became commercially available,22 Digibind, a relatively pure, very safe, and extremely effective Fab product, was produced. Another commercial product, DigiFab, approved by the US Food and Drug Administration (FDA) in 2001 is also currently available.23 It is very similar to Digibind except that it is prepared using a digoxin derivative (digoxin-dicarboxymethoxylamine) as the hapten.

Immediately following intravenous (IV) administration, DSFab antibody fragments bind intravascular unbound digoxin. Uncomplexed antibodies then diffuse into the interstitial space, binding free digoxin there. A concentration gradient is then established, ...

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