The Use of Antibodies As Therapeutic Agents in Toxicology.
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概要
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Antivenoms were first used in animals as immunotoxicotherapy in 1887 and were proposed for humans in 1908. But until the 1970's, immunoglobulins and purified antibodies were essentially used for research and diagnostic purposes. The treatment of a life-threatening digoxin poisoning in 1976 was the first documented clinical benefit of (ovine) Fab fragments. Presently extensive work has been directed towards tricyclic antidepressant drugs (murine antibodies), colchicine (caprine antibodies) and diverse snake envenimations. The basic mechanism of detoxification after administration of specific antibody is known: sequestration, extraction and elimination. The Fab fragment is the most frequently proposed antidotal binding site because of its diffusion properties in the peripheral compartments and its renal excretion by glomerular filtration. A limiting factor is the irreversible binding of the toxin and kinetics of toxin release from the receptor: negative results have been instructive in that sense such as for paraquat. Another limiting factor is the dose of antibody that might be required: equimolar administration is possible for toxins dangerous at the scale of milligrams (such as digoxin or colchicine). Most drugs in clinical use have toxic ranges 10 to 100 times higher and much larger doses would be needed. The administration of such large doses of drug-specific antibodies or their fragments has no clinical or experimental precedent. This approach may prove to be feasible but the efficacy 1/2 to 1/10 molar doses also warrants testing. Calculation of the amount of infused antibody should actually be derived from the slope of the dose-effect curve rather than stoichiometrically. Other improvements will stem from advances in immunologic methodology. Monoclonal and chimeric antibodies are new tools that should help to resolve the clinical problems of immunogenicity and adverse reactions associated with polyclonal antidotal binding sites.
- 一般社団法人 日本救急医学会の論文
一般社団法人 日本救急医学会 | 論文
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