[Do antidotes have a future? The example of 4-methylpyrazole and hydroxocobalamin]

In all probability the future progress in the "molecular" approach of therapy in acute poisoning within the next 20 years or so will be more rapid than the "mechanistic" approach, which undoubtedly has brought considerable improvements in the overall survival of these patients in the past. Principally molecular antidotes can act on three different levels, a) prior to the cellular targets (e.g. through modifications of toxokinetics), b) at specific cellular receptors through competition for binding (e.g. naloxone and flumazenil), and c) after the receptor sites through unspecific counteraction of toxic effects (e.g. betablockers for intoxications with theophylline). Immune-antidotes act prior to cellular receptors. Examples are the digoxin antibodies and the anti-venoms as well as the very recently developed and not yet clinically tested antibodies against antidepressive drugs and against colchicine. Two newer antidotes, the 4-methylpyrazole and the hydroxocobalamin, act also prior the cellular targets of the corresponding toxic compounds. Thus, 4-Methylpyrazole decreases the degradation of ethylene-glycol by inhibiting alcohol dehydrogenase, which results in a higher excretion of unchanged ethylene-glycol in urine. Hydroxycobalamin complexes with cyanides to form the physiologic vitamin B12. In order to allow an equimolar neutralization of ingested cyanides a concentrated preparation containing 5 g of hydroxycobalamin was developed, the pharmacokinetic properties of which are discussed.