The concept of pharmacologic cocaine interception as a treatment for drug abuse

Abstract

Cocaine access to brain tissue and associated cocaine-induced behaviors are substantially reduced in rats and mice by significant plasma levels of an enzyme that rapidly metabolizes the drug. Similar results have been obtained in rodents and humans with therapeutic anti-cocaine antibodies, which sequester the drug and prevent its entry into the brain. We show that an efficient cocaine hydrolase can lead to rapid unloading of anti-cocaine antibodies saturated with cocaine, and we provide a theoretical basis for the hypothesis that dual therapy with antibody and hydrolase enzyme may be especially effective.

Figure 1

Percent hydrolysis of free and antibody-bound cocaine is shown as a function of time. Drug (1 μM) was prepared at zero time in antibody-rich serum, “AB” (≈ 5 μM IgG) or saline, “SAL”. CocH (0.1 mg/ml) was added at 15 min (arrow), when baseline was < 1% hydrolysis.

Figure 2

Schematic illustration of cocaine uptake into brain after i.v. administration to subjects under four different conditions: “unprotected” (no pretreatment), “enzyme” (provided with an efficient cocaine hydrolase), “antibody” (given high affinity anti-cocaine IgG), and “enzyme + antibody” (given both pretreatments). Panels read from left to right as a time sequence. As shown, an unprotected subject will accumulate cocaine in brain after each repeated injection. An enzyme treated subject will not, so long as hydrolysis is nearly complete before the second injection. An antibody treated subject may do better than an enzyme treated subject at first, but a second injection can overwhelm the protection. Dual treatment is most effective.