A humanized anti-cocaine mAb blocks the cardiovascular effects of cocaine in rats

Cocaine use and abuse is associated with significant morbidity and mortality. Further, its use has significant effects on cardiovascular function in humans and has been associated with development of chest pain, myocardial ischemia and in rare cases cardiac death. Currently, the FDA has no approved pharmacotherapy for cocaine abuse. We have developed and generated a humanized anti-cocaine monoclonal antibody (mAb), h2E2, which dramatically decreases brain cocaine concentrations by sequestering cocaine in the plasma. As h2E2 proceeds into clinical trials, a significant question remains as to whether the increased plasma cocaine concentrations, increased circulation time of cocaine, and the decrease in cocaine excretion into the urine affects cardiac function. Therefore, the objective of this study was to determine the dose, duration and effects of cocaine administration in the presence and absence of mAb h2E2 on echocardiographic variables in an in vivo rat model. Echocardiography was performed on Sprague-Dawley rats with indwelling catheters using the Vevo 2100 ultrasound machine with a 20mHz probe. Baseline echocardiographic long axis M-mode images were collected prior to an i.v. cocaine push and at subsequent time points thereafter. Initial studies determined the dose-dependent effect of cocaine on cardiac parameters including ejection fraction (EF), heart rate (HR) and cardiac output (CO). The most significant increase in EF was observed with 1.68mg/kg cocaineHCl, which was then used in the subsequent experiments. As noted, cocaine administration increased EF, with inversely proportional changes in left ventricular systolic volume. In addition, cocaine produced an immediate decrease in HR, which did not fully return to baseline over the 45 minute time course, likely due to the anesthesia, as the saline control group demonstrated comparable effects. Similarly, cocaine caused an immediate decrease in CO, which normalized over time. Pre-administration of a single equimolar dose of h2E2 significantly blunted the effect of cocaine on EF, including both the initial drop as well as the subsequent increase. At one week and one month post h2E2, there was no significant blunting of the increased in cocaine-induced inotropy. However, the initial decrease in EF was still blocked after one week. The initial cocaine-induced drop in HR was blocked by h2E2, even at 1 week post-injection. h2E2 similarly blocked the increase in CO, however this effect was not detectable after 1 week or 1 month. In conclusion, there were no significant adverse cardiac effects noted with h2E2 administration and co-administration with cocaine resulted in significant blunting of both cocaine's inotropic and chronotropic effects. Elevated plasma cocaine concentrations are pharmacologically inert in the presence of h2E2. © FASEB.