Evaluation of the dopamine ß-hydroxylase (DßH) inhibitor nepicastat in participants who meet criteria for cocaine use disorder.

In the present study, we tested the hypothesis that the potent and selective dopamine-ß-hydroxylase (DßH) inhibitor nepicastat would have minimal effects on cardiovascular and pharmacokinetic parameters associated with cocaine administration and would reduce the positive subjective effects produced by cocaine. We conducted a double-blind, placebo-controlled, inpatient study of oral nepicastat (0, 80 and 160mg) concurrent with intravenous (IV) cocaine (0, 10, 20 and 40mg) in non-treatment seeking participants who metcriteria for cocaine use disorder. Safety analyses revealed that nepicastat was well-tolerated and there were no differences in adverse events observed after nepicastat plus cocaine vs. cocaine alone. In addition, the pharmacokinetic properties of cocaine administration were not altered by nepicastat treatment. Cocaine-induced cardiovascular and subjective effects were evaluated for completers in the cohort randomized to nepicastat (n=13) using a within-subjects statistical analysis strategy. Specifically, the cardiovascular and subjective effects of cocaine were assessed in the presence of placebo (0mg), 80mg of nepicastat or 160mg of nepicastat on study Days 4, 8 and 12, respectively. Analyses revealed a main effect of nepicastat to reduce several cocaine-induced positive subjective effects. Taken together, these data indicate that nepicastat is safe when co-administered with cocaine and may suppress its positive subjective effects, and may be viable as a pharmacotherapy for treatment of cocaine use disorder.

Differentiating ST elevation myocardial infarction and nonischemic causes of ST elevation by analyzing the presenting electrocardiogram.

Guidelines recommend that patients with suggestive symptoms of myocardial ischemia and ST-segment elevation (STE) in > or =2 adjacent electrocardiographic leads should receive immediate reperfusion therapy. Novel strategies aimed to reduce door-to-balloon time, such as prehospital wireless electrocardiographic transmission, may be dependent on the interpretation accuracy of the electrocardiogram (ECG) readers. We assessed the ability of experienced electrocardiographers to differentiate among STE, acute STE myocardial infarction (STEMI), and nonischemic STE (NISTE). A total of 116 consecutive ECGs showing STE were studied. Fifteen experienced cardiologists were asked to decide, based on the ECG and assuming that the patient had compatible symptoms, whether they would send each patient for primary percutaneous coronary intervention (PPCI). If NISTE was chosen, the reader selected 1 or more 12 possible options to explain the choice. Of 116 patients, only 8 had STEMI. The percentage of ECGs for which PPCI was recommended for the patient by the individual readers varied widely (7.8% to 33%). There was no significant difference between the North American and Other Countries readers (p = 0.13). The sensitivity and specificity of the individual readers ranged from 50% to 100% (average 75%) and 73% to 97% (average 85%), respectively. There were broad inconsistencies among the readers in the chosen reasons used to classify NISTE. In conclusion, we found wide variations among experienced electrocardiographers in reading ECGs with STE and differentiating STEMI with need for PPCI from NISTE. There is a need to revise our current electrocardiographic criteria for differentiating STEMI from NISTE.

The effect of augmented hemodynamics on blood flow during arteriovenous carbon dioxide removal.

Arteriovenous carbon dioxide removal (AVCO2R) as an alternative treatment for acute respiratory distress syndrome uses a low resistance gas exchanger in a simple arteriovenous shunt to achieve total CO2 removal and allow lung rest. We have previously shown in our clinically relevant LD40 ovine model of smoke/burn induced acute respiratory distress syndrome that AVCO2R allows significant decreases in respiratory rate, tidal volume, peak airway pressure, and FiO2, as compared with standard mechanical ventilation. In addition, we have shown in a prospective randomized outcomes study that AVCO2R increases ventilator free days, decreases ventilator dependent days, and significantly improves survival. The purpose of this study is to further define the limits of AVCO2R through hemodynamic augmentation and evaluation of peak end expiratory pressure (PEEP). Administration of an alpha agonist (phenylephrine) and a beta agonist (isoproterenol) increased mean arterial pressure (MAP) and cardiac output (CO), respectively. MAP increases ranged from 2.4% to 94.4% and CO increases ranged from 33% to 146%. Phenylephrine caused elevations in MAP (2.4-94.4%) and AVCO2R flow (9-67%), and CO never decreased more than 10%. Isoproterenol administration increased CO (33-146%), decreased MAP (9-54%), and decreased AVCO2R flow (11-42%). In a second group, PEEP was increased stepwise from 0 (baseline) to 20 cm H2O. Increasing PEEP did not result in significant hemodynamic changes (< 10% change from baseline PEEP) for MAP, CO, or AVCO2R flow. In conclusion, alpha agonist administration increased AVCO2R blood flow, whereas beta agonist administration decreased MAP and AVCO2R blood flow, despite CO elevation. Various levels of PEEP are well tolerated and thus allow a range of options during AVCO2R.