Differences in the Pharmacokinetics of Cocaine in Naive and Cocaine-Experienced Rats

Enhanced cocaine concentrations in brain and blood observed after an intraperitoneal challenge dose in rats exposed to cocaine for 10 days by subcutaneous administration are traced to a change in the absorption process from the site of an intraperitoneal injection to general circulation. This conclusion is reached by three sets of corroborating results: (a) Adipose tissue of rats treated for 10 days with repeat subcutaneous injections of cocaine did not reveal a buildup of cocaine in sufficient concentrations to account for the twofold increase in brain and blood concentrations seen during intraperitoneal administration; (b) administration of the drug by an intravenous route after 10-day cocaine treatment did not show a significant difference between treatment and control groups; (c) nonlinear regression on the intravenous and intraperitoneal data sets using a two-compartment open model indicated a difference in the absorption process but not in the metabolic and blood-brain transfer processes.     

The large spectrum of pulmonary complications following illicit drug use: Features and mechanisms

Damage to lungs may occur from systemic as well as inhalational exposure to various illegal drugs of abuse. Aspiration pneumonia probably represents the most common pulmonary complication in relation to consciousness impairment. Some pulmonary consequences may be specifically related to one given drug. Prolonged smoking of marijuana may result in respiratory symptoms suggestive of obstructive lung disease. Non-cardiogenic pulmonary edema has been attributed to heroin, despite debated mechanisms including attempted inspiration against a closed glottis, hypoxic damage to alveolar integrity, neurogenic vasoactive response to stress, and opiate-induced anaphylactoid reaction. Naloxone-related precipitated withdrawal resulting in massive sympathetic response with heart stunning has been mistakenly implicated. In crack users, acute respiratory syndromes called “crack-lung” with fever, hemoptysis, dyspnea, and pulmonary infiltration on chest X-rays have been reported up-to 48 h after free-base cocaine inhalation, with features of pulmonary edema, interstitial pneumonia, diffuse alveolar hemorrhage, and eosinophil infiltration. The high-temperature of volatilized cocaine and the presence of impurities, as well as cocaine-induced local vasoconstriction have been suggested to explain alveolar damage. Some other drug-related pulmonary insults result from the route of drug self-administration. In intravenous drug users, granulomatous pneumonia with multinodular patterns on thoracic imaging is due to drug contaminants like talcum. Septic embolism from right-sided endocarditis represents an alternative diagnosis in case of sepsis from pulmonary origin. Following inhalation, pneumothorax, and pneumomediastinum have been attributed to increased intrathoracic pressure in relation to vigorous coughing or repeated Valsalva maneuvers, in an attempt to absorb the maximal possible drug amount. In conclusion, pulmonary consequences of illicit drugs are various, resulting in both acute life-threatening conditions and long-term functional respiratory sequelae. A better understanding of their spectrum and the implicated mechanisms of injury should help to improve patient management.     

Tyrosine nitration of a humanized anti-cocaine mAb differentially affects ligand binding of cocaine and its metabolites

Tetranitromethane was used to selectively modify tyrosine residues of a humanized anti-cocaine mAb (h2E2), under development for the treatment of cocaine use disorders. The effect of mild tyrosine nitration on the affinity of cocaine and two high affinity cocaine metabolites, cocaethylene and benzoylecgonine, was assessed using differential scanning fluorimetry to measure ligand affinities via ligand-induced thermal stabilization of the mAb antigen binding region. Nitrated tyrosine residues were identified by mass spectral analysis of thermolysin peptides. One objective was to understand the binding affinity differences observed for these three ligands, which are not explained by the published crystal structure of the h2E2 mAb Fab fragment co-crystalized with benzoylecgonine, since the carboxylic acid of benzoylecgonine that is esterified to form cocaine and cocaethylene is not in contact with the mAb. Importantly, the binding affinity of the cocaine metabolite benzoylecgonine was not decreased by mild nitration, whereas the binding affinities of cocaine and cocaethylene were decreased about two-fold. These ligands differ only in the substituent attached to the carboxylate moiety of the compound, with benzoylecgonine having an unesterified carboxylate, and cocaine and cocaethylene having methyl and ethyl esters, respectively, at this position. The results are consistent with nitration of light chain tyrosine residue 34, resulting in a less favorable interaction with cocaine and cocaethylene carboxylate esters, while not affecting binding of benzoylecgonine. Thus, light chain Tyr34 residue may have molecular interactions with cocaine and cocaethylene not present for benzoylecgonine, leading to the observed affinity differences for these three ligands.     

Effect of Cocaine on the Histaminergic Neuron System in the Rat Brain

Abstract: To examine the effect of cocaine on the brain histamine neuron system, histamine levels and histamine N -methyl-transferase activity in the rat brain were measured after the administration of cocaine. Moreover, we examined the effect of l -histidine on cocaine-induced wheel-running behavior. The administration of cocaine (20 mg/kg) increased histamine levels and histamine N -methyltransferase activity in the striatum, nucleus accumbens, and amygdala 1 h later. The pretreatment with l -histidine (350 and 700 mg/kg) inhibited the cocaine (20 mg/kg)-induced increase of wheel-running activity in a dose-dependent manner. These findings suggest that cocaine activates the brain histamine neuron system, which may play the role of inhibiting the cocaine-induced wheel-running behavior.