Cardiovascular and hepatic toxicity of cocaine: potential beneficial effects of modulators of oxidative stress

Oxidative stress (OS) is thought to play an important role in the pharmacological and toxic effects of various drugs of abuse. Herein we review the literature on the mechanisms responsible for the cardiovascular and hepatic toxicity of cocaine with special focus on OS-related mechanisms. We also review the preclinical and clinical literature concerning the putative therapeutic effects of OS modulators (such as N-acetylcysteine, superoxide dismutase mimetics, nitroxides and nitrones, NADPH oxidase inhibitors, xanthine oxidase inhibitors, and mitochondriotropic antioxidants) for the treatment of cocaine toxicity. We conclude that available OS modulators do not appear to have clinical efficacy

Cardiovascular and Hepatic Toxicity of Cocaine: Potential Beneficial Effects of Modulators of Oxidative Stress

Oxidative stress (OS) is thought to play an important role in the pharmacological and toxic effects of various drugs of abuse. Herein we review the literature on the mechanisms responsible for the cardiovascular and hepatic toxicity of cocaine with special focus on OS-related mechanisms. We also review the preclinical and clinical literature concerning the putative therapeutic effects of OS modulators (such as N-acetylcysteine, superoxide dismutase mimetics, nitroxides and nitrones, NADPH oxidase inhibitors, xanthine oxidase inhibitors, and mitochondriotropic antioxidants) for the treatment of cocaine toxicity. We conclude that available OS modulators do not appear to have clinical efficacy

Stereoselective morphine-like discriminative properties of a new alkylaminonaphthalenic derivative

The morphine-like properties of a series of aminoalkyl- and cycloalkylamino-naphtalenic derivatives of 17-methyl-17-azaequilenine were studied in rats trained to discriminate morphine (5.6 mg/kg IP) from vehicle in a two-lever operant behavioral procedure reinforced by water access. It was found that one of the compounds tested (i.e., A8; 1-ethyl-1-hydroxy-1-[2-(6-hydroxynaphthyl)]-2-methyl-3-dimethylaminopropane) fully generalized for the-morphine stimulus. The discriminative effects of 8s were stereospecific, as indicated by the fact that (+)-(1R,2R)-A8 was three rimes more potent than the racemic compound and that the (-)-(1S,2S) enantiomer was completely inactive. (+)-(1R,2R)-A8 generalization for the morphine cue was inhibited by naloxone. None of the other five derivatives examined generalized for the morphine stimulus. In conclusion, the naphthalenic structure is a source of compounds with stereospecific and naloxone-reversible morphine-like properties. (C) 2000 Elsevier Science Inc

Ethanol combined with cocaine inhibits amylase release in guinea pig pancreatic lobules

Concurrent ingestion of alcohol and cocaine is a common occurrence in cocaine-dependent individuals. Cocaethylene is a pharmacologically active metabolite of cocaine that is formed in the liver in the presence of ethanol. The effects of ethanol combined with cocaine on the exocrine pancreas are not known. We studied the effect of ethanol and cocaine, alone or in combination, and cocaethylene on amylase release from isolated lobules of the guinea pig pancreas. Incubation of lobules with ethanol plus cocaine produced a more evident reduction of amylase release than each drug alone. An even larger reduction was observed with cocaethylene. HPLC analysis of incubation medium showed that no cocaethylene was formed in vitro in the presence of ethanol anti cocaine. It is concluded that cocaethylene could strongly contribute to inhibition of exocrine pancreatic secretion in individuals who coadminister alcohol with cocaine. (C) 2001 Academic Press

TYROSINASE-CATALYZED OXIDATION OF MET-ENKEPHALINS

Kinetic properties of the oxidation of several Met-enkephalins and of kyotorphin by tyrosinase are reported. The opioid peptides tested present an affinity for the enzyme equal or higher than tyrosine itself. Long lasting incubations of these opioid peptides with tyrosinase lead to the formation of DOPA, the presence of ascorbic acid improving the recovery of the aminoacid. Spectrophotometric measurements in the absence of ascorbic acid indicate the formation of dopachrome which reaches the maximum within 15-30 minutes

Analysis of cocaethylene, benzoylecgonine and cocaine in human urine by high-performance thin-layer chromatography with ultraviolet detection: a comparison with high-performance liquid chromatography

Cocaine and ethanol are frequently used at the same time, resulting in the formation of cocaethylene by transesterification. We studied the capability of high-performance thin-layer chromatography (HPTLC) to simultaneously detect cocaethylene, cocaine and benzoylecgonine in 16 urine specimens of drug addicts, previously tested as positive for benzoylecgonine at immunoenzymatic screening. Accuracy and precision, as well as detection and quantitation limits of the method, were evaluated by comparison with high-performance liquid chromatography (HPLC). HPTLC limit of quantitation was 1.0 mug/ml for the three compounds, whereas HPLC limits were 0.2 mug/ml for benzoylecgonine and cocaine, and 0.1 mug/ml for cocaethylene. The relative standard deviation (RSD) ranged from 1.03 to 12.60% and from 1.56 to 16.6% for intra- and inter-day HPTLC analysis, respectively. In the case of the HPLC method, the RSD for the intra-day precision ranged from 0.79 to 5.05%, whereas it ranged from 1.19 to 10.64% for the inter-day precision. In comparison with HPLC, HPTLC is less expensive and faster, requiring 2-3 h to analyze 10-12 samples on a single plate. In conclusion, HPTLC is suitable for determinations of the three analytes only for samples with high concentrations. (C) 2001 Elsevier Science B.V. All rights resented

ENKEPHALINS AND EXORPHINS OXIDATION BY TYROSINASE

Tyrosinase activity was tested on some tyrosine-containing peptides (enkephalins and exorphins). All they are substrates for tyrosinase, showing a good affinity for the enzyme, in some cases higher than tyrosine itself. Aminoacid analysis after hydrolysis of long-lasting incubation mixtures of tyrosinase with Leu-enkephalin in presence of reductants demonstrates the formation of DOPA. The production of a new peptide containing DOPA derived from the oxidation of Leu-enkephalin was revealed by high performance liquid chromatography (HPLC)