1,720,984 research outputs found
Stereoselective morphine-like discriminative properties of a new alkylaminonaphthalenic derivative
No full textThe 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
Cytoprotection by morphicetin and related casomorphins. Effects on ethanol induced stimulation of PG synthesis in gastric mucosa
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ENKEPHALINS AND EXORPHINS OXIDATION BY TYROSINASE
No full textTyrosinase 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)
Effect of repeated administrations of heroin, naltrexone, methadone, and alcohol on morphine glucuronidation in the rat
No full textRationale: Heroin is rapidly metabolized to morphine that in turn is transformed in morphine-3-glucuronide (M3G), an inactive metabolite, and morphine-6-glucuronide (M6G), a potent mu-opioid receptor (MOR) agonist. We have found that heroin addicts exhibit higher M6G/M3G ratios relative to morphine-treated control subjects. We have also shown that heroin-treated rats exhibit measurable levels of M6G (which is usually undetectable in this species) and reduced levels of M3G. Objective: We investigated the role of MOR in these effects of heroin, by examining the effects of methadone, a MOR agonist, and of naltrexone, a MOR antagonist, on morphine glucuronidation. We also investigated the effects of alcohol, which is known to alter drug metabolism and is frequently coabused by heroin addicts. Methods: Morphine glucuronidation was studied in liver microsomes obtained from rats exposed daily for 10 days to saline, heroin (10 mg/kg, i.p.), naltrexone (20-40 mg/kg, i.p.), heroin + naltrexone (10 mg/kg + 20-40 mg/kg, i.p.), methadone (5-20 mg/kg, i.p.), or 10% ethanol. Results: Heroin induced the synthesis of M6G and decreased the synthesis of M3G. Naltrexone exhibited intrinsic modulatory activity on morphine glucuronidation, increasing the synthesis of M3G via a low-affinity/ high-capacity reaction characterized by positive cooperativity. The rate of M3G synthesis in the heroin + naltrexone groups was not different from that of the naltrexone groups. Methadone and ethanol induced a modest increase in M3G synthesis and had no effect on M6G synthesis. Conclusion: The effects of heroin on morphine glucuronidation are not shared by methadone or alcohol (two drugs that figure prominently in the natural history of heroin addiction) and do not appear to depend on the activation of MOR
TYROSINASE-CATALYZED OXIDATION OF MET-ENKEPHALINS
No full textKinetic 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
Ethanol combined with cocaine inhibits amylase release in guinea pig pancreatic lobules
No full textConcurrent 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
High levels of morphine-6-glucuronide in street heroin addicts
No full textRATIONALE: In the body, heroin is rapidly transformed to 6-acetylmorphine (6-AM) and then to morphine, that in turn is mainly metabolized to morphine-3-glucuronide (M3G) and, at lesser extent, to morphine-6-glucuronide (M6G). Unlike M3G, M6G is a potent opioid agonist. Intravenous heroin abusers (IHU) are exposed to a wide array of drugs and contaminants that might affect glucuronidation. OBJECTIVES: We assessed plasma and urine concentrations of M3G and M6G in four groups of subjects: the first two included long-term IHU either exposed to street heroin ( n=8) or receiving a single IV injection of morphine ( n=4), while the other two groups included non-IHU patients receiving acute IV ( n=8) or chronic oral ( n=6) administrations of morphine. METHODS: After solid phase extraction plasma and urine concentrations of morphine metabolites were determined by HPLC analyses. RESULTS: M3G accounted for the greater part of morphine glucuronides detected in body fluids of non-IHU patients treated with morphine. This pattern of metabolism remained stable across 15 days of oral administration of incremental doses of morphine. In contrast, the two groups of IHU (street heroin taking or morphine-treated subjects) showed a reduction of blood and urine M3G concentrations in favor of M6G. Consequently, M6G/M3G ratio was significantly higher in the two IHU groups in comparison with the non-IHU groups. CONCLUSIONS: Chronic exposure to street heroin causes a relative increase in concentrations of the active metabolite, M6G. Since the pattern of M6G action seems closer to heroin than to morphine, the increased synthesis of M6G observed in IHU may prolong the narrow window of heroin effects
Development and validation of an analytical method based on high performance thin layer chromatography for the simultaneous determination of lamotrigine, zonisamide and levetiracetam in human plasma
No full textMethods based on HPLC technology are the most frequently adopted for monitoring blood levels of novel antiepileptics. Here a rapid method based on HPTLC was developed for quantitative determination of lamotrigine (LTG), zonisamide (ZNS) and levetiracetam (LVT) in human plasma and compared with HPLC and LC-MS/MS methods. Chromatographic separation was achieved on silical gel 60F(254) plates using ethylacetate:methanol:ammonia (91:10:15 v/v/v) as mobile phase. Quantitative analysis was carried out by densitometry at a wavelength of 312, 240 and 210 nm for LTG, ZNS and LVT, respectively. Calibration curves were linear over range of 0-200 ng for LTG and ZNS and 0-400 ng for and LVT. The limit of quantification of LTG, ZNS and LTV was found to be 3.69, 3.7 and 6.85 mu g/ml, respectively. Intra and inter-assay precision provided relative standard deviations lower than 10% for all three analytes. Correlation and Bland-Altman plot showed general agreement between HPTLC and LC-MS/MS quantification, with a mean bias of -0.25, -0.46 and 0.5 mu g/ml for LTG ZNS and LVT, respectively. Likewise, comparison between HPLC-UV and LC-MS/MS showed good agreement for all the three compounds analyzed. In conclusion, the proposed HPTLC method is simple, rapid, precise and accurate. It therefore is appropriate for the routine quantification of therapeutic levels of LTG, ZNS and LVT in human plasma. (C) 2011 Elsevier B.V. All rights reserved
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