29 results on '"Antonilli L"'
Search Results
2. Preparation and configuration of racemic and optically active analgesic dialkylaminoalkylnaphthalenes
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Ghislandi, V., Azzolina, O., SIMONA COLLINA, Paroli, E., Antonilli, L., Giuseppetti, G., and Tadini, C.
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Male ,Pharmacology ,Analgesics ,Molecular Structure ,Optical Rotation ,Organic Chemistry ,Stereoisomerism ,Naphthalenes ,Crystallography, X-Ray ,Catalysis ,Analytical Chemistry ,Mice ,Drug Discovery ,Animals ,Spectroscopy ,Pain Measurement - Abstract
The alkylaminoalkylnaphthalene 3 shows interesting opioid-like analgesic properties, mu-selective ligand competition, and enkephalin hydrolyzing enzyme inhibition. 3 possesses two chiral centers and can exist as two racemic pairs and four diastereomers. Since the binding of opioids with the receptor is stereoselective, it was important to have the two racemic pairs as well as the four diastereomers. In this paper the synthesis of the (1R,2R/1S,2S)- and (1R,2S/1S,2R)-racemates and the (1R,2R)- and (1S,2S)-enantiomers of the 1-ethyl-1-hydroxy-1-[2-(6-hydroxynaphthyl)]-2-methyl-3- dimethylaminopropane 3 is considered and the determination of absolute configuration is described. The (1R,2R/1S,2S)-3 and (1R,2S/1S,2R)-3 racemates and the (1R,2R)-3 and (1S,2S)-3 enantiomers were prepared by reaction of the racemic and optically active 1-dimethylamino-2-methylpentan-3-one 2, respectively, with the lithiation product obtained from 2-bromo-6-tetrahydropyranyloxynaphthalene and acidic hydrolysis. The optical resolution of aminoketone 2 was carried out via fractional crystallization of salts (+)- and (-)-dibenzoyltartrates. The configuration of the optically active compounds was determined by X-ray analysis of a crystal of (+)-(1R,2R)-3.HCl.H2O. Preliminary pharmacological tests showed that (+)-(1R,2R)-3 enantiomer is able to induce opioid-like analgesia with a relative potency 2.5 times that of (1R,2R/1S,2S)-3 and about 4 times that of morphine.
- Published
- 1994
3. Cognitive and motoric effects of metabotropic glutamate (mGlu5) receptors antagonist MPEP., (Autriche)
- Author
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Leonibus E., De, Managò, F., Giordani, F., Lopez, S., Amalric, Marianne, Antonilli, L., Petrosini, F., Oliverio, A., Mele, A., Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
- Subjects
[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] - Published
- 2006
4. Short-term efficacy of Disulfiram or Naltrexone in reducing positive urinalysis for both cocaine and cocaethylene in cocaine abusers: A pilot study
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GRASSI, M, primary, CIOCE, A, additional, GIUDICI, F, additional, ANTONILLI, L, additional, and NENCINI, P, additional
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- 2007
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5. 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
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ANTONILLI, L, primary, SURIANO, C, additional, GRASSI, M, additional, and NENCINI, P, additional
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- 2001
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6. Effects of β-casomorphins and Met-enkephalin on human natural killer activity
- Author
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Biffoni, M., primary, Paroli, E., additional, Carletti, M., additional, and Antonilli, L., additional
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- 1992
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7. Stereoselective Morphine-Like Discriminative Properties of a New Alkylaminonaphthalenic Derivative
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Fraioli, S., Antonilli, L., and Nencini, P.
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- 2000
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8. Glycoprotein distribution in non-histone chromatin proteins from pig liver
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Ferraro A, Antonilli L, maria d'erme, Eufemi M, Ma, Rosei, and Spoto G
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Molecular Weight ,Endodeoxyribonucleases ,Chromosomal Proteins, Non-Histone ,Swine ,Carbohydrates ,Animals ,Chromatin ,Glycoproteins - Abstract
Carbohydrate content of non-histone proteins from pig liver chromatin has been measured in different groups of chromatin fractions and does not seem to be related to the affinity of the proteins for DNA. Glycoproteins are preferentially located in the nuclease-sensitive fractions of chromatin. A 59,000 dalton glycoprotein has been identified as a characteristic components of a chromatin fraction solubilized by DNAase II.
- Published
- 1988
9. Beta-casomorphins and morphine inhibit phospholipase A2 activity and increase diacylglycerol production in rat stomach corpus mucosa
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Paroli, E. and Antonilli, L.
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- 1992
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10. Cannabis in epilepsy: From clinical practice to basic research focusing on the possible role of cannabidivarin.
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Morano A, Cifelli P, Nencini P, Antonilli L, Fattouch J, Ruffolo G, Roseti C, Aronica E, Limatola C, Di Bonaventura C, Palma E, and Giallonardo AT
- Abstract
Cannabidivarin (CBDV) and cannabidiol (CBD) have recently emerged among cannabinoids for their potential antiepileptic properties, as shown in several animal models. We report the case of a patient affected by symptomatic partial epilepsy who used cannabis as self-medication after the failure of countless pharmacological/surgical treatments. Clinical and video electroencephalogram (EEG) evaluations were periodically performed, and the serum levels of CBDV, CBD, and Δ9-tetrahydrocannabinol were repeatedly measured. After cannabis administration, a dramatic clinical improvement, in terms of both decrease in seizure frequency and recovery of cognitive functions, was observed, which might parallel high CBDV plasma concentrations. To widen the spectrum of CBDV possible mechanisms of action, electrophysiological methods were applied to investigate whether it could exert some effects on γ-aminobutyric acid (GABA)
A receptors. Our experiments showed that, in human hippocampal tissues of four patients affected by drug-resistant temporal lobe epilepsy (TLE) transplanted in Xenopus oocytes, there is decrease of current rundown (i.e., reduction of use-dependent GABAA current) after prolonged exposure to CBDV. This result has been confirmed using a single case of Rasmussen encephalitis (RE). Our patient's electroclinical improvement supports the hypothesis that cannabis could actually represent an effective, well-tolerated antiepileptic drug. Moreover, the experimental data suggest that CBDV may greatly contribute to cannabis anticonvulsant effect through its possible GABAergic action.- Published
- 2016
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11. Cardiovascular and Hepatic Toxicity of Cocaine: Potential Beneficial Effects of Modulators of Oxidative Stress.
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Graziani M, Antonilli L, Togna AR, Grassi MC, Badiani A, and Saso L
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- Acetylcysteine chemistry, Animals, Antioxidants pharmacology, Catecholamines metabolism, Cattle, Humans, Male, Mice, Mitochondria drug effects, Myocytes, Smooth Muscle metabolism, NADPH Oxidases antagonists & inhibitors, Nitrogen Oxides chemistry, Rats, Reactive Oxygen Species metabolism, Receptors, Adrenergic, alpha-1 metabolism, Receptors, Adrenergic, beta metabolism, Xanthine Oxidase antagonists & inhibitors, Cardiovascular Diseases chemically induced, Cocaine chemistry, Cocaine toxicity, Liver drug effects, Oxidative Stress
- Abstract
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.
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- 2016
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12. Pivaloylcodeine, a new codeine derivative, for the inhibition of morphine glucuronidation. An in vitro study in the rat.
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Antonilli L, Togna AR, Sabatini G, Venditti A, Guarcini L, Togna GI, Nicoletti R, Sanasi F, Bianco A, and Nencini P
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- Animals, Codeine chemical synthesis, Codeine chemistry, Codeine pharmacology, Dose-Response Relationship, Drug, Hepatocytes chemistry, Hepatocytes drug effects, Hepatocytes metabolism, Kinetics, Male, Microsomes, Liver chemistry, Microsomes, Liver drug effects, Microsomes, Liver metabolism, Molecular Structure, Morphine Derivatives chemistry, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Codeine analogs & derivatives, Morphine Derivatives metabolism
- Abstract
We have previously found that phenanthrenic opioids, including codeine, modulate morphine glucuronidation in the rat. Here codeine and five of its derivatives were compared in their effects on the synthesis of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) from morphine by rat liver microsomal preparations, and by primary cultures of rat hepatocytes previously incubated for 72 h with either codeine or its derivatives. Acetylcodeine and pivaloylcodeine shared the capability of the parent compound of inhibiting the synthesis of M3G by liver microsomes through a noncompetitive mechanism of action. Their IC50 were 3.25, 2.27, and 4.32 μM, respectively. Dihydrocodeine, acetyldihydrocodeine, and lauroylcodeine were ineffective. In all the experimental circumstances M6G was undetectable in the incubation medium. In primary hepatocyte cultures codeine only inhibited M3G formation, but with a lower efficacy than that observed with microsomes (IC50 20.91 vs 4.32 μM). Preliminary results show that at micromolar concentrations codeine derivatives exhibit a low rate of affinity for μ opiate receptors. In conclusion, acetyl and pivaloyl derivatives of codeine noncompetitively inhibit liver glucuronidation of morphine interacting with microsomes. This study further strengths the notion that phenanthrenic opioids can modulate morphine glucuronidation independently from their effects on μ opiate receptors., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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13. In vitro morphine metabolism by rat microglia.
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Togna AR, Antonilli L, Dovizio M, Salemme A, De Carolis L, Togna GI, Patrignani P, and Nencini P
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- Animals, Animals, Newborn, Calcium-Binding Proteins metabolism, Cells, Cultured, Cerebral Cortex cytology, Chromatography, Liquid, Dinoprostone metabolism, Dose-Response Relationship, Drug, Gene Expression Regulation, Enzymologic drug effects, Glucuronosyltransferase genetics, Glucuronosyltransferase metabolism, Microfilament Proteins metabolism, Microglia drug effects, Morphine Derivatives metabolism, Nitrites metabolism, Rats, Tandem Mass Spectrometry, Time Factors, Microglia metabolism, Morphine metabolism, Morphine pharmacology, Narcotics metabolism, Narcotics pharmacology
- Abstract
Morphine is mainly transformed to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in the liver. Glucuronidation is also performed by rat brain homogenates and UDP-glucuronosyltransferases (UGTs) are present in the brain. Here we investigated the possibility that microglia transforms morphine into its metabolites M3G and M6G. Primary cultures of neonatal rat microglia were incubated for different intervals of time in basal conditions or with different concentrations of morphine. The following measures were performed on these cultures and/or in the medium: (i) morphine as well as M3G and M6G concentrations; (ii) levels of mRNA coding for UGT1A1, UGT1A6, UGT1A7, and UGT2B1 as well as their protein levels; (iii) released prostaglandin (PG)E2 and nitrite concentrations. Results show that in basal conditions morphine and M3G are produced by microglia; accordingly, these cells expressed UGT1A1, UGT1A6 and UGT1A7, but not UGT2B1. When cultures were exposed to different concentrations of exogenous morphine, M6G was also synthesized. This shift in the glucuronidation was associated with variations in the expression of UGT isozymes. In particular, UGT1A7 expression was rapidly upregulated and this event was translated into enhanced protein levels of UGT1A7; lesser effects were exerted on UGT1A1 and UGT1A6. Upon prolonged exposure to morphine, microglial cell UGT expression returned to baseline conditions or even to reduced levels of expression. Morphine exposure did not affect the synthesis of both PGE2 and nitrites, ruling out a generalized priming of microglia by morphine. In conclusion, this study suggests that morphine glucuronides found in the cerebrospinal liquor upon peripheral morphine administration may at least in part be brain-born, reconciling the conceptual gap between the high hydrophilic features of morphine glucuronides and their presence beyond the blood-brain barrier., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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14. Fractalkine (CX3CL1) enhances hippocampal N-methyl-D-aspartate receptor (NMDAR) function via D-serine and adenosine receptor type A2 (A2AR) activity.
- Author
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Scianni M, Antonilli L, Chece G, Cristalli G, Di Castro MA, Limatola C, and Maggi L
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- Animals, Chromatography, Liquid, Excitatory Postsynaptic Potentials physiology, Mass Spectrometry, Mice, Mice, Inbred C57BL, Neuroglia metabolism, Organ Culture Techniques, Patch-Clamp Techniques, Chemokine CX3CL1 metabolism, Hippocampus metabolism, Receptors, Adenosine A2 metabolism, Receptors, N-Methyl-D-Aspartate metabolism, Serine metabolism
- Abstract
Background: N-Methyl-D-aspartate receptors (NMDARs) play fundamental roles in basic brain functions such as excitatory neurotransmission and learning and memory processes. Their function is largely regulated by factors released by glial cells, including the coagonist d-serine. We investigated whether the activation of microglial CX3CR1 induces the release of factors that modulate NMDAR functions., Methods: We recorded the NMDAR component of the field excitatory postsynaptic potentials (NMDA-fEPSPs) elicited in the CA1 stratum radiatum of mouse hippocampal slices by Shaffer collateral stimulation and evaluated D-serine content in the extracellular medium of glial primary cultures by mass spectrometry analysis., Results: We demonstrated that CX3CL1 increases NMDA-fEPSPs by a mechanism involving the activity of the adenosine receptor type A2 (A2AR) and the release of the NMDAR coagonist D-serine. Specifically (1) the selective A2AR blocker 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH58261) and the genetic ablation of A2AR prevent CX3CL1 action while the A2AR agonist 5-(6-amino-2-(phenethylthio)-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydrofuran-2-carboxamide (VT7) mimics CX3CL1 effect, and (2) the selective blocking of the NMDAR glycine (and D-serine) site by 5,7-dicholorokynurenic acid (DCKA), the enzymatic degradation of D-serine by D-amino acid oxidase (DAAO) and the saturation of the coagonist site by D-serine, all block the CX3CL1 effect. In addition, mass spectrometry analysis demonstrates that stimulation of microglia and astrocytes with CX3CL1 or VT7 increases D-serine release in the extracellular medium., Conclusions: CX3CL1 transiently potentiates NMDAR function though mechanisms involving A2AR activity and the release of D-serine.
- Published
- 2013
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15. Repeated exposure to codeine alters morphine glucuronidation by affecting UGT gene expression in the rat.
- Author
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Antonilli L, De Carolis L, Brusadin V, Togna AR, Dovizio M, Togna GI, Patrignani P, and Nencini P
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- Analgesics, Opioid pharmacokinetics, Animals, Cells, Cultured, Codeine pharmacokinetics, Hepatocytes drug effects, Hepatocytes metabolism, Male, Microsomes, Liver metabolism, Morphine Derivatives metabolism, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Analgesics, Opioid administration & dosage, Codeine administration & dosage, Gene Expression Regulation, Enzymologic drug effects, Glucuronosyltransferase genetics, Morphine metabolism
- Abstract
We have previously found that phenantrenic opioids, such as heroin or naltrexone, modulate morphine glucuronidation in the rat. Here we further investigated the effects of phenantrenic opioids on morphine glucuronidation comparing the effects of codeine and heroin. In particular, we measured the synthesis of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) from morphine: in the liver microsomal preparations obtained from rats repeatedly treated with two different doses of codeine (ex vivo study); in primary cultures of rat hepatocytes previously incubated for 72h with codeine, or heroin (in vitro study); in the latter conditions, the levels of expression of genes coding for uridine-5'-diphosphate-glucuronosyltransferases (UGTs) A1, A6, A7 and 2B1 were also determined; finally, the levels of glucuronic acid in rat hepatocytes previously incubated for 72h with codeine or heroin were assessed. The ex vivo study shows that codeine exposure in vivo stimulated liver microsomal M3G formation and de novo synthesis of M6G. Differently, in primary hepatocyte cultures both codeine and heroin inhibited M3G formation, whereas heroin only stimulated de novo synthesis of M6G; moreover, codeine significantly reduced UGT2B1 expression at 6h and caused a trend toward inhibition of UGT1A1 expression at 72h; heroin enhanced UGT2B1 expression and inhibited that of UGT1A1 at 72h; finally, both codeine and heroin depleted UDPGA content of hepatocytes. In conclusion, codeine affects liver glucuronidation of morphine enlightening the possible contribution of changes in the spectrum of UGT gene expression and co-factor synthesis in this phenomenon., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2012
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16. Induction of morphine-6-glucuronide synthesis by heroin self-administration in the rat.
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Meringolo M, Brusadin V, De Luca MT, Montanari C, Antonilli L, Nencini P, and Badiani A
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- Animals, Heroin administration & dosage, Infusions, Intravenous, Injections, Intraperitoneal, Male, Rats, Rats, Sprague-Dawley, Self Administration, Heroin pharmacokinetics, Microsomes, Liver metabolism, Morphine Derivatives metabolism
- Abstract
Rationale: Heroin is rapidly metabolized to morphine that in turn is transformed into morphine-3-glucuronide (M3G), an inactive metabolite at mu-opioid receptor (MOR), and morphine-6-glucuronide (M6G), a potent MOR agonist. We have found that rats that had received repeated intraperitoneal injections of heroin exhibit measurable levels of M6G (which is usually undetectable in this species)., Objective: The goal of the present study was to investigate whether M6G synthesis can be induced by intravenous (i.v.) heroin self-administration (SA)., Materials and Methods: Rats were trained to self-administer either heroin (50 μg/kg per infusion) or saline for 20 consecutive 6-h sessions and then challenged with an intraperitoneal challenge of 10 mg/kg of heroin. Plasma levels of heroin, morphine, 6-mono-acetyl morphine, M3G, and M6G were quantified 2 h after the challenge. In vitro morphine glucuronidation was studied in microsomal preparations obtained from the liver of the same rats., Results: Heroin SA induced the synthesis of M6G, as indicated by detectable plasma levels of M6G (89.7 ± 37.0 ng/ml vs. 7.35 ± 7.35 ng/ml after saline SA). Most important, the in vitro V (max) for M6G synthesis was correlated with plasma levels of M6G (r (2) = 0.78). Microsomal preparations from saline SA rats produced negligible amounts of M6G., Conclusion: Both in vivo and in vitro data indicate that i.v. heroin SA induces the synthesis of M6G. These data are discussed in the light of previous studies conducted in heroin addicts indicating that in humans heroin enhances the synthesis of the active metabolite of heroin and morphine.
- Published
- 2012
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17. 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.
- Author
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Antonilli L, Brusadin V, Filipponi F, Guglielmi R, and Nencini P
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- Calibration, Drug Monitoring methods, Humans, Lamotrigine, Levetiracetam, Linear Models, Mass Spectrometry, Piracetam blood, Reference Standards, Reproducibility of Results, Sensitivity and Specificity, Zonisamide, Anticonvulsants blood, Chromatography, Thin Layer methods, Isoxazoles blood, Piracetam analogs & derivatives, Triazines blood
- Abstract
Methods 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 (91:10:15v/v/v) as mobile phase. Quantitative analysis was carried out by densitometry at a wavelength of 312, 240 and 210nm for LTG, ZNS and LVT, respectively. Calibration curves were linear over range of 0-200ng for LTG and ZNS and 0-400ng for and LVT. The limit of quantification of LTG, ZNS and LTV was found to be 3.69, 3.7 and 6.85μg/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 0.5μg/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., (Copyright © 2011 Elsevier B.V. All rights reserved.)
- Published
- 2011
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18. Adenosine A1 receptors and microglial cells mediate CX3CL1-induced protection of hippocampal neurons against Glu-induced death.
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Lauro C, Cipriani R, Catalano M, Trettel F, Chece G, Brusadin V, Antonilli L, van Rooijen N, Eusebi F, Fredholm BB, and Limatola C
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- Adenosine pharmacology, Adenosine A1 Receptor Antagonists, Adenosine Deaminase pharmacology, Adenosine Diphosphate analogs & derivatives, Adenosine Diphosphate pharmacology, Animals, Animals, Newborn, Brain-Derived Neurotrophic Factor pharmacology, CX3C Chemokine Receptor 1, Cell Death drug effects, Cell Death genetics, Cell Movement drug effects, Clodronic Acid pharmacology, Erythropoietin pharmacology, Glutamic Acid toxicity, Green Fluorescent Proteins genetics, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microglia chemistry, Organ Culture Techniques, Rats, Receptor, Adenosine A1 deficiency, Receptors, Adenosine A2 deficiency, Receptors, Chemokine genetics, Xanthines pharmacology, Hippocampus cytology, Microglia physiology, Neurons drug effects, Receptor, Adenosine A1 metabolism, Receptors, Chemokine physiology
- Abstract
Fractalkine/CX3CL1 is a neuron-associated chemokine, which modulates microglia-induced neurotoxicity activating the specific and unique receptor CX3CR1. CX3CL1/CX3CR1 interaction modulates the release of cytokines from microglia, reducing the level of tumor necrosis factor-alpha, interleukin-1-beta, and nitric oxide and induces the production of neurotrophic substances, both in vivo and in vitro. We have recently shown that blocking adenosine A(1) receptors (A(1)R) with the specific antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) abolishes CX3CL1-mediated rescue of neuronal excitotoxic death and that CX3CL1 induces the release of adenosine from microglia. In this study, we show that the presence of extracellular adenosine is mandatory for the neurotrophic effect of CX3CL1 as reducing adenosine levels in hippocampal cultures, by adenosine deaminase treatment, strongly impairs CX3CL1-mediated neuroprotection. Furthermore, we confirm the predominant role of microglia in mediating the neuronal effects of CX3CL1, because the selective depletion of microglia from hippocampal cultures treated with clodronate-filled liposomes causes the complete loss of effect of CX3CL1. We also show that hippocampal neurons obtained from A(1)R(-/-) mice are not protected by CX3CL1 whereas A(2A)R(-/-) neurons are. The requirement of functional A(1)R for neuroprotection is not unique for CX3CL1 as A(1)R(-/-) hippocampal neurons are not rescued from Glu-induced cell death by other neurotrophins such as brain-derived neurotrophic factor and erythropoietin, which are fully active on wt neurons.
- Published
- 2010
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19. Non-opioid induction of morphine-6-glucuronide synthesis is elicited by prolonged exposure of rat hepatocytes to heroin.
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Graziani M, Antonilli L, Togna AR, Brusadin V, Viola S, Togna G, Badiani A, and Nencini P
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- Animals, Cell Separation, Cells, Cultured, Chromatography, High Pressure Liquid, Half-Life, Hepatocytes drug effects, In Vitro Techniques, Male, Naltrexone pharmacology, Narcotic Antagonists pharmacology, Rats, Rats, Sprague-Dawley, Analgesics, Opioid pharmacology, Hepatocytes metabolism, Heroin pharmacology, Morphine Derivatives metabolism
- Abstract
Background: Liver metabolism of morphine leads to the formation of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), the latter possessing strong opioid activity that however differs from that of the parent compound. In previous studies conducted in rats we have shown that repeated in vivo exposure to phenanthrene class of mu opioid receptor (MOR) agonists or antagonists (heroin, morphine, and naltrexone), but not to non-phenanthrene class of MOR agonist methadone, affects morphine glucuronidation by liver microsomes., Methods: In the present study, we measured the in vitro formation of M3G and M6G by rat hepatocytes incubated for 120 min with morphine (0.1-1.0 mM) after 72h pre-incubation with one of the following MOR agonists: heroin (3.3 or 6.6 microM), morphine (7.8 microM), or methadone (12 microM). The MOR antagonist naltrexone (10 or 25 microM) was also tested, alone or in combination with heroin. The amount of M3G and M6G synthesized was then measured by HPLC method., Results: Heroin inhibited M3G synthesis and induced the formation of M6G, which under basal conditions is not synthesized in rats. Heroin effects were not blocked by naltrexone. Morphine, but not methadone, produced effects similar to those of heroin but more modest in intensity. Pre-incubation with naltrexone alone slightly increased M3G synthesis, but had no effect on M6G formation., Conclusions: These results are in agreement with those of previous ex vivo studies and indicate that exposure to heroin or, to a lesser extent, morphine, can affect morphine glucuronidation via direct non-opioid actions on the hepatocytes.
- Published
- 2008
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20. In vivo chronic exposure to heroin or naltrexone selectively inhibits liver microsome formation of estradiol-3-glucuronide in the rat.
- Author
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Antonilli L, Brusadin V, Milella MS, Sobrero F, Badiani A, and Nencini P
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- Animals, Chromatography, High Pressure Liquid, Estradiol biosynthesis, Glucuronosyltransferase metabolism, Male, Microsomes, Liver enzymology, Microsomes, Liver metabolism, Polymerase Chain Reaction, Rats, Rats, Sprague-Dawley, Spectrometry, Fluorescence, Estradiol analogs & derivatives, Heroin pharmacology, Microsomes, Liver drug effects, Naltrexone pharmacology, Narcotic Antagonists pharmacology, Narcotics pharmacology
- Abstract
We have previously found that repeated exposure to heroin reduces liver synthesis of morphine-3-glucuronide (M3G) and increases the production of morphine-6-glucuronide (M6G), which normally is not formed in the rat. By contrast repeated exposure to naltrexone does not activate M6G synthesis but increases the V(max) of M3G formation. M3G synthesis depends on the activity of two isoforms of the UDP-glucuronosyltransferase (UGT), UGT1A1 and UGT2B1. These isozymes also activate the formation of estradiol-3-glucuronide (E3G) and estradiol-17-glucuronide (E17G), respectively. The goal of the present study was to investigate the role of UGT1A1 and UGT2B1 in the effects of heroin and naltrexone by determining their influence on the synthesis of E3G and E17G. Estradiol glucuronidation was performed using microsomes of rats treated daily, for 10 days, with saline, heroin (10mg/kg, i.p.), or naltrexone (40mg/kg, i.p.). Moreover, liver expression of both UGT1A1 and UGT2B1 was studied in the same experimental conditions by polymerase chain reaction analysis. Kinetic analysis showed that the V(max) for E3G formation was significantly reduced by both heroin (168.82+/-9.73nmol/mg/min) and naltrexone (194.60+/-16.6) relative to saline (624.60+/-17.6). Moreover, homotropic kinetic of E3G formation (Hill coefficient: 1.8) was transformed in Michaelis-Menten kinetic by both heroin (0.88) and naltrexone (1.15). The synthesis of E17G was not affected by either opioid. The expression of liver UGT1A1 and UGT2B1 did not differ across groups. The present results suggest that heroin and naltrexone can reduce estradiol glucuronidation via a specific interaction with UGT1A1 isoform.
- Published
- 2008
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21. Activity of adenosine receptors type 1 Is required for CX3CL1-mediated neuroprotection and neuromodulation in hippocampal neurons.
- Author
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Lauro C, Di Angelantonio S, Cipriani R, Sobrero F, Antonilli L, Brusadin V, Ragozzino D, and Limatola C
- Subjects
- Animals, Cell Line, Cells, Cultured, Hippocampus cytology, Mice, Mice, Mutant Strains, Neuroprotective Agents metabolism, Purinergic P1 Receptor Antagonists, Rats, Xanthines pharmacology, Chemokine CX3CL1 metabolism, Hippocampus metabolism, Neurons metabolism, Receptors, AMPA metabolism, Receptors, Purinergic P1 metabolism
- Abstract
The chemokine fractalkine (CX(3)CL1) is constitutively expressed by central neurons, regulating microglial responses including chemotaxis, activation, and toxicity. Through the activation of its own specific receptor, CX(3)CR1, CX(3)CL1 exerts both neuroprotection against glutamate (Glu) toxicity and neuromodulation of the glutamatergic synaptic transmission in hippocampal neurons. Using cultured hippocampal neuronal cell preparations, obtained from CX(3)CR1(-/-) (CX(3)CR1(GFP/GFP)) mice, we report that these same effects are mimicked by exposing neurons to a medium conditioned with CX(3)CL1-treated mouse microglial cell line BV2 (BV2-st medium). Furthermore, CX(3)CL1-induced neuroprotection from Glu toxicity is mediated through the adenosine receptor 1 (AR(1)), being blocked by neuronal cell preparations treatment with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), a specific inhibitor of AR(1), and mimicked by both adenosine and the specific AR(1) agonist 2-chloro-N(6)-cyclopentyladenosine. Similarly, experiments from whole-cell patch-clamped hippocampal neurons in culture, obtained from CX(3)CR1(+/+) mice, show that CX(3)CL1-induced depression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid- (AMPA-) type Glu receptor-mediated current (AMPA-current), is associated with AR(1) activity being blocked by DPCPX and mimicked by adenosine. Furthermore, BV2-st medium induced a similar AMPA-current depression in CX(3)CR1(GFP/GFP) hippocampal neurons and this depression was again blocked by DPCPX. We also report that CX(3)CL1 induced a significant release of adenosine from microglial BV2 cells, as measured by HPLC analysis. We demonstrate that (i) CX(3)CL1, along with AR(1), are critical players for counteracting Glu-mediated neurotoxicity in the brain and (ii) AR(1) mediates neuromodulatory action of CX(3)CL1 on hippocampal neurons.
- Published
- 2008
- Full Text
- View/download PDF
22. Effect of repeated administrations of heroin, naltrexone, methadone, and alcohol on morphine glucuronidation in the rat.
- Author
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Antonilli L, Petecchia E, Caprioli D, Badiani A, and Nencini P
- Subjects
- Animals, Male, Microsomes, Liver drug effects, Rats, Rats, Sprague-Dawley, Receptors, Opioid, mu agonists, Ethanol pharmacology, Heroin pharmacology, Heroin Dependence metabolism, Methadone pharmacology, Morphine pharmacology, Morphine Derivatives metabolism, Naltrexone pharmacology
- Abstract
Rationale: 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.
- Published
- 2005
- Full Text
- View/download PDF
23. Repeated exposures to heroin and/or cadmium alter the rate of formation of morphine glucuronides in the rat.
- Author
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Antonilli L, Suriano C, Paolone G, Badiani A, and Nencini P
- Subjects
- Analgesics, Opioid toxicity, Animals, Chromatography, High Pressure Liquid, Guinea Pigs, Male, Microsomes, Liver drug effects, Microsomes, Liver metabolism, Rats, Rats, Sprague-Dawley, Cadmium toxicity, Heroin toxicity, Morphine metabolism, Morphine Derivatives analysis
- Abstract
After absorption, heroin is transformed into mono-acetyl-morphine and then into morphine. Morphine, in turn, is metabolized to morphine-3-glucuronide (M3G), an inactive compound, and morphine-6-glucuronide (M6G), a potent opioid agonist. Thus, changes in the rate of formation of M6G may alter the pharmacological consequences of a treatment with heroin or morphine. In this study, we investigate the effect of repeated exposures (10 daily i.p. injections) to heroin, morphine, cadmium (which has been previously shown to inhibit M3G formation in vitro), or heroin + cadmium on morphine glucuronidation both in vivo and ex vivo (i.e., microsomal preparation obtained from rats treated in vivo). Repeated heroin (2.5, 5.0, and 10 mg/kg) increased plasma levels of M6G (which was undetectable in all other groups) and reduced those of M3G. Also, the microsomal preparations obtained from the liver of repeated heroin rats, when incubated with morphine, yielded significant amounts of M6G (which was undetectable in all other groups) and decreased levels of M3G relative to the control groups. These effects were reversible upon discontinuation of heroin administration. In contrast, repeated morphine (10, 20, and 40 mg/kg) only slightly reduced M3G formation at the dose of 40 mg/kg. Repeated cadmium (5, 15, and 45 microg/kg) reduced the rate of M3G formation without inducing M6G synthesis. The effects of the repeated coadministration of heroin (10 mg/kg) and cadmium (15 microg/kg) were virtually identical to those of repeated heroin alone. In summary, repeated exposure of rats to heroin can shift morphine glucuronidation toward the formation of the active metabolite M6G.
- Published
- 2003
- Full Text
- View/download PDF
24. High levels of morphine-6-glucuronide in street heroin addicts.
- Author
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Antonilli L, Semeraro F, Suriano C, Signore L, and Nencini P
- Subjects
- Adult, Aged, Analgesics, Opioid administration & dosage, Analysis of Variance, Chromatography, High Pressure Liquid, Drug Administration Schedule, Female, Heroin administration & dosage, Humans, Male, Middle Aged, Morphine administration & dosage, Morphine blood, Morphine urine, Narcotics administration & dosage, Time Factors, Heroin Dependence blood, Heroin Dependence urine, Morphine Derivatives blood, Morphine Derivatives urine
- Abstract
Rationale: 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.
- Published
- 2003
- Full Text
- View/download PDF
25. Role of the oligosaccharide inner core in the inhibition of human leukocyte elastase by chondroitin sulfates.
- Author
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Antonilli L and Paroli E
- Subjects
- Animals, Cartilage metabolism, Cattle, Chemical Fractionation, Computer Simulation, Electrophoresis, Polyacrylamide Gel, Fishes, Humans, Hydrolysis, In Vitro Techniques, Leukocyte Elastase, Trachea metabolism, Chondroitin Sulfates pharmacology, Pancreatic Elastase antagonists & inhibitors
- Abstract
A chondroitin 4-sulfate and 6-sulfate mixture (CS) extracted from selachian cartilage and a purified preparation of the above glycosaminoglycans from bovine trachea, have been comparatively assayed with respect to the kinetics of human elastase activity. The selachian extract CS, but not the bovine one, inhibited the hydrolysis of N-tert-butyloxycarbonyl p-nitrophenyl ester in vitro (ki = 4.0 micrograms/ml). By fractioning both extracts on Sephadex, the inhibition was found to be related to the presence of a 40-50 KD peak (ki = 2.3 micrograms/ml). This particular fraction was present in the selachian extract CS from matrix, being absent from the bovine trachea extract CS (70% CSC) from Sigma. It showed a single Coomassie- and PAS-stained band approximately 47 kDa in m.w. on sodium dodecylsulfate polyacrylamide gel electrophoresis. Cleavage of the O-glycoside link by alkali hydrolysis of the eluted band, did not influence the enzyme inhibition (ki = 2.1 micrograms/ml). At variance, extensive hydrolysis of ester linkages by fluoride ion resulted in the lowering of inhibition (ki = 5.8 micrograms/ml). Apparently, the preservation of the trisaccharide region in the carbohydrate residues of proteoglycan is mandatory for the inhibition of elastase by low-sulfated chondroitinsulfates.
- Published
- 1993
26. Effects of beta-casomorphins and met-enkephalin on human natural killer activity.
- Author
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Biffoni M, Paroli E, Carletti M, and Antonilli L
- Subjects
- Cell Line, Humans, Monocytes drug effects, Morphine pharmacology, Endorphins pharmacology, Enkephalin, Methionine pharmacology, Killer Cells, Natural drug effects
- Published
- 1992
- Full Text
- View/download PDF
27. A pharmacological approach to glycosaminoglycans.
- Author
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Paroli E, Antonilli L, and Biffoni M
- Subjects
- Animals, Glycosaminoglycans biosynthesis, Glycosaminoglycans physiology, Humans, Glycosaminoglycans pharmacology
- Abstract
A pharmacological approach to glycosaminoglycans (GAG) is presented, reviewing their synthesis, functions and in particular their mechanism as drugs. The application of GAG sulfates in osteoarthritis therapy is examined in detail.
- Published
- 1991
28. Biochemical and immunological studies of deglycosylated Rhus vernicifera laccase.
- Author
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Graziani MT, Antonilli L, Sganga P, Citro G, Mondovi B, and Rosei MA
- Subjects
- Antigen-Antibody Complex immunology, Copper analysis, Cross Reactions immunology, Electrophoresis, Polyacrylamide Gel, Glycoside Hydrolases, Glycosylation, Isoelectric Focusing, Laccase, Oxidoreductases metabolism, Oxidoreductases chemistry, Oxidoreductases immunology, Plants, Toxic, Toxicodendron enzymology
- Abstract
Rhus vernicifera laccase (Japanese) was deglycosylated by treating it with exo- and endoglycosidases. In absence of unfolding agents deglycosylation does not exceed 32% while in denaturating conditions only 10% of saccharides are not digested. In the former case specific activity seems to be directly related to the amount of the residual carbohydrates. After deglycosylation in denaturing conditions the modified enzyme exhibits an electrophoretic component of about 60-65 Kd. A stabilizing effect of saccharide moiety on the catalytic site of native laccase was demonstrated. Antiserum raised against the enzyme recognized native Japanese, Vietnamese as well as deglycosylated laccase indicating that the two isoforms are immunologically similar.
- Published
- 1990
29. Enkephalins and exorphins oxidation by tyrosinase.
- Author
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Rosei MA, Antonilli L, Coccia R, and Foppoli C
- Subjects
- Amino Acid Sequence, Chromatography, High Pressure Liquid, Dihydroxyphenylalanine analysis, Enkephalin, Leucine metabolism, Kinetics, Molecular Sequence Data, Oxidation-Reduction, Catechol Oxidase metabolism, Enkephalins metabolism, Monophenol Monooxygenase metabolism, Peptides metabolism
- Abstract
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).
- Published
- 1989
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