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See detailEffects of formoterol and ipratropium bromide on repeated cadmium inhalation -induced pulmonary inflammation and emphysema in rats
Zhang, Whenhui; Fievez, Laurence ULg; Zhang, F. et al

in European Journal of Pharmacology (2010), 25(647), 178-187

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See detailAnti-inflammatory effects of formoterol and ipratropium bromide against acute cadmium-induced pulmonary inflammation in rats.
Zhang, W.; Fievez, Laurence ULg; Cheu, Esteban ULg et al

in European Journal of Pharmacology (2010), 628(1-3), 171-178

In this study, the anti-inflammatory properties of formoterol and ipratropium bromide, alone or in combination, were investigated in a rat model of acute pulmonary inflammation induced by cadmium ... [more ▼]

In this study, the anti-inflammatory properties of formoterol and ipratropium bromide, alone or in combination, were investigated in a rat model of acute pulmonary inflammation induced by cadmium inhalation. Airway resistance and inflammatory responses, including matrix metalloproteinease-2 (MMP-2) and matrix metalloproteinease-9 (MMP-9) activities, were evaluated. Compared to values obtained in rats exposed to cadmium, pretreatment by bronchodilators administered alone significantly prevented the cadmium-induced increase of airway resistance. Formoterol elicited a significant decrease in total cell number, neutrophil and macrophage counts in bronchoalveolar lavage fluid, whereas ipratropium bromide reduced neutrophil numbers. The two compounds administered alone significantly attenuated the lung lesions associated with parenchyma inflammatory cell influx and congestion observed in the cadmium group. The increased MMP-9 activity was significantly attenuated. Although only formoterol induced a decrease protein concentration in bronchoalveolar lavage fluid, both compounds inhibited the pulmonary edema by reducing wet-to-dry weight ratio which returned to values similar to those recorded in the sham group. All the effects of formoterol on the cadmium-induced inflammatory responses were reversed by propranolol. Similar anti-inflammatory effects were obtained in rats pretreated with ilomastat which showed a significant reduction on inflammatory cell infiltration and MMP-9 activity in bronchoalveolar lavage fluid. Neither synergistic nor additive effects were obtained when the two bronchodilators were administered in combination. In conclusion, formoterol and ipratropium bromide partially protect the lungs against the inflammation by reducing neutrophilic infiltration. This protective effect is associated with reduced MMP-9 activity known to play an important pro-inflammatory role in acute inflammatory process. [less ▲]

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See detailEffects of betamethasone on inflammation and emphysema induced by cadmium nebulisation in rats
Fievez, Laurence ULg; Kirschvink, N.; Zhang, Wenhui H. et al

in European Journal of Pharmacology (2009), 606(1-3), 210-214

Cadmium (Cd) induces centrilobular emphysema and is suspected to contribute to tobacco related lung diseases as chronic obstructive pulmonary disease (COPD). This study aimed to check whether the ... [more ▼]

Cadmium (Cd) induces centrilobular emphysema and is suspected to contribute to tobacco related lung diseases as chronic obstructive pulmonary disease (COPD). This study aimed to check whether the inflammatory process observed in rats exposed to nebulised Cd is resistant to betamethasone as observed in COPD and to determine the influence of this drug on airspace enlargement together with the MMP-2-9/TIMP-1-2 imbalance. Our results showed that betamethasone induced emphysema by itself in healthy rats. Moreover, pre-treatment of rats with betamethasone could only partially modulate the increase in bronchoalveolar lavage fluid cell counts and the absence of preventive effect of this compound against emphysema development is associated with its inability to rebalance the MMP-2-9/TIMP-1-2 ratio. [less ▲]

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See detailAmphetamine- and cocaine-induced conditioned place preference and concomitant psychomotor sensitization in mice with genetically inactivated melanin-concentrating hormone MCH(1) receptor.
Tyhon, Amélie ULg; Lakaye, Bernard ULg; Adamantidis, Antoine ULg et al

in European Journal of Pharmacology (2008), 599(1-3), 72-80

The melanin-concentrating hormone MCH(1) receptor has been proposed to exert an inhibitory control on monoaminergic (especially dopaminergic) activity within the mesolimbic system, which underpins drug ... [more ▼]

The melanin-concentrating hormone MCH(1) receptor has been proposed to exert an inhibitory control on monoaminergic (especially dopaminergic) activity within the mesolimbic system, which underpins drug seeking and reward. That hypothesis predicts that an inactivation of these receptors should enhance the sensitivity to drug rewarding effects. To test that prediction, we examined the propensity of mice lacking the melanin-concentrating receptor (MCH(1) KO) and their intact counterparts (WT) to form cocaine- and amphetamine-induced conditioned place preference. The conditioned rewarding effects induced by 0.375, 0.75, 1.5 and 3 mg/kg amphetamine were assessed in two sub-experiments and those induced by 1, 2, 4 and 8 mg/kg cocaine in two other sub-experiments. All mice were tested under saline for place preference 24 h following four every-other-day conditioning trials and an initial pre-conditioning session under saline. Most of the cocaine and amphetamine doses induced place preference, but without any genotype difference being revealed. Also, none of the cocaine doses induced psychomotor sensitization during conditioning, whereas amphetamine generated clear-cut dose-dependent sensitization in both genotypes. Albeit MCH(1) KO mice exhibited higher levels of psychomotor activation, the rates of sensitization were comparable across genotypes at 1.5 and 3 mg/kg amphetamine. Moreover, 0.375 and especially 0.75 mg/kg amphetamine produced a slight but yet significant sensitization in MCH(1) KO but not in their WT counterparts. Despite such an effect, the results cannot be considered as unambiguously supportive of the tested prediction. [less ▲]

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See detailMatrix metalloproteinases (MMPs) and tissue inhibitors of MMPs in the respiratory tract: Potential implications in asthma and other lung diseases
Guéders, Maud ULg; Foidart, Jean-Michel ULg; Noël, Agnès ULg et al

in European Journal of Pharmacology (2006), 533(1-3), 133-144

In healthy lung, Matrix Metalloproteinases (MMPs) and their physiological inhibitors, tissue inhibitors of matrix metalloproteinases (TIMPs), are produced in the respiratory tract by a panel of different ... [more ▼]

In healthy lung, Matrix Metalloproteinases (MMPs) and their physiological inhibitors, tissue inhibitors of matrix metalloproteinases (TIMPs), are produced in the respiratory tract by a panel of different structural cells. These activities are mandatory for many physiological processes including development, wound healing and cell trafficking. Deregulation of proteolytic-antiproteolytic network and inappropriate secretion of various MMPs by stimulated structural or inflammatory cells is thought to take part to pathophysiology of numerous lung diseases including asthma, chronic obstructive pulmonary disease (COPD), lung fibrosis and lung cancer. Cytokines and growth factors are involved in these inflammatory processes and some of those mediators interact directly with MMPs and TIMPs leading either to a regulation of their expression or changes in their biological activities by proteolytic cleavage. In turn, cytokines and growth factors modulate secretion of MMPs establishing a complex network of reciprocal interactions. Every MMP seem to play a rather specific role and some variations of their expression are observed in different lung diseases. The precise role of these enzymes and their inhibitors is now studied in depth as they could represent relevant therapeutic targets for many diseases. Indeed, MMP inhibition can lead either to a decrease of the intensity of a pathological process or, in the contrary for some of them, to an increase of disease severity. In this review, we focus on the role played by MMPs and TIMPs in asthma and we provide an overview of their potential roles in COPD, lung fibrosis and lung cancer, with a special emphasis on loops including MMPs and cytokines and growth factors relevant in these diseases. [less ▲]

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See detailStudy of the interaction of antiplasmodial strychnine derivatives with the glycine receptor
Philippe, Geneviève ULg; Nguyen, Laurent ULg; Angenot, Luc ULg et al

in European Journal of Pharmacology (2006), 530(1-2), 15-22

Strychnos icaja Baill. (Loganiaccae) is a liana found in Central Africa known to be an arrow and ordeal poison but also used by traditional medicine to treat malaria. Recently, many dimeric or trimeric ... [more ▼]

Strychnos icaja Baill. (Loganiaccae) is a liana found in Central Africa known to be an arrow and ordeal poison but also used by traditional medicine to treat malaria. Recently, many dimeric or trimeric indolomonoterpenic alkaloids with antiplasmodial properties have been isolated from its rootbark. Since these alkaloids are derivatives of strychnine, it was important, in view of their potential use as antimalarial drugs, to assess their possible convulsant strychnine-like properties. In that regard, their interaction with the strychnine-sensitive glycine receptor was investigated by whole-cell patch-clamp recordings on glycine-gated currents in mouse spinal cord neurons in culture and by [H-3]strychnine competition assays on membranes from adult rat spinal cord. These experiments were carried out on sungucine (leading compound of the chemical class) and on the antiplasmodial strychnogucine B (dimeric) and strychnohexamine (trimeric). In comparison with strychnine, all compounds interact with a very poor efficacy and only at concentrations > I mu M with both [H-3]strychnine binding and glycine-gated currents. Furthermore, the effects of strychnine and protostrychnine, a monomeric alkaloid (without antiplasmodial activity) also isolated from S. icaja and differing from strychnine only by a cycle opening, were compared in the same way. The weak interaction of protostrychnine confirms the importance of the G cycle ring structure in strychnine for its binding to the glycine receptor and its antagonist properties. (c) 2005 Elsevier B.V. All rights reserved. [less ▲]

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See detailDoes insulin release kinins in rats?
Damas, Jacques ULg; Garbacki, Nancy ULg; Lefebvre, P. J.

in European Journal of Pharmacology (2005), 525(1-3), 154-160

Rat uterus maintained in situ was used as a bioassay of kinins possibly released in vivo by hyperglycaemia or insulin. Intravenous injections of bradykinin induced contractions of rat uterus which were ... [more ▼]

Rat uterus maintained in situ was used as a bioassay of kinins possibly released in vivo by hyperglycaemia or insulin. Intravenous injections of bradykinin induced contractions of rat uterus which were suppressed by HOE 140, a bradykinin B-2 receptor antagonist. Des-Arg(9)-bradykinin, a kinin B-1 receptor agonist, did not elicit any response. After propranolol, the effects of bradykinin were enhanced and dose-dependent. This potentiation did not appear in adrenalectomized rats. Captopril, an angiotensin-converting enzyme (ACE) inhibitor, largely increased the effects of bradykinin. In animals pretreated with propranolol, captopril and atosiban, an oxytocin antagonist, intravenous infusion of glucose induced hyperglycaemia and after a delay increased the uterine contractile activity. This contractile effect of glucose was abolished by HOE 140. Infusion of insulin with glucose induced contractions of the uterus. These responses did not appear or were suppressed by HOE 140 or by soya bean trypsin inhibitor (SBTI), a plasma kallikrein inhibitor. These results are direct evidence that insulin induces a release of kinins. (c) 2005 Elsevier B.V. All rights reserved. [less ▲]

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See detailPropofol scavenges reactive oxygen species and inhibits the protein nitration induced by activated polymorphonuclear neutrophils
Thiry, J. C.; Hans, Pol ULg; Deby-Dupont, G. et al

in European Journal of Pharmacology (2004), 499(1-2), 29-33

Activated polymorphonuclear neutrophils may damage tissues through the release of biochemical mediators. Among them, peroxynitrite is responsible for hydroxylation reactions and nitration of proteins, or ... [more ▼]

Activated polymorphonuclear neutrophils may damage tissues through the release of biochemical mediators. Among them, peroxynitrite is responsible for hydroxylation reactions and nitration of proteins, or is metabolised into nitrate. We investigated the effect of propofol on the production of reactive oxygen species, the nitration of proteins and the formation of nitrate by activated human polymorphonuclear neutrophils. Propofol dose-dependently inhibited chemiluminescence, nitration of proteins and nitrate production in a concentration range from 10(-3) to 10(-6) mM. A significant correlation was observed between the logarithm of propofol concentration and the intensity of chemiluminescence (r(2) = 0.90), the nitration of proteins (r(2) = 0.67) and the production of nitrate (r(2) = 0.79). Those results are consistent with the scavenging effect of propofol on peroxynitrite and could confer a protective property to propofol in pathological situations involving polymorphonuclear neutrophils activation. (C) 2004 Elsevier B.V. All rights reserved. [less ▲]

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See detailLocalization and photoaffinity labelling of the levetiracetam binding site in rat brain and certain cell lines
Fuks, Bruno; Gillard, Michel; Michel, Philippe et al

in European Journal of Pharmacology (2003), 478(1), 11-19

Levetiracetam (2S-(2-oxo-1-pyrrolidinyl)butanamide, KEPPRA(R)), a novel antiepileptic drug, has been shown to bind to a specific binding site located in the brain (Eur. J. Pharmacol. 286 (1995) 137). To ... [more ▼]

Levetiracetam (2S-(2-oxo-1-pyrrolidinyl)butanamide, KEPPRA(R)), a novel antiepileptic drug, has been shown to bind to a specific binding site located in the brain (Eur. J. Pharmacol. 286 (1995) 137). To identify the protein constituent of the levetiracetam binding site in situ, we synthesized the photoaffinity label [H-3]ucb 30889 ((2S)-2-[4-(3-azidophenyl)-2-oxopyrrolidin-1-yl]butanamide), a levetiracetam analog with higher affinity for the levetiracetam binding site. This radioligand was used to map the levetiracetam binding site within the brain and to study its cellular and subcellular distribution. Autoradiography experiments using [H-3]ucb 30889 in rat brain revealed a unique distribution profile that did not match that of classical receptors known to be involved in the generation of epileptic seizures. There was a high level of binding in the dentate gyrus, the superior colliculus, several thalamic nuclei, the molecular layer of the cerebellum and to a lesser extent in the cerebral cortex, the striatum and the hypothalamus. The levetiracetam binding site was restricted to neuronal cell types, undifferentiated PC 12 cells and was highly enriched in synaptic vesicles. [H-3]ucb 30889 was also used in photoaffinity labelling studies and shown to bind covalently to a membrane protein with a molecular weight of approximately 90 kDa. (C) 2003 Elsevier B.V. All rights reserved. [less ▲]

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See detailPre- and post-treatment with pirlindole and dehydropirlindole protects cultured brain cells against nitric oxide-induced death.
Boland, André ULg; Gérardy, Jean; Mossay, Danielle ULg et al

in European Journal of Pharmacology (2003), 466

We have previously shown that pirlindole and dehydropirlindole, two monoamine oxidase type-A inhibitors, protect cultured brain cells against iron-induced toxicity through a mechanism unrelated to ... [more ▼]

We have previously shown that pirlindole and dehydropirlindole, two monoamine oxidase type-A inhibitors, protect cultured brain cells against iron-induced toxicity through a mechanism unrelated to monoamine oxidase type-A inhibition. The current study was performed to test whether the protective effect of pirlindole and dehydropirlindole could be extended to a nitric oxide (NO)-induced insult. A comparison with other monoamine oxidase inhibitors (brofaromine, moclobemide and deprenyl) and with trolox was made. In a first series of experiments, rat hippocampal or cortical cultured cells were exposed to a drug for 3 h, then 5 muM sodium nitroprusside, a NO donor, was added and the incubation was continued for 16 h. Cell survival assessment showed that pirlindole, dehydropirlindole and trolox significantly protected cultures against NO-induced toxicity in a concentration-dependent manner with respective EC50's of 7, 3 and 17 muM. Similarly, pirlindole, dehydropirlindole or trolox, at a concentration of 50 muM, significantly decreased both intracellular peroxide production and lipoperoxidation. Other drugs were ineffective. In a post-hoc treatment protocol (3- or 6-h pre-incubation in the presence of sodium nitroprusside, then addition of one of the above mentioned compounds), only pirlindole and dehydropirlindole significantly improved cell survival in a concentration-dependent manner with respective EC50'S of 9 and 4 muM. The maximal protection in terms of cell survival was 90% and 78% after 3 and 6 h, respectively. They also reduced the production of both lipoperoxides and endoperoxides. Our results show that pirlindole and dehydropirlindole protect neurons against NO-induced toxicity at pharmacologically relevant concentrations. Moreover, their protective effect is still apparent when they are applied after the start of the insult. Therefore, our preclinical study suggests a new strategy that may be efficient to reduce NO-induced damage in the central nervous system. (C) 2003 Elsevier Science B.V. All rights reserved. [less ▲]

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See detailDifferential taurine responsiveness to ethanol in high- and low-alcohol sensitive rats : a brain microdialysis study
Quertemont, Etienne ULg; Linotte, Sylvie; De Witte, Philippe

in European Journal of Pharmacology (2002), 444(3), 143-150

Several microdialysis studies have investigated the effects of acute ethanol on extracellular amino acids in various rat brain regions, However, these studies led to conflicting results, suggesting that ... [more ▼]

Several microdialysis studies have investigated the effects of acute ethanol on extracellular amino acids in various rat brain regions, However, these studies led to conflicting results, suggesting that individual differences between rat strains and lines may play an important role. In the present study, high-alcohol sensitive (HAS) and low-alcohol sensitive (LAS) rats were used to investigate the possible relationship between ethanol sensitivity and the concentrations of extracellular amino acids in the nucleus accumbens. Several groups of HAS and LAS rats were injected with either saline or ethanol (1.0, 2.0 or 3.0 g/kg, i.p.) and the concentrations of amino acids in the nucleus accumbens microdialysates were assayed by electrochemical detection. Acute ethanol induced a dose-dependent increase in extracellular taurine concentrations. However, this increase was significantly reduced at 2,0 and 3.0 g,,kg ethanol in HAS rats relative to LAS rats. Since the biological functions of taurine suggest its implication in the reduction of ethanol adverse effects, a higher increase in taurine concentrations may contribute to the lower ethanol sensitivity of LAS rats. Although 2.0 and 3.0 g/kg ethanol did not affect extracellular glutamate concentrations, a significant increase in glutamate was observed after 1.0 g/kg ethanol to HAS rats but not to LAS rats. Such an effect remains unexplained but suggests that discrepancies between the results of previous microdialysate studies may be related to differences in the ethanol sensitivities of various rat strains. (C) 2002 Elsevier Science B.V All rights reserved. [less ▲]

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See detailRole of Substance P and Tachykinin Receptor Antagonists in Citric Acid-Induced Cough in Pigs
Moreaux, B.; Nemmar, A.; Vincke, G. et al

in European Journal of Pharmacology (2000), 408(3), 305-312

The purpose of this work was to investigate the role of tachykinins in cough induced by citric acid (0.8 M) in pigs. With this object, we have studied the effect of citric acid on substance P content in ... [more ▼]

The purpose of this work was to investigate the role of tachykinins in cough induced by citric acid (0.8 M) in pigs. With this object, we have studied the effect of citric acid on substance P content in the tracheo-bronchial tree and the effects of substance P and of tachykinin receptor antagonists on citric acid-induced cough. Citric acid exposure significantly increased substance P concentration in both broncho-alveolar and tracheal lavage fluids, while it decreased significantly the substance P content in tracheal mucosa. Substance P did not elicit cough, but significantly potentiated the citric acid-induced cough frequency. Tachykinin NK(1), NK(2) or NK(3) receptor antagonists, SR 140333 (nolpitantium), SR 48968 (saredutant) and SR 142801 (osanetant), respectively, significantly inhibited citric acid-induced cough. The same inhibitory effect of tachykinin receptor antagonists was observed, when substance P was nebulised before citric acid challenge. We conclude that citric acid induces in pigs a release of substance P in the tracheo-bronchial tree, which plays a sensitising role on the cough reflex. The involvement of tachykinin NK(1), NK(2), NK(3) receptors are also demonstrated in this reflex. [less ▲]

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See detailAge-dependence of the anticonvulsant effects of the GABA uptake inhibitor tiagabine in vitro
Sabau, A; Frahm, C; Pfeiffer, M et al

in European Journal of Pharmacology (1999), 383(3), 259-266

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See detailModulatory Effect of Imetit, a Histamine H3 Receptor Agonist, on C-Fibers, Cholinergic Fibers and Mast Cells in Rabbit Lungs in Vitro
Nemmar, A.; Delaunois, Annie ULg; Beckers, Jean-François ULg et al

in European Journal of Pharmacology (1999), 371(1), 23-30

The pharmacological mechanisms involved in the interactions between C-fibers, cholinergic fibers and mast cells were investigated in tracheally perfused rabbit lungs by measuring the simultaneous release ... [more ▼]

The pharmacological mechanisms involved in the interactions between C-fibers, cholinergic fibers and mast cells were investigated in tracheally perfused rabbit lungs by measuring the simultaneous release of substance P and histamine in lung effluents. The amounts of substance P and histamine released in lung superfusates were measured by radioimmunoassay (RIA) after administration of capsaicin and carbachol. Capsaicin (10(-4) M) induced a simultaneous increase in substance P (273 +/- 56% of baseline) and histamine (460 +/- 138%) release. Similarly, carbachol (10(-4) M) caused an increase in the release of both substance P (367 +/- 111%) and histamine (1379 +/- 351%). The effect of capsaicin was prevented by pretreating the lungs with the tachykinin NK1 receptor antagonist SR 140333 (10(-7) M), and atropine (10(-6) M). SR 140333 prevented the carbachol-induced release of substance P but not of histamine. Exogenous substance P induced an increase in histamine release (136 +/- 7%) which was significantly greater in lungs perfused with the neutral endopeptidase inhibitor, thiorphan (10(-5) M) (272 +/- 35%). This effect was prevented by atropine (10(-6) M). Pretreatment of lungs with imetit (5 x 10(-8) M), a selective H3 receptor agonist, prevented the capsaicin-induced release of both mediators. Imetit also blocked the carbachol-induced release of substance P but not of histamine. Exogenous substance P-evoked histamine release was inhibited by imetit. Therefore, it can be concluded that substance P released through the action of capsaicin can activate cholinergic fibers, leading to cholinoceptor stimulation with subsequent activation of C-fibers and mast cells. While the presence of presynaptic H3 receptors modulating substance P-induced acetylcholine release was only surmised, the existence of modulating histamine H3 receptors on C-fibers was confirmed. [less ▲]

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See detailNeonatal and Preweanling Rats Are Able to Express Short-Term Behavioral Sensitization to Cocaine
Tirelli, Ezio ULg; Ferrara, Marie-Antoinette ULg

in European Journal of Pharmacology (1997), 328(2-3), 103-14

The present study assessed the ability of suckling rats to express short-term behavioral sensitization to cocaine prior to weaning. Rat pups, aged either 3, 5, 10, 12, 17 or 19 days at the beginning of ... [more ▼]

The present study assessed the ability of suckling rats to express short-term behavioral sensitization to cocaine prior to weaning. Rat pups, aged either 3, 5, 10, 12, 17 or 19 days at the beginning of the experiment, were placed in a chamber after daily injection with cocaine (7.5 or 15 mg/kg. i.p.) for either 2 or 4 consecutive days, and were tested for behavioral responsiveness to cocaine in the same chamber 24 h later (at either 7, 14 or 21 days of age). Such a short post-treatment interval was adopted, along with a consistent pairing of the testing context with the drug effect and a sensitive technique of behavioral measurement (video recording), in order to maximize the possibility of detecting any cocaine sensitization. Locomotion was sensitized at all ages, after both regimens in 14-day-old pups, but solely after 2 injections in 21- and 4 injections in 7-day-old pups. Sensitization was also expressed via behaviors specific to each age. Four cocaine injections augmented cocaine-induced uncoordinated movements of head, paws and body (horizontal activity) in 7-day-old pups, and mouth movements in 14-day-old pups. In 21-day-old pups, sensitization was dose- and regimen-dependently expressed via adult-like stereotyped head movements. In neonatal 7-day-old pups, cocaine sensitization was also visible as reductions in immobility (both injection regimens). Contrary to previous studies, these results indicate that, given the use of an appropriate methodology, short-term sensitization to the motoric effects of cocaine can be expressed by suckling rats prior to weaning, even after relatively short regimens of daily injections. [less ▲]

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See detailEnhancement of Tamoxifen-Induced E-Cadherin Function by Ca2+ Channel Antagonists in Human Breast Cancer Mcf7/6 Cells
Charlier, Corinne ULg; Bruyneel, E.; Lechanteur, Chantal ULg et al

in European Journal of Pharmacology (1996), 317(2-3), 413-6

Despite its intensive use in adjuvant breast cancer therapy for more than 30 years, the exact mechanisms of action of tamoxifen have not yet been fully characterized. Tamoxifen was recently shown to ... [more ▼]

Despite its intensive use in adjuvant breast cancer therapy for more than 30 years, the exact mechanisms of action of tamoxifen have not yet been fully characterized. Tamoxifen was recently shown to restore the E-cadherin function of human breast cancer MCF7/6 cells and to suppress their invasive phenotype. Because tamoxifen interacts with targets implicated in Ca2+ homeostasis, we explored the possibility that the restoration of E-cadherin function in MCF7/6 cells induced by this drug could be affected by Ca2+ modulators. Two different Ca2+ channel antagonists (verapamil and nifedipine) potentiated the effect of tamoxifen on E-cadherin function, as evaluated with a fast cell aggregation assay. These molecules decreased the tamoxifen concentration needed to restore the E-cadherin function from 10(-6) M to 10(-7) M. When incubated with a Ca2+ channel agonist, Bay K8644 (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoro-methylphenyl)- pyridine-5-carboxylate), the effect of tamoxifen on E-cadherin function was completely abolished. These results demonstrate that the restoration of the E-cadherin function induced by tamoxifen depends, at least in part, on a Ca2+ pathway, and support the evidence of an effect of tamoxifen on Ca(2+)-dependent mechanisms. Our data also suggest that Ca2+ channel modulators could make it possible to decrease the dose of tamoxifen administered to patients without reducing the therapeutic effects. [less ▲]

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See detailInteraction Of The Macrolide Azithromycin With Phospholipids .2. Biophysical And Computer-Aided Conformational Studies
Montenez, Jp.; Vanbambeke, F.; Piret, J. et al

in European Journal of Pharmacology (1996), 314(1-2), 215-27

In a comparison paper, we show the azithromycin causes a lysosomal phospholipidosis in cultured cells, binds in vitro to negatively charged bilayers without causing aggregation or fusion, and inhibits ... [more ▼]

In a comparison paper, we show the azithromycin causes a lysosomal phospholipidosis in cultured cells, binds in vitro to negatively charged bilayers without causing aggregation or fusion, and inhibits lysosomal phospholipase A1. In this paper, we show that azithromycin decreases the mobility of the phospholipids in negatively charged liposomes (using 31P nuclear magnetic resonance) and that it increases the fluidity of the acyl chains close to the hydrophilic/hydrophobic interface, but not deeper into the hydrophobic domain (assessed by measuring the fluorescence polarization of trimethylammonium-diphenylhexatriene and diphenyhexatriene, respectively). Computer-aided conformational analysis of mixed monolayers of azithromycin and phosphatidylinositol shows that the drug can be positioned largely in the hydrophobic domain, but close to the interface, with the macrocycle facing the C1 of the fatty acids (allowing the N9a endocyclic tertiary amine to interact with the phospho-groups), the cladinose located on the hydrophobic side of the lipid/water interface and the desosamine projected into the hydrophobic domain. This position is consistent with the experimental data. Analysis of virtual molecules shows that this unanticipated behavior to the shielding of the ionizable N3' amino-group in the desosamine by methyl-groups, and to the wide dispersion of hydrophobic domains all over the molecule. The interaction of azithromycin with phospholipids may account for some of its unusual pharmacokinetic properties and for its potential to cause lysosomal phospholipidosis. [less ▲]

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