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Contribution of alpha(4)beta(1) integrin to the antiallergic effect of levocabastine.
No full textBiochem Pharmacol. 2008 Sep 15;76(6):751-62. Epub 2008 Jul 15.
Contribution of alpha4beta1 integrin to the antiallergic effect of levocabastine.
Qasem AR, Bucolo C, Baiula M, Spartà A, Govoni P, Bedini A, Fascì D, Spampinato S.
Source
Department of Medicine, Health Science Campus, University of Toledo, OH, USA.
Abstract
Levocabastine is an antiallergic drug acting as a histamine H1-receptor antagonist. In allergic conjunctivitis (AC), it may also antagonize up-regulation of the intercellular adhesion molecule-1 (ICAM-1) expressed on epithelial conjunctival cells. However, little is known about its effects on eosinophils, important effector cells in AC. The adhesion molecule integrin alpha(4)beta(1) is expressed in eosinophils; it interacts with the vascular cell adhesion molecule-1 (VCAM-1) and fibronectin (FN) in vascular endothelial cells and contributes to eosinophil activation and infiltration in AC. This study provides evidence that in a scintillation proximity assay levocabastine (IC(50) 406 microM), but not the first-generation antihistamine chlorpheniramine, displaced (125)I-FN binding to human integrin alpha(4)beta(1) and, in flow cytometry analysis, levocabastine antagonized the binding of a primary antibody to integrin alpha(4) expressed on the Jurkat cell surface. Levocabastine, but not chlorpheniramine, binds the alpha(4)beta(1) integrin and prevents eosinophil adhesion to VCAM-1, FN or human umbilical vascular endothelial cells (HUVEC) in vitro. Similarly, levocabastine affects alpha(L)beta(2)/ICAM-1-mediated adhesion of Jurkat cells. In a model of AC levocabastine eye drops reduced the clinical aspects of the late-phase reaction and the conjunctival expression of alpha(4)beta(1) integrin by reducing infiltrated eosinophils. We propose that blockade of integrin-mediated cell adhesion might be a target of the antiallergic action of levocabastine and may play a role in preventing eosinophil adhesion and infiltration in AC
Hyaluronan-induced stimulation of corneal wound healing is a pure pharmacological effect
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Effects of Mipragoside® on Ocular Allergic Inflammation in the Rabbit
No full textWe evaluated the pharmacodynamic and pharmacokinetic profile of MipragosideR, a monosialoganglioside isopropyl-ester (as 0.57% w/w ophthalmic gel), on allergic inflammation of the eye induced by reverse passive Arthus reaction, on a non-immune mast cell degranulation elicited by compound 48/80 and on ocular inflammation produced by horse serum. Conjunctiva was sensitized by injection of rabbit antisera to bovine proteins and the allergic conjunctivitis was triggered by intravenous administration of bovine gamma globulin. The permeability of the blood-conjunctival barrier was evaluated by a fluorometric method. Compound 48/80 was topically administered at concentration of 50mg/ml and histological analysis of conjunctiva was performed. Horse serum was administered by intravenous injection at different days. The pharmacokinetic profile of topical 3H-Mipragoside® on 48/80 model was investigated and compared with untreated animals. Mipragoside® treatment significantly reduced (p<0.05 vs placebo) the conjunctival vasopermeability induced by reverse passive Arthus reaction as well as successfully reduced the eosinophil levels in the conjunctival epithelium (p<0.01 vs placebo) elicited by compound 48/80. Further, Mipragoside® successfully reduced the primary signs of ocular inflammation produced by horse serum administration. A radiotracer technique was used to evaluate the disposition of 3H-Mipragoside® in the rabbit ocular tissues. Disposition of the drug was monitored at 30, 60, 120 and 240 min. 3H-Mipragoside® levels in the inflamed conjunctiva were significantly higher (p<0.01) than in the control eye. © 1993, Mary Ann Liebert, Inc. All rights reserved
Possible involvement of nitric oxide in morphine-induced miosis and reduction of intraocular pressure in rabbits.
No full textThe role of μ3 opioid receptors in morphine-induced intraocular pressure (IOP) lowering effect and miosis was evaluated in conscious, dark-adapted New Zealand white (NZW) rabbits using a masked-design study. IOP and pupil diameter (PD) measurements were taken at just before and 0.5, 1, 2, 4, 6 h after monolateral instillation of morphine (10, 50 and 100 μg/30 μl) as compared to vehicle administered in the contralateral eye. Morphine-induced ocular effects were challenged by a pre-treatment with the non-selective opioid receptor antagonist, naloxone (100 μg/30 μl), the nitric oxide synthase inhibitor, Nω-nitro-l-arginine methyl ester (l-NAME, 1%, 30 μl), or the non-selective μ3 opioid receptor inhibitor, reduced l-glutathione (GSH, 1%, 30 μl). Morphine induced a dose-dependent decrease in IOP and PD. Pre-treatment with naloxone totally prevented morphine-induced decrease in IOP and miosis. Ocular administration of l-NAME or GSH alone failed to affect IOP or PD of NZW rabbits. However, pre-treatment with either drugs significantly reduced, but not totally prevented ocular effects of morphine. These results suggest that biochemical mechanisms related to nitric oxide release are involved, at least in part, in morphine effects on the eye. Since the μ3 opioid receptor subtype is able to release nitric oxide and is sensitive to inactivation by GSH, it may be possible that μ3 opioid receptors are involved in morphine-induced miosis and reduction in IOP. © 2006 Elsevier B.V. All rights reserved
Ocular hypotensive action of topical flunarizine in the rabbit: Role of σ1 recognition sites
No full textIn a previous study we ascertained the presence of σ1, and σ2 recognition sites in the rabbit iris-ciliary body, an ocular structure involved in aqueous humor production and drainage. We characterized the σ1 sites using the preferential ligand (+)- pentazocine, which caused a significant reduction of intraocular pressure (IOP). In the present study, flunarizine, a calcium channel blocker with a complex pharmacological profile, bound to σ1, sites expressed in the iris-ciliary body with moderate affinity (K1 = 68 nM). Unilateral topical flunarizine (0.01-0.1 %) caused a dose-related reduction of IOP in ocular normotensive rabbits and in the α-chymotrypsin model of ocular hypertension, without altering the IOP of the contralateral eye. This activity was blocked by the σ1 site antagonist NE-100 [N,N- dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine HCI] which, by itself, had no effect on IOP. Detection of flunarizine in rabbit iris-ciliary body homogenates, after topical instillation, showed that it adequately penetrates the rabbit eye. To investigate mechanisms that may contribute to ocular hypotension induced by σ1 agonists, we carried out in vitro studies on the isolated rabbit iris-ciliary body. Flunarizine (IC50 = 5.96 nM) and (+)-pentazocine (IC50 = 3. 81 nM) inhibited [3H]norepinephrine release. Moreover, flunarizine (IC50 = 6.34 nM) and (+)-pentazocine (IC50 = 27.26 nM) also antagonized isoproterenol-induced cAMP accumulation. The action of flunarizine and (+)-pentazocine was sensitive to NE-100 antagonism; however, this latter compound partially prevented their effect on [3H]norepinephrine and cAMP accumulation. These findings indicate that flunarizine and (+)-pentazocine interact with ocular σ1 sites and may prove effective in the control of ocular hypertension
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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