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Articles de revues sur le sujet "S1P receptor antagonists"
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Sumida, Grant M., et W. Daniel Stamer. « S1P2 receptor regulation of sphingosine-1-phosphate effects on conventional outflow physiology ». American Journal of Physiology-Cell Physiology 300, no 5 (mai 2011) : C1164—C1171. http://dx.doi.org/10.1152/ajpcell.00437.2010.
Texte intégralRésumé :
Elevated intraocular pressure is the main risk factor in primary open-angle glaucoma, involving an increased resistance to aqueous humor outflow in the juxtacanalicular region of the conventional outflow pathway which includes the trabecular meshwork (TM) and the inner wall of Schlemm's canal (SC). Previously, sphingosine-1-phosphate (S1P) was shown to decrease outflow facility in porcine and human eyes, thus increasing outflow resistance and intraocular pressure. Owing to S1P's known effect of increasing barrier function in endothelial cells and the robust expression of the S1P1 receptor on the inner wall of SC, we hypothesized that S1P1 receptor activation promotes junction formation and decreases outflow facility. The effects of subtype-specific S1P receptor compounds were tested in human and porcine whole-eye perfusions and human primary cultures of SC and TM cells to determine the receptor responsible for S1P effects on outflow resistance. The S1P1-specific agonist SEW2871 failed to both mimic S1P effects in paired human eye perfusions, as well as increase myosin light chain (MLC) phosphorylation in cell culture, a prominent outcome in S1P-treated SC and TM cells. In contrast, the S1P2 antagonist JTE-013, but not the S1P1 or S1P1,3 antagonists, blocked the S1P-promoted increase in MLC phosphorylation. Moreover, JTE-013 prevented S1P-induced decrease in outflow facility in perfused human eyes ( P < 0.05, n = 6 pairs). Similarly, porcine eyes perfused with JTE-013 + S1P did not differ from eyes with JTE-013 alone ( P = 0.53, n = 3). These results demonstrate that S1P2, and not S1P1 or S1P3, receptor activation increases conventional outflow resistance and is a potential target to regulate intraocular pressure.
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Lukas, Susan, Lori Patnaude, Sokol Haxhinasto, Anthony Slavin, Melissa Hill-Drzewi, Josh Horan et Louise Kelly Modis. « No Differences Observed among Multiple Clinical S1P1 Receptor Agonists (Functional Antagonists) in S1P1 Receptor Down-regulation and Degradation ». Journal of Biomolecular Screening 19, no 3 (3 septembre 2013) : 407–16. http://dx.doi.org/10.1177/1087057113502234.
Texte intégralRésumé :
Sphingosine-1-phosphate (S1P) is a bioactive metabolite with pleiotropic effects on multiple cellular processes in health and disease. Responses elicited by S1P are a result of binding to five specific G-protein–coupled receptors. We have developed multiple assays to systematically study the downstream signaling of these receptors, including early events such as direct receptor activation (GTPγS) as well as more distal events such as S1P1 receptor degradation. Employing such assays, we have characterized and compared multiple S1P1 agonists that are in clinical development including FTY720, BAF312, CS-0777, and other molecules from the S1P1 patent literature. Our parallel assessment has allowed us to compare their potency against S1P1, their selectivity against the four other S1P receptors, as well as species cross-reactivity. We note that all of the compounds studied signal in an identical manner through S1P1, leading to receptor degradation.
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Zhang, Dong Dong, Bona Linke, Jing Suo, Aleksandra Zivkovic, Yannick Schreiber, Nerea Ferreirós, Marina Henke, Gerd Geisslinger, Holger Stark et Klaus Scholich. « Antinociceptive effects of FTY720 during trauma-induced neuropathic pain are mediated by spinal S1P receptors ». Biological Chemistry 396, no 6-7 (1 juin 2015) : 783–94. http://dx.doi.org/10.1515/hsz-2014-0276.
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Abstract FTY720 (fingolimod) is, after its phosphorylation by sphingosine kinase (SPHK) 2, a potent, non-selective sphingosine-1-phosphate (S1P) receptor agonist. FTY720 has been shown to reduce the nociceptive behavior in the paclitaxel model for chemotherapy-induced neuropathic pain through downregulation of S1P receptor 1 (S1P1) in microglia of the spinal cord. Here, we investigated the mechanisms underlying the antinociceptive effects of FTY720 in a model for trauma-induced neuropathic pain. We found that intrathecal administration of phosphorylated FTY720 (FTY720-P) decreased trauma-induced pain behavior in mice, while intraplantar administered FTY720-P had no effect. FTY720-P, but not FTY720, reduced the nociceptive behavior in SPHK2-deficient mice, suggesting the involvement of S1P receptors. Fittingly, intrathecal administration of antagonists for S1P1 or S1P3, W146 and Cay10444 respectively, abolished the antinociceptive effects of systemically administered FTY720, demonstrating that activation of both receptors in the spinal cord is necessary to induce antinociceptive effects by FTY720. Accordingly, intrathecal administration of S1P1 receptor agonists was not sufficient to evoke an antinociceptive effect. Taken together, the data show that, in contrast to its effects on chemotherapy-induced neuropathy, FTY720 reduces trauma-induced neuropathic pain by simultaneous activation of spinal S1P1 and S1P3 receptor subtypes.
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Hafizi, Redona, Faik Imeri, Roland H. Wenger et Andrea Huwiler. « S1P Stimulates Erythropoietin Production in Mouse Renal Interstitial Fibroblasts by S1P1 and S1P3 Receptor Activation and HIF-2α Stabilization ». International Journal of Molecular Sciences 22, no 17 (31 août 2021) : 9467. http://dx.doi.org/10.3390/ijms22179467.
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Erythropoietin (Epo) is the critical hormone for erythropoiesis. In adults, Epo is mainly produced by a subset of interstitial fibroblasts in the kidney, with minor amounts being produced in the liver and the brain. In this study, we used the immortalized renal interstitial fibroblast cell line FAIK F3-5 to investigate the ability of the bioactive sphingolipid sphingosine 1-phosphate (S1P) to stimulate Epo production and to reveal the mechanism involved. Stimulation of cells with exogenous S1P under normoxic conditions (21% O2) led to a dose-dependent increase in Epo mRNA and protein levels and subsequent release of Epo into the medium. S1P also enhanced the stabilization of HIF-2α, a key transcription factor for Epo expression. S1P-stimulated Epo mRNA and protein expression was abolished by HIF-2α mRNA knockdown or by the HIF-2 inhibitor compound 2. Furthermore, the approved S1P receptor modulator FTY720, and its active form FTY720-phosphate, both exerted a similar effect on Epo expression as S1P. The effect of S1P on Epo was antagonized by the selective S1P1 and S1P3 antagonists NIBR-0213 and TY-52156, but not by the S1P2 antagonist JTE-013. Moreover, inhibitors of the classical MAPK/ERK, the p38-MAPK, and inhibitors of protein kinase (PK) C and D all blocked the effect of S1P on Epo expression. Finally, the S1P and FTY720 effects were recapitulated in the Epo-producing human neuroblastoma cell line Kelly, suggesting that S1P receptor-dependent Epo synthesis is of general relevance and not species-specific. In summary, these data suggest that, in renal interstitial fibroblasts, which are the primary source of plasma Epo, S1P1 and 3 receptor activation upregulates Epo under normoxic conditions. This may have a therapeutic impact on disease situations such as chronic kidney disease, where Epo production is impaired, causing anemia, but it may also have therapeutic value as Epo can mediate additional tissue-protective effects in various organs.
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Werth, Stephan, Helge Müller-Fielitz et Walter Raasch. « Obesity-stimulated aldosterone release is not related to an S1P-dependent mechanism ». Journal of Endocrinology 235, no 3 (décembre 2017) : 251–65. http://dx.doi.org/10.1530/joe-16-0550.
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Aldosterone has been identified as an important factor in obesity-associated hypertension. Here, we investigated whether sphingosine-1-phosphate (S1P), which has previously been linked to obesity, increases aldosterone release. S1P-induced aldosterone release was determined in NCI H295R cells in the presence of S1P receptor (S1PR) antagonists. In vivo release of S1P (100–300 µg/kgbw) was investigated in pithed, lean Sprague Dawley (SD) rats, diet-obese spontaneous hypertensive rats (SHRs), as well as in lean or obese Zucker rats. Aldosterone secretion was increased in NCI H295R cells by S1P, the selective S1PR1 agonist SEW2871 and the selective S1PR2 antagonist JTE013. Treatment with the S1PR1 antagonist W146 or fingolimod and the S1PR1/3 antagonist VPbib2319 decreased baseline and/or S1P-stimulated aldosterone release. Compared to saline-treated SD rats, plasma aldosterone increased by ~50 pg/mL after infusing S1P. Baseline levels of S1P and aldosterone were higher in obese than in lean SHRs. Adrenal S1PR expression did not differ between chow- or CD-fed rats that had the highest S1PR1 and lowest S1PR4 levels. S1P induced a short-lasting increase in plasma aldosterone in obese, but not in lean SHRs. However, 2-ANOVA did not demonstrate any difference between lean and obese rats. S1P-induced aldosterone release was also similar between obese and lean Zucker rats. We conclude that S1P is a local regulator of aldosterone production. S1PR1 agonism induces an increase in aldosterone secretion, while stimulating adrenal S1PR2 receptor suppresses aldosterone production. A significant role of S1P in influencing aldosterone secretion in states of obesity seems unlikely.
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Zhang, Gengqian, Sulei Xu, Yan Qian et Pingnian He. « Sphingosine-1-phosphate prevents permeability increases via activation of endothelial sphingosine-1-phosphate receptor 1 in rat venules ». American Journal of Physiology-Heart and Circulatory Physiology 299, no 5 (novembre 2010) : H1494—H1504. http://dx.doi.org/10.1152/ajpheart.00462.2010.
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Sphingosine-1-phosphate (S1P) has been demonstrated to enhance endothelial barrier function in vivo and in vitro. However, different S1P receptor subtypes have been indicated to play different or even opposing roles in the regulation of vascular barrier function. This study aims to differentiate the roles of endogenous endothelial S1P subtype receptors in the regulation of permeability in intact microvessels using specific receptor agonist and antagonists. Microvessel permeability was measured with hydraulic conductivity ( Lp) in individually perfused rat mesenteric venules. S1P-mediated changes in endothelial intracellular Ca2+ concentration ([Ca2+]i) was measured in fura-2-loaded venules. Confocal images of fluorescent immunostaining illustrated the spatial expressions of three S1P subtype receptors (S1PR1–3) in rat venules. The application of S1P (1 μM) in the presence of S1PR1–3 inhibited platelet-activating factor- or bradykinin-induced permeability increase. This S1P effect was reversed only with a selective S1PR1 antagonist, W-146, and was not affected by S1PR2 or S1PR3 antagonists JTE-013 and CAY-10444, respectively. S1PR1 was also identified as the sole receptor responsible for S1P-mediated increases in endothelial [Ca2+]i. S1PR2 or S1PR3 antagonist alone affected neither basal Lp nor platelet-activating factor-induced permeability increase. The selective S1PR1 agonist, SEW-2871, showed similar [Ca2+]i and permeability effect to that of S1P. These results indicate that, despite the presence of S1PR1–3 in the intact venules, only the activation of endothelial S1PR1 is responsible for the protective action of S1P on microvessel permeability and that endogenous S1PR2 or S1PR3 did not exhibit functional roles in the regulation of permeability under basal or acutely stimulated conditions.
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Corvino, Angela, Ida Cerqua, Alessandra Lo Bianco, Giuseppe Caliendo, Ferdinando Fiorino, Francesco Frecentese, Elisa Magli et al. « Antagonizing S1P3 Receptor with Cell-Penetrating Pepducins in Skeletal Muscle Fibrosis ». International Journal of Molecular Sciences 22, no 16 (17 août 2021) : 8861. http://dx.doi.org/10.3390/ijms22168861.
Texte intégralRésumé :
S1P is the final product of sphingolipid metabolism, which interacts with five widely expressed GPCRs (S1P1-5). Increasing numbers of studies have indicated the importance of S1P3 in various pathophysiological processes. Recently, we have identified a pepducin (compound KRX-725-II) acting as an S1P3 receptor antagonist. Here, aiming to optimize the activity and selectivity profile of the described compound, we have synthesized a series of derivatives in which Tyr, in position 4, has been substituted with several natural aromatic and unnatural aromatic and non-aromatic amino acids. All the compounds were evaluated for their ability to inhibit vascular relaxation induced by KRX-725 (as S1P3 selective pepducin agonist) and KRX-722 (an S1P1-selective pepducin agonist). Those selective towards S1P3 (compounds V and VII) were also evaluated for their ability to inhibit skeletal muscle fibrosis. Finally, molecular dynamics simulations were performed to derive information on the preferred conformations of selective and unselective antagonists.
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Toebbe, JT, et Mary Beth Genter. « An Update on Sphingosine-1-Phosphate and Lysophosphatidic Acid Receptor Transcripts in Rodent Olfactory Mucosa ». International Journal of Molecular Sciences 23, no 8 (14 avril 2022) : 4343. http://dx.doi.org/10.3390/ijms23084343.
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Olfactory neurons connect the external environment and the brain, allowing the translocation of materials from the nasal cavity into the brain. The olfactory system is involved in SARS-CoV-2 infections; early in the pandemic declared in 2020, a loss of the sense of smell was found in many infected patients. Attention has also been focused on the role that the olfactory epithelium appears to play in the entry of the SARS-CoV-2 virus into the brain. Specifically, SARS-CoV-2 enters cells via the angiotensin-converting enzyme 2 protein (ACE2), which is found on supporting cells in the olfactory epithelium. The intranasal administration of sphingosine has been proposed to prevent the binding of SARS-CoV-2 to ACE2. Further, sphingosine-1-phosphate (S1P) receptors appear to facilitate the entry of SARS-CoV-2 into the brain. The goal of these studies was to characterize S1P receptor expression status in rodent olfactory mucosa. The expression of receptors for a related sphingolipid, lysophosphatidic acid (LPA), was also assessed. The results confirm previous reports of S1P1 and S1P3 receptor expression, as well as LPA receptor 1, in mouse olfactory mucosa; moreover, they extend the previous findings to identify additional S1P and LPA receptor transcripts in rat and mouse olfactory mucosa, as well as in cultured olfactory neurons. These findings may enhance the utility of rodent models in identifying agonists and/or antagonists of S1P and LPA receptors that may block the entry of SARS-CoV-2 and other viruses into nasal epithelial cells, and prevent transmission from the nasal cavity into the brain.
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Godessart, Nuria, Sanam Mustafa, Vlad Dolgachev, Mariona Aulí, Núria Aguilar, Judit Cabedo, Marta Calbet et al. « The S1P1 receptor antagonist W146 induces lymphopenia in mice. Demonstration that functional antagonism of S1P1 is the mechanism of lymphopenia evoked by fingolimod-like compounds. (140.15) ». Journal of Immunology 184, no 1_Supplement (1 avril 2010) : 140.15. http://dx.doi.org/10.4049/jimmunol.184.supp.140.15.
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Abstract Agonists of sphingosine 1-phosphate receptor 1 (S1P1) are a novel class of immunosuppressants. S1P is the endogenous agonist of S1P1 and promotes lymphocyte egress from lymph nodes (LN) into blood. However, synthetic agonists like fingolimod prevent the egress, causing systemic lymphopenia. This apparent contradiction is explained by the concept of functional antagonism, according to which synthetic S1P1 agonists induce receptor internalization, making cells unresponsive to the endogenous S1P. If this mechanism is true, S1P1 antagonists should induce lymphopenia. We have fully characterized compound W146, a S1P1 antagonist, by binding and cellular assays. We then administered W146 and several S1P1 agonists to mice and measured blood lymphocytes and plasma levels of compounds in different experimental conditions. All compounds induced lymphopenia in blood and a concomitant increase of CD4+ and CD8+ T cells in LN. These results indicated that lymphopenia evoked by W146 was due to S1P1 blockade and not to another mechanism, like cytotoxicity. By Western blot, FACS and immunocytochemistry we showed that all compounds but W146 induce S1P1 internalization. W146 is able to prevent the internalization induced by an agonist. We report, for the first time, lymphopenia with a S1P1 antagonist. Plasma levels needed to surmount the effects of endogenous S1P are achieved in our experimental conditions. Our studies strongly support the validity of the concept of functional antagonism.
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Juarez, Julius G., Nadia Harun, Marilyn Thien, Robert Welschinger, Rana Baraz, Aileen Dela Pena, Stuart M. Pitson et al. « Sphingosine-1-phosphate facilitates trafficking of hematopoietic stem cells and their mobilization by CXCR4 antagonists in mice ». Blood 119, no 3 (19 janvier 2012) : 707–16. http://dx.doi.org/10.1182/blood-2011-04-348904.
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Abstract CXCL12 and VCAM1 retain hematopoietic stem cells (HSCs) in the BM, but the factors mediating HSC egress from the BM to the blood are not known. The sphingosine-1-phosphate receptor 1 (S1P1) is expressed on HSCs, and S1P facilitates the egress of committed hematopoietic progenitors from the BM into the blood. In the present study, we show that both the S1P gradient between the BM and the blood and the expression of S1P1 are essential for optimal HSC mobilization by CXCR4 antagonists, including AMD3100, and for the trafficking of HSCs during steady-state hematopoiesis. We also demonstrate that the S1P1 agonist SEW2871 increases AMD3100-induced HSC and progenitor cell mobilization. These results suggest that the combination of a CXCR4 antagonist and a S1P1 agonist may prove to be sufficient for mobilizing HSCs in normal donors for transplantation purposes, potentially providing a single mobilization procedure and eliminating the need to expose normal donors to G-CSF with its associated side effects.
Thèses sur le sujet "S1P receptor antagonists"
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Puliti, Elisa. « Role of sphingosine 1-phosphate metabolism and signalling in skeletal muscle atrophy and fibrosis ». Doctoral thesis, Università di Siena, 2022. http://hdl.handle.net/11365/1195603.
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In the last 30 years, multiple roles of S1P have been demonstrated in the regulation of skeletal muscle biology. The presented study is focused on the role of S1P metabolism in myogenic differentiation, where SPL was found playing a crucial role in regulating S1P cellular levels and responsible for onset of myogenic program. The role of S1P axis was also confirmed in skeletal muscle atrophy induced by TNF-alpha. S1P signalling pathwayplays a crucial role in the development and maintenance of the fibrotic process. New S1P3 antagonists were tested to antagonise the receptor involved in fibrosis, and new SK inhibitors have been designed on the base of PF-543, with the aim to develop glycohybrids as potential pharmacological tool in skeletal muscle fibrosis. The metabolism of S1P appears a promising drug targets for pharmacological therapies in skeletal muscle repair.
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Collier, Lauren Michele. « Relationship Between CB1 and S1P Receptors in the Central Nervous System ». VCU Scholars Compass, 2006. http://scholarscompass.vcu.edu/etd/733.
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There is significant sequence homology and anatomical co-distribution between cannabinoid (CB1) and sphingosine-1-phosphate (S1P) receptors in the CNS, but potential functional relationships between these lysolipid receptors have not been examined. Therefore, to investigate possible relationships between these two systems at the level of G-protein activation, agonist-stimulated [35S]GTPγS binding and autoradiography were conducted. Autoradiographic studies were first performed to localize receptor-mediated G-protein activation in mouse brain. Coronal brain slices were processed for stimulation of [35S]GTPγS binding using the synthetic cannabinoid agonist WIN 55,212-2 (WIN) or SIP. High levels of WIN- and S1P-stimulated [35S]GTPγS binding were observed in the caudate putamen, hippocampus, substantia nigra, and cerebellum. To further characterize the relationship between S1P-and CB1-mediated G-protein activation, spinal cords from adult male CB1 receptor knockout mice, CNS-deleted S1Pl receptor knockout mice and wild type C57 mice were collected, and assessed using agonist-stimulated [35S]GTPγS binding. Results from this experiment revealed that the S1Pl receptor is predominant in mouse spinal cord. To further investigate potential CBl and SIP receptor interactions spinal cords were collected from adult male ICR mice. Additivity studies were preformed using agonist-stimulated [35S]GTPγs binding. Results showed significantly less than additive stimulation when spinal cord tissue was treated with both WIN and SIP. These results suggest an interaction between the CB1 and S1P receptors in the mouse spinal cord. The effect of cannabinoid antagonists, SR141716A (CB1) and SR144528 (CB2) on S1P-and WIN-stimulated [35S]GTPγS binding were also examined in mouse spinal cord homogenates. These results showed that there was no significant difference between S1P-stimulated [35S]GTPγS binding in the presence of SR141716A or SR144528 compared to vehicle control. This shows that S1P produced stimulation independent of the CBl or CB2receptor. In addition WIN-stimulated [35S]GTPγS binding was not affected by SR144528, but was inhibited by SR141716A, confirming that this action is due to the CB1 receptor. The combined results of this project demonstrate an interaction between CB1 and S1P receptors in certain CNS regions where they are co-distributed, such as the caudate putamen, hippocampus, substantia nigra, cerebellum and spinal cord. These results may be due to convergence on a common pool of G-proteins via dimerization or co-localization in lipid rafts, or a possible direct ligand-receptor interaction.
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Janse, van Rensburg Hendrika Nicolien. « A longitudinal study of the usage of acid reducing medicine using a medicine claims database / Hendrika Nicolien Janse van Rensburg ». Thesis, North-West University, 2007. http://hdl.handle.net/10394/1903.
Texte intégralRésumé :
Acid-related disorders are common, chronic conditions that have considerable impact on a patient's quality of life. In a study conducted by Majumdar et al. (2003:2411) the prevalence of chronic acid-related disorders was 2.3%. Acid-related disorders represent a major financial consideration with respect to the costs of drug prescribing (Whitaker, 1998:6). Health care cost increases each year. This leads to an increased interest in economic evaluation of health care and medical technologies (Anell & Svarvar, 2000:175). Health care providers no longer make treatment decisions independent of the consideration of the resultant cost. The treatment provided must not only provide value but the value must be documented to justify spending money. Economic evaluation research has emerged to offer guidance to policy makers, practitioners, health plans and institutions facing difficult treatment and coverage decisions (Ellis era/., 2002:271).
The main objectives of this study were to investigate the prescribing patterns and cost of acid reducing medicine with special reference to proton pump inhibitors and histamine-2 receptor antagonists in a section of the private health care sector of South Africa from 2001 to 2006. A longitudinal retrospective drug utilisation study was done on acid reducing medicine items claimed through a national medicine claims database. The five study years were 2001, 2002, 2004, 2005 and 2006. All the study years stretched from 1 January to 31 December.
It was determined that acid reducing medicine items prescribed decreased from 2.74% during 2001 to 2.50% during 2006 of all medicine items claimed. The same decreasing trend was observed regarding the cost of acid reducing medicine items. The cost percentage decreased from 4.89% (2001) to 3.72% (2006). However, the average cost per medicine item for the acid reducers increased by 5.35% from 2001 (R230.04 ± 176.29) to 2002 (R243.72 ± 184.18) and then decreased by 15.23% from 2002 to 2004. It again decreased with 15.05% from 2004
(R206.19 ± 179.42) to 2006 (R175.70 ± 172.55). The changes in the average cost of acid reducers were of no practical significance.
Proton pump inhibitors represented about half of the acid reducing medicine items prescribed and more than 70% of the total cost of acid reducing medicine items during the study years. The average cost of PPIs revealed a practical significant decrease (d > 0.8) from 2002 (R372.42 ± 156.62) to 2006 (R241.56 ± 177.21). H2RAs contributed between 15.00% and 18.26% of all acid reducing medicine items while contributing to between 9.68% and 16.85% of the total cost of all acid reducers.
The active ingredient most often prescribed was lansoprazole during 2001 and 2002, esomeprazole during 2004 and omeprazole during 2005 and 2006. Lanzor® 30mg was the acid reducer with the highest cost from 2001 to 2005, while Pariet® 20mg took the lead in 2006. Zantac® 150mg effervescent tablets were the H2RA, with the highest cost, during the five study years.
The percentage innovator items decreased by 4.50% from 2001 to 2002, increased by 1.01% from 2002 to 2004 and decreased again by 31.06% from 2004 to 2006. The slight increase in the percentage innovator medicine items claimed from 2002 to 2004 may be explained by the introduction of Nexiam® (esomeprazole) into the market in 2002. The total number of generic medicine items claimed contributed between 9.62% (n = R1 788 242.25) in 2001 and 30.75% (n = R3 196 163.34) in 2006 of the total cost of acid reducing medicine items.
The average cost per day of innovator medicine items was higher than the average cost per day of generic medicine items. This might be explained by a lower average cost for generic medicine items.
It was also determined that the prevalence of the two-drug regimens was the highest during the five study years. The Helicobacter pylori (H.pylori) eradication treatments, which included different antibiotics, increased from 2.72% in 2001 to 5.05% in 2006.
The PDD for most of the active ingredients of H2RAs and PPIs remained stable during the study years. However, it appears that the PDDs, of the PPIs, active ingredients were more constant than the PDDs, or the H2RAs, active ingredients. The median of the different PPI active ingredients was reasonably more constant than the median of the different H2RA active ingredients. Thus the changes between the PPIs' and H2RAs' active ingredients might be explained by the variation in the median (the number of days the relevant medicine item was claimed for).
It is then also recommended that the aspects of generic substitution as well as the usage of H2RAs as prescribed vs. self medication should be further investigated to increase possible cost savings.Thesis (M.Pharm. (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2008.
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Zhu, Ran. « Synthesis and biological evaluation of conformationally constrained sphingosine-1-phosphate analogs as subtype selective S1P receptor agonist/antagonist / ». 2008. http://wwwlib.umi.com/dissertations/fullcit/3294775.
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Clemens, Jeremy Justin. « Synthesis of subtype-selective sphingosine-1-phosphate (SIP) receptor agonists and antagonists : elucidation of a structure-activity relationship for SIP and the mechanism of action of FTY720 / ». 2004. http://wwwlib.umi.com/dissertations/fullcit/3144658.
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Van, Rensburg Hendrika Nicolien Janse. « A longitudinal study of the usage of acid reducing medicine using a medicine claims database / H.N. Janse van Rensburg ». Thesis, 2007. http://hdl.handle.net/10394/1903.
Texte intégralLivres sur le sujet "S1P receptor antagonists"
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Alhazzani, Waleed, et Deborah J. Cook. Stress ulcer prophylaxis and treatment drugs in critical illness. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199600830.003.0041.
Texte intégralRésumé :
Many changes have occurred over the last three decades in the field of stress ulcer gastrointestinal bleeding and its prevention. The topic is controversial, fuelled by disparate data, studies at risk of bias, and the impression that the problem is not as serious as it once was. Indeed, compared with over four decades ago when mucosal ulceration of the stomach causing serious bleeding was first described, a relatively small proportion of critically-ill patients now develop clinically important bleeding. Acid suppression is commonly prescribed for stress ulcer prophylaxis (SUP), targeting subgroups of patients at high risk in the intensive care unit (ICU), rather than universal prevention. The randomized clinical trials to date suggest a significant reduction in CIB with use of histamine-2-receptor antagonists (H2RAs) compared with no SUP, with no impact on pneumonia, ICU mortality, or length of stay. However, these trials are of moderate quality. More recent RCTs suggest proton pump inhibitors compared with H2RAs may significantly reduce the risk of CIB without influencing the risk of pneumonia, ICU mortality, or length of stay. These trials are also of moderate quality. Today, the decision whether to use SUP, and which agent to use, is complex. Clinical considerations include local epidemiological data (for centres documenting these outcomes), and patient-specific risks of gastrointestinal bleeding and infection, indexed to case mix.
Chapitres de livres sur le sujet "S1P receptor antagonists"
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Bergeron, R., C. de Montigny et P. Blier. « Potentiation of the Antidepressant Effect of Selected Drugs by the Antagonism of Presynaptic 5-HT1AReceptors ». Dans New Therapeutic Indications of Antidepressants, 12–25. Basel : KARGER, 1997. http://dx.doi.org/10.1159/000061356.
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Shah, Manoj. « Intervention of PAR-2 Mediated CGRP in Animal Model of Visceral Hyperalgesia ». Dans Animal Models and Experimental Research in Medicine [Working Title]. IntechOpen, 2023. http://dx.doi.org/10.5772/intechopen.106859.
Texte intégralRésumé :
Protease-activated receptor-2 (PAR-2) mediates calcitonin gene-related peptide (CGRP) release and collectively plays a crucial role in inflammation-induced visceral hyperalgesia (VH). The present review chapter outlines the substantial advances that elucidated the underlying role of PAR-2 and CGRP in gut inflammation-induced VH and highlights their relevancies in the management of VH. PAR-2 is expressed in a wide range of gastrointestinal cells and its activation on primary afferent nerves by tryptase, trypsin or cathepsin-S is the key mechanism of sensitization during intestinal inflammation. The activated PAR-2 sensitizes transient receptor potential vanilloid subtype-1 receptors and triggers the release of substance-P (SP) and CGRP that are involved both in the transmission and modulation of VH. Approximately, two-thirds of sensory neurons express PAR-2 and 40% of the PAR-2-expressing sensory neurons also express SP and CGRP. Accumulating set of experiments devised that the blockade or antagonism of PAR-2 in inflammatory diseases of the gut depicts double advantages of reducing inflammation and VH. Simultaneously, the uses of CGRP-antagonists inhibit VH and completely suppress PAR-2-agonists-induced intestinal inflammation in animals. However, further study is imperative to improve our understanding of the blockade or antagonism of PAR-2 and CGRP release before its implication as a novel therapeutic for the clinical management of VH in human patients.
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Theard, M. Angele, et Alexandra Bastien. « Intraoperative Hyperkalemia ». Dans Anesthesiology : A Problem-Based Learning Approach, sous la direction de Tracey Straker et Shobana Rajan, 269–74. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780190850692.003.0031.
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Patients with hypertension, diabetes, and heart disease are at risk for chronic kidney disease and therefore require close monitoring of potassium (K+) levels in order to avoid some of the more concerning consequences of hyperkalemia. Medical therapy in these patients, which often includes angiotensin converting enzyme inhibitors, angiotensin receptor blockers, renin inhibitors, and mineralocorticoid receptor antagonists, while helpful in managing some of the aforementioned comorbidities and ameliorating chronic kidney disease in these patients, places them at increased risk for unwanted K+ elevations. Symptoms of hyperkalemia maybe nonspecific (fatigue, weakness, and gastrointestinal upset), requiring attention therefore to preoperative laboratory analysis to avert the potentially lethal intraoperative consequences of hyperkalemia like asystole and ventricular fibrillation. Emergency surgery in these patients after trauma complicated by crush injury is particularly challenging requiring that the anesthesiologist be well-versed in recognizing the signs of and managing intraoperative hyperkalemia.
Actes de conférences sur le sujet "S1P receptor antagonists"
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Vanhoutte, Paul M. « PLATELETS, ENDOTHELIUM AND VASOSPASM ». Dans XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643722.
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The endothelium can secrete both relaxing and contracting substances. One of the most powerful stimuli to the release of the former are thrombin and aggregating platelets. This contributes to the protective role of the endothelium against inappropriate intraluminal platelet aggregation and coagulation in blood vessels with an intact intima. Thrombin-induced, endothelium-dependent relaxations have been obtained in isolated arteries of different species, including humans. Endothelium-dependent relaxations can be evoked by autologous platelets in isolated blood vessels of the dog, pig and rat; they can be obtained in canine coronary arteries with human platelets. The major platelet-products involved in these endothelium-dependent relaxations are 5-hydroxytryptamine (serotonin) and the adenine nucleotides. Although platelet-activating factor (PAF) can evoke endothelium-dependent relaxation it only does so at concentrations much higher than those occurring under physiological conditions; since the relaxations are not prevented by PAF-antagonists, they are non-specific in nature.The receptor mediating the endothelium-dependent relaxations to serotonin released from the aggregating platelets can be subtyped as a S1~(5HT1) serotonergic receptor;those mediating the response to the adenine nucleotides as P2y-purinergic receptors. In the absence of the endothelium aggregating platelets cause contractions of vascular smooth muscle; these are mediated by a mixture of S1-like and S2~serotoner-gic receptors in coronary arteriesof the dog, and by S2-serotonergic receptors in those of the pig. Thus, in the porcine coronary artery, the S2-serotonergic antagonist ketanserin markedly enhances the platelet-induced endothelium-dependent relaxation. After previous (four weeks) injury, the regenerated endothelium of the porcine coronary artery loses the ability to respond to serotonin,and is unable to prevent the constrictionsevoked by aggregating platelets. The endothelium-dependent relaxations of porcine coronary arteries evoked by aggregating platelets are potentiated by chronic treatmentof the donor animals with cod liver oil. These studies emphasize the protective roleof the endothelial cells against the vasoconstriction (vasospasm) induced by aggregating platelets. This role is depressed after previous injury, and can be facilitatedby dietary adj ustments.
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Mansfield, B., P. Huang, R. Bruce, T.-R. Ho, X. Du, Q. Huang, W. Wang et al. « T4 Calcium-sensing receptor antagonists (calcilytics) as a novel therapeutic for alarmin-driven inflammatory lung disease ». Dans British Thoracic Society Winter Meeting 2019, QEII Centre, Broad Sanctuary, Westminster, London SW1P 3EE, 4 to 6 December 2019, Programme and Abstracts. BMJ Publishing Group Ltd and British Thoracic Society, 2019. http://dx.doi.org/10.1136/thorax-2019-btsabstracts2019.4.
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Birring, SS, LP McGarvey, JA Smith, AH Morice, MR Sher, J. Schelfhout, A. Mehta et DR Muccino. « S28 Benefits observed with patient-reported outcomes in a phase 2b clinical trial of gefapixant, a P2X3 receptor antagonist, in chronic cough ». Dans British Thoracic Society Winter Meeting 2019, QEII Centre, Broad Sanctuary, Westminster, London SW1P 3EE, 4 to 6 December 2019, Programme and Abstracts. BMJ Publishing Group Ltd and British Thoracic Society, 2019. http://dx.doi.org/10.1136/thorax-2019-btsabstracts2019.34.
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Bailo, M., L. Dunning, J. Brzeszczynska, K. McIntosh, R. Plevin, SL Martin, GP Sergeant et al. « S100 Reduction of inflammatory cytokine production in chronic obstructive pulmonary disease (COPD) epithelial cells by protease activated receptor 2 (PAR2) antagonism ». Dans British Thoracic Society Winter Meeting 2019, QEII Centre, Broad Sanctuary, Westminster, London SW1P 3EE, 4 to 6 December 2019, Programme and Abstracts. BMJ Publishing Group Ltd and British Thoracic Society, 2019. http://dx.doi.org/10.1136/thorax-2019-btsabstracts2019.106.
Texte intégralRapports d'organisations sur le sujet "S1P receptor antagonists"
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Rafaeli, Ada, Russell Jurenka et Chris Sander. Molecular characterisation of PBAN-receptors : a basis for the development and screening of antagonists against Pheromone biosynthesis in moth pest species. United States Department of Agriculture, janvier 2008. http://dx.doi.org/10.32747/2008.7695862.bard.
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The original objectives of the approved proposal included: (a) The determination of species- and tissue-specificity of the PBAN-R; (b) the elucidation of the role of juvenile hormone in gene regulation of the PBAN-R; (c) the identificationof the ligand binding domains in the PBAN-R and (d) the development of efficient screening assays in order to screen potential antagonists that will block the PBAN-R. Background to the topic: Moths constitute one of the major groups of pest insects in agriculture and their reproductive behavior is dependent on chemical communication. Sex-pheromone blends are utilised by a variety of moth species to attract conspecific mates. In most of the moth species sex-pheromone biosynthesis is under circadian control by the neurohormone, PBAN (pheromone-biosynthesis-activating neuropeptide). In order to devise ideal strategies for mating disruption/prevention, we proposed to study the interactions between PBAN and its membrane-bound receptor in order to devise potential antagonists. Major conclusions: Within the framework of the planned objectives we have confirmed the similarities between the two Helicoverpa species: armigera and zea. Receptor sequences of the two Helicoverpa spp. are 98% identical with most changes taking place in the C-terminal. Our findings indicate that PBAN or PBAN-like receptors are also present in the neural tissues and may represent a neurotransmitter-like function for PBAN-like peptides. Surprisingly the gene encoding the PBAN-receptor was also present in the male homologous tissue, but it is absent at the protein level. The presence of the receptor (at the gene- and protein-levels), and the subsequent pheromonotropic activity are age-dependent and up-regulated by Juvenile Hormone in pharate females but down-regulated by Juvenile Hormone in adult females. Lower levels of pheromonotropic activity were observed when challenged with pyrokinin-like peptides than with HezPBAN as ligand. A model of the 3D structure of the receptor was created using the X-ray structure of rhodopsin as a template after sequence alignment of the HezPBAN-R with several other GPCRs and computer simulated docking with the model predicted putative binding sites. Using in silico mutagenesis the predicted docking model was validated with experimental data obtained from expressed chimera receptors in Sf9 cells created by exchanging between the three extracellular loops of the HezPBAN-R and the Drosophila Pyrokinin-R (CG9918). The chimera receptors also indicated that the 3ʳᵈ extracellular loop is important for recognition of PBAN or Diapause hormone ligands. Implications: The project has successfully completed all the objectives and we are now in a position to be able to design and screen potential antagonists for pheromone production. The successful docking simulation-experiments encourage the use of in silico experiments for initial (high-throughput) screening of potential antagonists. However, the differential responses between the expressed receptor (Sf9 cells) and the endogenous receptor (pheromone glands) emphasize the importance of assaying lead compounds using several alternative bioassays (at the cellular, tissue and organism levels). The surprising discovery of the presence of the gene encoding the PBAN-R in the male homologous tissue, but its absence at the protein level, launches opportunities for studying molecular regulation pathways and the evolution of these GPCRs. Overall this research will advance research towards the goal of finding antagonists for this important class of receptors that might encompass a variety of essential insect functions.