Platelet Activation by Low Density Lipoprotein and High Density LipoproteinKorporaal S.J.A. · Akkerman J.-W.N.
Thrombosis and Haemostasis Laboratory, Department of Haematology, University Medical Center Utrecht and The Institute for Biomembranes, University of Utrecht, Utrecht, The Netherlands
Do you have an account?
- Rent for 48h to view
- Buy Cloud Access for unlimited viewing via different devices
- Synchronizing in the ReadCube Cloud
- Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00
Cardiovascular disease is the main cause of death and disability in the Western society. Lipoproteins are important in the development of cardiovascular disease since they change the properties of different cells involved in atherosclerosis and thrombosis. The interaction of platelets with lipoproteins has been under intense investigation. Particularly the initiation of platelet signaling pathways by low density lipoprotein (LDL) has been studied thoroughly, since platelets of hypercholesterolemic patients, whose plasma contains elevated LDL levels due to absent or defective LDL receptors, show hyperaggregability in vitro and enhanced activity in vivo. These observations suggest that LDL enhances platelet responsiveness. Several signaling pathways induced by LDL have been revealed in vitro, such as signaling via p38 mitogen-activated protein kinase and p125 focal adhesion kinase. High density lipoprotein (HDL) consists of two subtypes, HDL2 and HDL3, which have opposing effects on platelet activation. This review provides a summary of the activation of signaling pathways after platelet-LDL and platelet-HDL interaction, with special emphasis on their role in the development of thrombosis and atherosclerosis.
© 2006 S. Karger AG, Basel
- Ginsberg HN: Lipoprotein physiology. Endocrinol Metab Clin North Am 1998;27:503–519.
- Betteridge DJ, Cooper MB, Saggerson ED, Prichard BN, Tan KC, Ling E, Barbera G, McCarthy S, Smith CC: Platelet function in patients with hypercholesterolaemia. Eur J Clin Invest 1994;24:30–33.
- Surya II, Mommersteeg M, Gorter G, Erkelens DW, Akkerman JWN: Abnormal platelet functions in a patient with abetalipoproteinemia. Thromb Haemost 1991;65:306–311.
Relou IAM, Hackeng CM, Akkerman JWN, Malle E: Low density lipoprotein and its effects on human blood platelets. Cell Mol Life Sci 2003;60:961–971.
- Malle E, Sattler W: Platelets and the lipoproteins: native, modified and platelet modified lipoproteins. Platelets 1994;5:70–83.
- Krauss RM: Atherogenicity of triglyceride-rich lipoproteins. Am J Cardiol 1998;81:13B–17B.
- Garlichs CD, John S, Schmeisser A, Eskafi S, Stumpf C, Karl M, Goppelt-Struebe M, Schmieder R, Daniel WG: Upregulation of CD40 and CD40 ligand (CD154) in patients with moderate hypercholesterolemia. Circulation 2001;104:2395–2400.
- Sanguigni V, Pignatelli P, Caccese D, Pulcinelli FM, Lenti L, Magnaterra R, Martini F, Lauro R, Violi F: Increased superoxide anion production by platelets in hypercholesterolemic patients. Thromb Haemost 2002;87:796–801.
- Pawlowska Z, Swiatkowska M, Krzeslowska J, Pawlicki L, Cierniewski CS: Increased platelet-fibrinogen interaction in patients with hypercholesterolemia and hypertriglyceridemia. Atherosclerosis 1993;103:13–20.
- Cooper MB, Tan KC, Betteridge DJ: Platelet transmembrane signalling responses to collagen in familial hypercholesterolaemia. Eur J Clin Invest 1994;24:737–743.
- Broijersen A, Hamsten A, Eriksson M, Angelin B, Hjemdahl P: Platelet activity in vivo in hyperlipoproteinemia – importance of combined hyperlipidemia. Thromb Haemost 1998;79:268–275.
- Davi G, Gresele P, Violi F, Basili S, Catalano M, Giammarresi C, Volpato R, Nenci GG, Ciabattoni G, Patrono C: Diabetes mellitus, hypercholesterolemia, and hypertension but not vascular disease per se are associated with persistent platelet activation in vivo. Evidence derived from the study of peripheral arterial disease. Circulation 1997;96:69–75.
- Huo Y, Schober A, Forlow SB, Smith DF, Hyman MC, Jung S, Littman DR, Weber C, Ley K: Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med 2003;9:61–67.
- Boren J, Lee I, Zhu W, Arnold K, Taylor S, Innerarity TL: Identification of the low density lipoprotein receptor-binding site in apolipoprotein B100 and the modulation of its binding activity by the carboxyl terminus in familial defective apo-B100. J Clin Invest 1998;101:1084–1093.
- Aviram M, Brook JG, Lees AM, Lees RS: Low density lipoprotein binding to human platelets: role of charge and of specific amino acids. Biochem Biophys Res Commun 1981;99:308–318.
- Weisgraber KH, Innerarity TL, Mahley RW: Role of lysine residues of plasma lipoproteins in high affinity binding to cell surface receptors on human fibroblasts. J Biol Chem 1978;253:9053–9062.
- Relou IAM, Gorter G, van Rijn HJM, Akkerman JWN: Platelet activation by the apoB/E receptor-binding domain of LDL. Thromb Haemost 2002;87:880–887.
- Hackeng CM, Relou IAM, Pladet MW, Gorter G, van Rijn HJM, Akkerman JWN: Early platelet activation by low density lipoprotein via p38MAP kinase. Thromb Haemost 1999;82:1749–1756.
- Pedreño J, de Castellarnau C, Cullaré C, Sánchez JL, Gómez-Gerique J, Ordóñez-Llanos J, González-Sastre F: LDL binding sites on platelets differ from the ‘classical’ receptor of nucleated cells. Arterioscler Thromb 1992;12:1353–1362.
- Korporaal SJA, Relou IAM, van Eck M, Strasser V, Bezemer M, Gorter G, van Berkel ThJC, Nimpf J, Akkerman JWN, Lenting PJ: Binding of low-density lipoprotein to platelet apolipoprotein E receptor 2’ results in phosphorylation of p38MAPK. J Biol Chem 2004;279:52526–52534.
- Bu G: Receptor-associated protein: a specialized chaperone and antagonist for members of the LDL receptor gene family. Curr Opin Lipidol 1998;9:149–155.
- Riddell DR, Vinogradov DV, Stannard AK, Chadwick N, Owen JS: Identification and characterization of LRP8 (apoER2) in human blood platelets. J Lipid Res 1999;40:1925–1930.
- Hussain MM: Structural, biochemical and signaling properties of the low-density lipoprotein receptor gene family. Front Biosci 2001;6:D417–D428.
- Koller E, Koller F, Binder BR: Purification and identification of the lipoprotein-binding proteins from human blood platelet membrane. J Biol Chem 1989;264:12412–12418.
- Pedreño J, Fernandez R, Cullare C, Barcelo A, Elorza MA, de Castellarnau C: Platelet integrin alpha IIb beta 3 (GPIIb-IIIa) is not implicated in the binding of LDL to intact resting platelets. Arterioscler Thromb Vasc Biol 1997;17:156–163.
- Hackeng CM, Huigsloot M, Pladet MW, Nieuwenhuis HK, van Rijn HJM, Akkerman JWN: Low-density lipoprotein enhances platelet secretion via integrin-αIIbβ3-mediated signaling. Arterioscler Thromb Vasc Biol 1999;19:239–247.
- Pedreño J, Fernandez R: Proteolytic susceptibility of platelet low density lipoprotein receptor. Lipids 1995;30:927–933.
- Korporaal SJA, Gorter G, van Rijn HJM, Akkerman JWN: The effect of oxidation on the platelet-activating properties of low density lipoprotein. Arterioscler Thromb Vasc Biol 2005;25:867–872.
- Pedreño J, Hurt-Camejo E, Wiklund O, Badimon L, Masana L: Low-density lipoprotein (LDL) binds to a G-protein coupled receptor in human platelets. Evidence that the proaggregatory effect induced by LDL is modulated by down-regulation of binding sites and desensitization of its mediated signaling. Atherosclerosis 2001;155:99–112.
van Willigen G, Gorter G, Akkerman JWN: LDLs increase the exposure of fibrinogen binding sites on platelets and secretion of dense granula. Arterioscler Thromb Vasc Biol 1994;14:41–46.
- Ardlie NG, Selley ML, Simons LA: Platelet activation by oxidatively modified low density lipoproteins. Atherosclerosis 1989;76:117–124.
- Nofer J, Tepel M, Kehrel B, Wierwille S, Walter M, Seedorf U, Zidek W, Assmann G: Low-density lipoproteins inhibit the Na+/H+ antiport in human platelets. A novel mechanism enhancing platelet activity in hypercholesterolemia. Circulation 1997;95:1370–1377.
- Surya II, Gorter G, Mommersteeg M, Akkerman JWN: Enhancement of platelet functions by low density lipoproteins. Biochim Biophys Acta 1992;1165:19–26.
- Block LH, Knorr M, Vogt E, Locher R, Vetter W, Groscurth P, Qiao BY, Pometta D, James R, Regenass M: Low density lipoprotein causes general cellular activation with increased phosphatidylinositol turnover and lipoprotein catabolism. Proc Natl Acad Sci USA 1988;85:885–889.
- Dunn RC, Schachter M, Miles CM, Feher MD, Tranter PR, Bruckdorfer KR, Sever PS: Low-density lipoproteins increase intracellular calcium in aequorin-loaded platelets. FEBS Lett 1988;238:357–360.
- Hackeng CM, Pladet MW, Akkerman JWN, van Rijn HJM: Low density lipoprotein phosphorylates the focal adhesion-associated kinase p125FAK in human platelets independent of integrin alphaIIb beta3. J Biol Chem 1999;274:384–388.
- Relou IAM, Bax LA, van Rijn HJM, Akkerman JWN: Site-specific phosphorylation of platelet focal adhesion kinase by low-density lipoprotein. Biochem J 2003;369:407–416.
- Raingeaud J, Gupta S, Rogers JS, Dickens M, Han J, Ulevitch RJ, Davis RJ: Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem 1995;270:7420–7426.
- Kramer RM, Roberts EF, Strifler BA, Johnstone EM: Thrombin induces activation of p38 MAP kinase in human platelets. J Biol Chem 1995;270:27395–27398.
- Saklatvala J, Rawlinson L, Waller RJ, Sarsfield S, Lee JC, Morton LF, Barnes MJ, Farndale RW: Role for p38 mitogen-activated protein kinase in platelet aggregation caused by collagen or a thromboxane analogue. J Biol Chem 1996;271:6586–6589.
- Borsch-Haubold AG, Kramer RM, Watson SP: Cytosolic phospholipase A2 is phosphorylated in collagen- and thrombin-stimulated human platelets independent of protein kinase C and mitogen-activated protein kinase. J Biol Chem 1995;270:25885–25892.
- Relou IAM, Gorter G, Ferreira IA, van Rijn HJM, Akkerman JWN: Platelet endothelial cell adhesion molecule-1 (PECAM-1) inhibits low density lipoprotein-induced signaling in platelets. J Biol Chem 2003;278:32638–32644.
- Newman PJ, Berndt MC, Gorski J, White GC, Lyman S, Paddock C, Muller WA: PECAM-1 (CD31) cloning and relation to adhesion molecules of the immunoglobulin gene superfamily. Science 1990;247:1219–1222.
- Henshall TL, Jones KL, Wilkinson R, Jackson DE: Src homology 2 domain-containing protein-tyrosine phosphatases, SHP-1 and SHP-2, are required for platelet endothelial cell adhesion molecule-1/CD31-mediated inhibitory signaling. J Immunol 2001;166:3098–3106.
- Hua CT, Gamble JR, Vadas MA, Jackson DE: Recruitment and activation of SHP-1 protein-tyrosine phosphatase by human platelet endothelial cell adhesion molecule-1 (PECAM-1). Identification of immunoreceptor tyrosine-based inhibitory motif-like binding motifs and substrates. J Biol Chem 1998;273:28332–28340.
- Edmead CE, Crosby DA, Southcott M, Poole AW: Thrombin-induced association of SHP-2 with multiple tyrosine-phosphorylated proteins in human platelets. FEBS Lett 1999;459:27–32.
- Jackson DE, Kupcho KR, Newman PJ: Characterization of phosphotyrosine binding motifs in the cytoplasmic domain of platelet/endothelial cell adhesion molecule-1 (PECAM-1) that are required for the cellular association and activation of the protein-tyrosine phosphatase, SHP-2. J Biol Chem 1997;272:24868–24875.
- Masuda M, Osawa M, Shigematsu H, Harada N, Fujiwara K: Platelet endothelial cell adhesion molecule-1 is a major SH-PTP2 binding protein in vascular endothelial cells. FEBS Lett 1997;408:331–336.
- Sagawa K, Kimura T, Swieter M, Siraganian RP: The protein-tyrosine phosphatase SHP-2 associates with tyrosine-phosphorylated adhesion molecule PECAM-1 (CD31). J Biol Chem 1997;272:31086–31091.
- Sundaresan P, Farndale RW: P38 mitogen-activated protein kinase dephosphorylation is regulated by protein phosphatase 2A in human platelets activated by collagen. FEBS Lett 2002;528:139–144.
- Hildebrand JD, Schaller MD, Parsons JT: Identification of sequences required for the efficient localization of the focal adhesion kinase, pp125FAK, to cellular focal adhesions. J Cell Biol 1993;123:993–1005.
- Zhang X, Chattopadhyay A, Ji QS, Owen JD, Ruest PJ, Carpenter G, Hanks SK: Focal adhesion kinase promotes phospholipase C-gamma1 activity. Proc Natl Acad Sci USA 1999;96:9021–9026.
- Chen HC, Appeddu PA, Isoda H, Guan JL: Phosphorylation of tyrosine 397 in focal adhesion kinase is required for binding phosphatidylinositol 3-kinase. J Biol Chem 1996;271:26329–26334.
- Calalb MB, Polte TR, Hanks SK: Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: a role for Src family kinases. Mol Cell Biol 1995;15:954–963.
- Schlaepfer DD,Hunter T: Evidence for in vivo phosphorylation of the Grb2 SH2-domain binding site on focal adhesion kinase by Src-family protein-tyrosine kinases. Mol Cell Biol 1996;16:5623–5633.
- Schlaepfer DD, Jones KC, Hunter T: Multiple Grb2-mediated integrin-stimulated signaling pathways to ERK2/mitogen-activated protein kinase: summation of both c-Src- and focal adhesion kinase-initiated tyrosine phosphorylation events. Mol Cell Biol 1998;18:2571–2585.
- Schlaepfer DD, Hunter T: Focal adhesion kinase overexpression enhances ras-dependent integrin signaling to ERK2/mitogen-activated protein kinase through interactions with and activation of c-Src. J Biol Chem 1997;272:13189–13195.
- Haimovich B, Lipfert L, Brugge JS, Shattil SJ: Tyrosine phosphorylation and cytoskeletal reorganization in platelets are triggered by interaction of integrin receptors with their immobilized ligands. J Biol Chem 1993;268:15868–15877.
- Salazar EP, Rozengurt E: Bombesin and platelet-derived growth factor induce association of endogenous focal adhesion kinase with Src in intact Swiss 3T3 cells. J Biol Chem 1999;274:28371–28378.
- Lipfert L, Haimovich B, Schaller MD, Cobb BS, Parsons JT, Brugge JS: Integrin-dependent phosphorylation and activation of the protein tyrosine kinase pp125FAK in platelets. J Cell Biol 1992;119:905–912.
- Schaller MD, Hildebrand JD, Shannon JD, Fox JW, Vines RR, Parsons JT: Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src. Mol Cell Biol 1994;14:1680–1688.
- Schaller MD, Hildebrand JD, Parsons JT: Complex formation with focal adhesion kinase: a mechanism to regulate activity and subcellular localization of Src kinases. Mol Biol Cell 1999;10:3489–3505.
- Salazar EP, Rozengurt E: Src family kinases are required for integrin-mediated but not for G protein-coupled receptor stimulation of focal adhesion kinase autophosphorylation at Tyr-397. J Biol Chem 2001;276:17788–17795.
- Eisenberg S: High density lipoprotein metabolism. J Lipid Res 1984;25:1017–1058.
- Patsch JR, Prasad S, Gotto AM Jr, Patsch W: High density lipoprotein2. Relationship of the plasma levels of this lipoprotein species to its composition, to the magnitude of postprandial lipemia, and to the activities of lipoprotein lipase and hepatic lipase. J Clin Invest 1987;80:341–347.
- Chung BH, Segrest JP, Smith K, Griffin FM, Brouillette CG: Lipolytic surface remnants of triglyceride-rich lipoproteins are cytotoxic to macrophages but not in the presence of high density lipoprotein. A possible mechanism of atherogenesis? J Clin Invest 1989;83:1363–1374.
- Saxena U, Ferguson E, Bisgaier CL: Apolipoprotein E modulates low density lipoprotein retention by lipoprotein lipase anchored to the subendothelial matrix. J Biol Chem 1993;268:14812–14819.
- Parthasarathy S, Barnett J, Fong LG: High-density lipoprotein inhibits the oxidative modification of low-density lipoprotein. Biochim Biophys Acta 1990;1044:275–283.
- Ohta T, Takata K, Horiuchi S, Morino Y, Matsuda I: Protective effect of lipoproteins containing apoprotein A-I on Cu2+-catalyzed oxidation of human low density lipoprotein. FEBS Lett 1989;257:435–438.
- Navab M, Hama SY, Anantharamaiah GM, Hassan K, Hough GP, Watson AD, Reddy ST, Sevanian A, Fonarow GC, Fogelman AM: Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: steps 2 and 3. J Lipid Res 2000;41:1495–1508.
- Navab M, Imes SS, Hama SY, Hough GP, Ross LA, Bork RW, Valente AJ, Berliner JA, Drinkwater DC, Laks H: Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein 1 synthesis and is abolished by high density lipoprotein. J Clin Invest 1991;88:2039–2046.
- Norata GD, Callegari E, Inoue H, Catapano AL: HDL3 induces cyclooxygenase-2 expression and prostacyclin release in human endothelial cells via a p38 MAPK/CRE-dependent pathway: effects on COX-2/PGI-synthase coupling. Arterioscler Thromb Vasc Biol 2004;24:871–877.
- Vinals M, Martinez-Gonzalez J, Badimon L: Regulatory effects of HDL on smooth muscle cell prostacyclin release. Arterioscler Thromb Vasc Biol 1999;19:2405–2411.
- Sugano M, Tsuchida K, Makino N: High-density lipoproteins protect endothelial cells from tumor necrosis factor-alpha-induced apoptosis. Biochem Biophys Res Commun 2000;272:872–876.
- Nofer JR, Levkau B, Wolinska I, Junker R, Fobker M, von Eckardstein A, Seedorf U, Assmann G: Suppression of endothelial cell apoptosis by high density lipoproteins (HDL) and HDL-associated lysosphingolipids. J Biol Chem 2001;276:34480–34485.
- Griffin JH, Fernandez JA, Deguchi H: Plasma lipoproteins, hemostasis and thrombosis. Thromb Haemost 2001;86:386–394.
- Koller E: Lipoprotein-binding proteins in the human platelet plasma membrane. FEBS Lett 1986;200:97–102.
- Nofer JR, Walter M, Kehrel B, Seedorf U, Assmann G: HDL3 activates phospholipase D in normal but not in glycoprotein IIb/IIIa-deficient platelets. Biochem Biophys Res Commun 1995;207:148–154.
- Curtiss LK, Plow EF: Interaction of plasma lipoproteins with human platelets. Blood 1984;64:365–374.
- Surya II, Akkerman JWN: The influence of lipoproteins on blood platelets. Am Heart J 1993;125:272–275.
- Pedreño J, de Castellarnau C, Masana L: Platelet HDL(3) binding sites are not related to integrin alpha(IIb)beta(3) (GPIIb-IIIa). Atherosclerosis 2001;154:23–29.
- Shattil SJ: Function and regulation of the beta 3 integrins in hemostasis and vascular biology. Thromb Haemost 1995;74:149–155.
- Pedreño J, Vila M, Masana L: Mechanisms for regulating platelet high density lipoprotein type3 binding sites: evidence that binding sites are downregulated by a protein kinase C-dependent mechanism. Thromb Res 1999;94:33–44.
- Weisgraber KH, Mahley RW: Subfractionation of human high density lipoproteins by heparin-Sepharose affinity chromatography. J Lipid Res 1980;21:316–325.
- Imachi H, Murao K, Cao W, Tada S, Taminato T, Wong NC, Takahara J, Ishida T: Expression of human scavenger receptor b1 on and in human platelets. Arterioscler Thromb Vasc Biol 2003;23:898–904.
- Liadaki KN, Liu T, Xu S, Ishida BY, Duchateaux PN, Krieger JP, Kane J, Krieger M, Zannis VI: Binding of high density lipoprotein (HDL) and discoidal reconstituted HDL to the HDL receptor scavenger receptor class B type I. Effect of lipid association and APOA-I mutations on receptor binding. J Biol Chem 2000;275:21262–21271.
- Pitas RE, Innerarity TL, Arnold KS, Mahley RW: Rate and equilibrium constants for binding of apo-E HDLc (a cholesterol-induced lipoprotein) and low density lipoproteins to human fibroblasts: Evidence for multiple receptor binding of apo-E HDLc. Proc Natl Acad Sci USA 1979;76:2311–2315.
- Desai K, Bruckdorfer KR, Hutton RA, Owen JS: Binding of apoE-rich high density lipoprotein particles by saturable sites on human blood platelets inhibits agonist-induced platelet aggregation. J Lipid Res 1989;30:831–840.
- Hassall DG, Owen JS, Bruckdorfer KR: The aggregation of isolated human platelets in the presence of lipoproteins and prostacyclin. Biochem J 1983;216:43–49.
- Nofer J, Tepel M, Kehrel B, Walter M, Seedorf U, Assmann G, Zidek W: High density lipoproteins enhance the Na+/H+ antiport in human platelets. Thromb Haemost 1996;75:635–641.
- Aviram M, Brook JG: The effect of blood constituents on platelet function: role of blood cells and plasma lipoproteins. Artery 1983;11:297–305.
- Aviram M, Brook JG: Platelet interaction with high and low density lipoproteins. Atherosclerosis 1983;46:259–268.
- Aviram M, Sirtori CR, Colli S, Maderna P, Morazzoni G, Tremoli E: Plasma lipoproteins affect platelet malondialdehyde and thromboxane B2 production. Biochem Med 1985;34:29–36.
- Knorr M, Locher R, Vogt E, Vetter W, Block LH, Ferracin F, Lefkovits H, Pletscher A: Rapid activation of human platelets by low concentrations of low-density lipoprotein via phosphatidylinositol cycle. Eur J Biochem 1988;172:753–759.
- Mehta JL, Chen LY: Reversal by high-density lipoprotein of the effect of oxidized low-density lipoprotein on nitric oxide synthase protein expression in human platelets. J Lab Clin Med 1996;127:287–295.
- Shattil SJ, Anaya-Galindo R, Bennett J, Colman RW, Cooper RA: Platelet hypersensitivity induced by cholesterol incorporation. J Clin Invest 1975;55:636–643.
- Riddell DR, Owen JS: Inhibition of ADP-induced platelet aggregation by apoE is not mediated by membrane cholesterol depletion. Thromb Res 1996;81:597–606.
- Riddell DR, Graham A, Owen JS: Apolipoprotein E inhibits platelet aggregation through the L-arginine:nitric oxide pathway. Implications for vascular disease. J Biol Chem 1997;272:89–95.
- Higashihara M, Kinoshita M, Teramoto T, Kume S, Kurokawa K: The role of apoE in inhibitory effects of apoE-rich HDL on platelet function. FEBS Lett 1991;282:82–86.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.