Free Access
Pharmacology 2010;85:1–17
(DOI:10.1159/000259044)

Amyloidosis and Neurodegenerative Diseases: Current Treatments and New Pharmacological Options

Tillement J.-P.a · Lecanu L.b, c · Papadopoulos V.a–e
aAcadémie Nationale de Médecine Paris, Paris, France; bResearch Institute, McGill University Health Centre, and Departments of cMedicine, dPharmacology and Therapeutics and eBiochemistry, McGill University, Montreal, Que., Canada
email Corresponding Author


 goto top of outline Key Words

  • Alzheimer’s disease
  • Parkinson’s disease
  • Huntington’s disease
  • Spinocerebellar ataxia
  • Multiple systemic atrophy
  • Niemann-Pick disease
  • Progressive supranuclear palsy
  • Amyotrophic lateral sclerosis
  • Prions
  • Amyloid proteins
  • Cholesterol
  • Mitochondria

 goto top of outline Abstract

Most neurodegenerative diseases share several clinical, genetic and pathophysiological features, and an irreversible evolution as well. They are characterized by an endogenous production of abnormal proteins called amyloid proteins (AP), which are not hydrosoluble, form depots, and are only partly cleared by autophagy and the ubiquitin-protease system. Despite their different structures, they are probably generated by a common pathological pathway, a misfolding process. This hypothesis suggests a common pharmacological approach, which can consist of either the blockade of the misfolding process, the elimination of AP or both. The currently validated treatments are mostly palliative ones, trying to supplant the function of destroyed neurons. New trends involve the regulation of the cerebral cholesterol metabolism and the preservation of neuron mitochondrial functions. Special attention is given to already marketed drugs used for other indications, which are also able to act on neurodegeneration.

Copyright © 2009 S. Karger AG, Basel


 goto top of outline References
  1. Rosenberg RD: The molecular and genetic basis of AD: the end of the beginning. The 2000 Wartenberg lecture. Neurology 2000;54:2045–2054.
  2. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F, Guido T, Hagopian S, Johnson-Wood K, Khan K, Lee M, Leibowitz P, Lieberburg I, Little S, Masliah E, McConlogue L, Montoya-Zavala M, Mucke L, Paganini L, Penniman E, Power M, Schenk D, Seubert P, Snyder B, Soriano F, Tan H, Vitale J, Wadsworth S, Wolozin B, Zhao J: Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 1995;373:523–527.
  3. Price DL, Tanzi RE, Porchelt DR, Sisodia SS: Alzheimer disease: genetic studies and transgenic models. Annu Rev Genet 1998;32:461–493.
  4. Lecanu L, Greeson J, Papadopoulos V: Beta-amyloid and oxidative stress jointly induce neuronal death, amyloid deposits, gliosis, and memory impairment in the rat brain. Pharmacology 2006;76:19–33.
  5. Prusiner SB: Novel proteinaceous infectious particles cause scrapie. Science 1982;216:136–144.
  6. Forman MS, Trojanowski JQ, Lee VM-Y: Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs. Nat Med 2004;10:1055–1063.
  7. Skovronsky DM, Lee VM-Y, Trojanowski JQ: Neurodegenerative diseases: new concepts of pathogenesis and their therapeutic implications. Annu Rev Pathol 2006;1:151–170.
  8. Dobson CM: Protein folding and misfolding. Nature 2003;406:884–890.

    External Resources

  9. Bukau B, Horwich AL: The Hsp70 and Hsp60 chaperone machines. Cell 1998;92:351–366.
  10. Hartl FU, Hayer-Hartl M: Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 2002;295:1852–1858.
  11. Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotma CW, Glabe CG: Common structure of soluble amyloid oligomers implies common mechanisms of pathogenesis. Science 2003;300:486–489.
  12. Giasson BI, Forman MS, Higuchi M, Golbe LL, Graves CL, Kotzbauer PT, Trojanowski JQ: Initiation and synergic fibrillization of tau and alpha-synuclein. Science 2003;300:636–640.
  13. Burn DJ: Parkinson’s disease dementia: what’s in a Lewy body? J Neural Transm Suppl 2006;70:361–365.
  14. Takashima A: Preselenin 1 associates with glycogen synthetase kinase-3 and its substrate tau. Proc Natl Acad Sci USA 1998;95:9637–9641.
  15. Leverenz JB, Umar I, Wang Q, Montine TJ, McMillan PJ, Tsuang DW, Jin J, Pan C, Shin J, Zhu D, Zhang J: Proteomic identification of novel proteins in cortical Lewy bodies. Brain Pathol 2007;17:139–145.
  16. Ghribi O, Golovko MY, Larsen B, Schrag M, Murphy EJ: Deposition of iron and beta-amyloid plaques is associated with cortical cellular damage in rabbit fed with long-term cholesterol-enriched diet. J Neurochem 2006;99:438–449.
  17. Golbe LI: The genetics of Parkinson’s disease: a reconsideration. Neurology 1990;40(suppl 3):7–14.
  18. Zeviani M, Spinazzola A, Carelli V: Nuclear genes in mitochondrial disorders. Curr Opin Genet Dev 2003;13:262–270.
  19. Young-Pearse TL, Bai J, Chan R, Zheng JB, LoTurco JL, Selkoe DJ: A critical function for β-amyloid precursor protein in neuronal migration revealed by in utero RNA interference. J Neurosci 2007;27:14459–14469.
  20. Young-Pearse TL, Chen AC, Chang R, Zheng JB, Marquez C, Selkoe DJ: Secreted APP regulates the function of full-length APP in neurite outgrowth through interaction with integrin beta I. Neural Dev 2008;3:15.

    External Resources

  21. Schrenk-Siemens K, Perez-Alcala S, Richter J, Lacroix E, Rahuel J, Korte M, Müller U, Barde Y, Bibel M: Embryonic stem cell-derived neurons as a cellular system to study gene function: lack of amyloid precursor proteins APP and APLP2 leads to defective synaptic transmission. Stem Cells 2008;26:2153–2163.
  22. Bai Y, Markham K, Chen F, Weerasekera R, Watts J, Home P, Wakutani Y, Bagshaw R, Mathews PM, Fraser PE, Westaway D, St George-Hyslop P, Schmitt-Ulms G: The in vivo brain interactome of the amyloid precursor protein. Mol Cell Proteomics 2008;7:15–34.
  23. Simons M, Keller P, de Strooper B, Beyreuther K, Dotti CG, Simons K: Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons. Proc Natl Acad Sci USA 1998;95:6460–6464.
  24. Bergmann C, Simons M, Jäkäiä P: Cholesterol depletion inhibits intracellular production of Aβ40 and Aβ42 Alzheimer’s disease amyloid peptides (abstract 319). Soc Neurosci Abstracts 1999;25.
  25. Yao ZX, Papadopoulos V: Function of β-amyloid in cholesterol transport: a lead to neurotoxicity. FASEB J 2002;16:1677–1679.
  26. Yang LB, Lindholm K, Yan R, Citron M, Xia W, Yang XL, Beach T, Sue L, Wong P, Price D, Li R, Shen Y: Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med 2003;9:3–4.
  27. Li R, Lindholm K, Yang LB, Yue X, Citron M, Yan R, Beach T, Sue L, Sabbagh M, Cai H, Wong P, Price D, Shen Y: Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer’s disease patients. Proc Natl Acad Sci USA 2004;101:3632–3637.
  28. Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C: Reconstitution of gamma-secretase activity. Nat Cell Biol 2003;5:486–488.
  29. Sato C, Morohashi Y, Tomita T, Iwatsubo T: Structure of the catalytic pore of gamma-secretase probed by the accessibility of substituted cysteines. J Neurosci 2006;26:12081–12088.
  30. Yamasaki A, Eimer S, Okochi M, Smialowska A, Kaether C, Baumeister R, Haass R, Steiner H: The GxGD motif of presenilin contributes to catalytic function and substrate identification of gamma-secretase. J Neurosci 2006;26:3821–3828.
  31. Drechsel DN, Hyman AA, Cobb MH, Kirschner MW: Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau. Mol Biol Cell 1992;3:1141–1154.
  32. Mazanetz MP, Fisher PM: Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases. Nat Rev Drug Discov 2007;6:464–479.
  33. Nordlund A, Leinartaite L, Saraboji K, Aisenbrey C, Grobner G, Zetterstrom P, Danielsson J, Logan DT, Oliveberg M: Functional features cause misfolding of the ALS-provoking enzyme SOD1. Proc Natl Acad Sci USA 2009;106:9667–9672.
  34. Neumann M: Molecular neuropathology of TDP-43 proteinopathies. Int J Mol Sci 2009;10:232–246.
  35. Peña F, Gutiérrez-Lerma A, Quiroz-Baez R, Arias C: The role of beta-amyloid protein in synaptic function: implications for Alzheimer’s disease therapy. Curr Neuropharmacol 2006;4:149–163.
  36. Zhu X, Lee HG, Perry G, Smith MA: Alzheimer disease, the two-hit hypothesis: an update. Biochim Biophys Acta 2007;1772:494–502.
  37. Olney JW, Ho OL: Brain damage in infant mice following oral intake of glutamate, aspartate or cystein. Nature 1970;227:609–611.
  38. Parihar MS, Brewer GJ: Mitoenergetic failure in Alzheimer disease. Am J Physiol Cell Physiol 2007;292:C8–C23.
  39. Farlow MR: NMDA receptor antagonists: a new therapeutic approach for Alzheimer’s disease. Geriatrics 2004;59:22–27.
  40. Coskun PE, Beal MF, Wallace DC: Alzheimer’s brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci USA 2004;101:10726–10731.
  41. Onyango IG, Khan SM: Oxidative stress, mitochondrial dysfunction, and stress signaling in Alzheimer disease. Curr Alzheimer Res 2006;3:339–349.
  42. Zeviani M, Spinazzola A, Carelli V: Nuclear genes in mitochondrial disorders. Curr Opin Genet Dev 2003;13:262–270.
  43. Augy T, Bonin-Guillaume S, Blin O: New therapeutic approaches in Alzheimer disease. Encephale 2006;32:641–649.
  44. Pogacić V, Herrling P: List of drugs in development for neurodegenerative diseases: update June 2007. Neurodegener Dis 2007;4:443–486.
  45. Talley TT, Harel M, Hibbs RE, Radic Z, Tomizawa M, Casida JE, Taylor P: Atomic interactions of neonicotinoid agonists with AChBP: molecular recognition of the distinctive electronegative pharmacophore. Proc Natl Acad Sci USA 2008;105:7606–7611.
  46. Lecanu L, Papadopoulos V: Cutting-edge patents in Alzheimer’s disease drug discovery: anticipation of potential future treatments. Recent Pat CNS Drug Discov 2007;2:113–123.
  47. Lecanu L, Tillement L, Rammouz G, Tillement JP, Greeson J, Papadopoulos V: Caprospinol: moving from a neuroactive steroid to a neurotropic drug. Expert Opin Investig Drugs 2009;18:265–276.
  48. Creeley CE, Wozniak DF, Nardi A, Farber NB, Olney JW: Donepezil markedly potentiates memantine neurotoxicity in the adult rat brain. Neurobiol Aging 2008;29:153–167.
  49. Frémont L: Biological effects of resveratrol. Life Sci 2000;66:663–673.
  50. Orgogozo JM, Dartigues JF, Lafont S, Letenneur L, Commenges D, Salamon R, Renaud S, Breteler MB: Wine consumption and dementia in the elderly: a community prospective study in the Bordeaux area. Rev Neurol (Paris) 1997;153:185–192.
  51. Tillement J-P: In vitro protection of cerebral mitochondria function by E-resveratrol in anoxia followed by re-oxygenation. Bull Acad Natl Med 2001;185:1429–1445.
  52. Mazza M, Capuano A, Bria P, Mazza S: Ginkgo biloba and donepezil: a comparison in the treatment of Alzheimer’s dementia in a randomized placebo-controlled double-blind study. Eur J Neurol 2006;13:981–985.
  53. Vellass B, Andrieu S, Ousset PJ, Ouzid M, Mathiex-Fortunet H, GuidAge Study Group: The GuidAge Study – methodological issues: a 5-year double-blind randomized trial of the efficacy of EGb761 for prevention of Alzheimer disease in patients over 70 with a memory complaint. Neurology 2006;67:S6–S11.

    External Resources

  54. Schapira AH, Bezard E, Brotchie J, Calon F, Collingridge GL, Ferger B, Hengerer B, Hirsch E, Jenner P, Le Novère N, Obeso JA, Schwarzschild MA, Spampinato U, Davidai G: Novel pharmacological targets for the treatment of Parkinson’s disease. Nat Rev Drug Discov 2006;5:845–854.
  55. Fornai F, Longone P, Cafaro L, Kastsiuchenka O, Ferruci M, Manca ML, Lazzeri G, Spalloni A, Bellio N, Lenzi P, Modugno N, Siciliano G, Isidoro C, Murri L, Ruggieri S, Paparelli A: Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 2008;105:2052–2057.
  56. Carter CJ: Convergence of genes implicated in Alzheimer’s disease on the cerebral cholesterol shuttle: APP, cholesterol, lipoproteins and atherosclerosis. Neurochem Int 2007;50:12–38.
  57. Wolozin B, Kellman W, Rousseau P, Celesia GG, Siegel G: Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. Arch Neurol 2000;57:1439–1443.
  58. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I, Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twome C, Westendorp RG, PROPER study group: Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. PROspective Study of Pravastatin in the Elderly at Risk. Lancet 2002;360:1623–1630.
  59. Simons M, Keller P, de Strooper B, Beyreuther K, Dotti CG, Simons K: Cholesterol depletion inhibits the generation of [beta]-amyloid in hippocampal neurons. Proc Natl Acad Sci USA 1998;95:6460–6464.
  60. Papadopoulos V, Lecanu L, Brown RC, Han Z, Yao ZK: Peripheral-type benzodiazepine receptor in neurosteroid biosynthesis, neuropathology and neurological disorders. Neuroscience 2006;138:749–756.
  61. Lacor P, Gandolfo P, Tonon MC, Brault E, Dalibert I, Schumacher M, Benavides J, Ferzaz B: Regulation of the expression of peripheral benzodiazepine receptors and their endogenous ligands during rat sciatic nerve degeneration and regeneration: a role for PBR in neurosteroidogenesis. Brain Res 1999;815:70–80.
  62. Lacapère JJ, Papadopoulos V: Peripheral-type benzodiazepine receptor: structure and function of a cholesterol-binding protein in steroid and bile acid biosynthesis. Steroids 2003;68:569–585.
  63. Wright G, Reichenberger V: The effects of superoxide and the peripheral benzodiazepine receptor ligands on the mitochondrial processing of manganese-dependent superoxide dismutase. Exp Cell Res 1999;246:443–450.
  64. Hauet T, Yao ZX, Bose HS, Wall CT, Han Z, Hales DB, Miller WL, Culty M, Papadopoulos V: Peripheral-type benzodiazepine receptor-mediated action of steroidogenic acute regulatory protein on cholesterol entry into Leydig cell mitochondria. Mol Endocrinol 2005;19:540–554.
  65. Xie C, Lund EG, Turley SD, Russel DW, Dietschy JM: Quantification of two pathways for cholesterol excretion from the brain in normal mice with neurodegeneration. J Lipid Res 2003;44:1780–1789.
  66. Barbaccia ML: Neurosteroidogenesis: relevance to neurosteroid actions in brain and modulation by psychotropic drugs. Crit Rev Neurobiol 2004;18:67–74.

    External Resources

  67. Puglielli L, Konopka G, Pack-Chung E, Ingano LA, Berezovska O, Hyman BT, Chang TY, Tanzi RE, Kovacs DM: Acyl-coenzyme A:cholesterol acyltransferase modulates the generation of the amyloid β-peptide. Nat Cell Biol 2001;3:905–912.
  68. Lütjohann D, Papassotiropoulos A, Björkhem I, Locatelli S, Bagli M, Gehring RD, Schlegel U, Jessen F, Rao ML, von Bergmann K, Heun R: Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients. J Lipid Res 2000;41:195–198.

    External Resources

  69. Papassotiropoulos A, Lütjohann D, Bagli M, Locatelli S, Jessen F, Buschfort R, Ptok U, Björkhem I, von Bergmann K, Heun R: 24S-hydroxycholesterol in cerebrospinal fluid is elevated in early stages of dementia. J Psychiatr Res 2002;36:27–32.
  70. Delavoie F, Li H, Hardwick M, Robert JC, Giatzakis C, Péranzi G, Yao ZX, Maccario J, Lacapère JJ, Papadopoulos V: In vivo and in vitro peripheral-type benzodiazepine receptor polymerisation: functional significance in drug ligand and cholesterol binding. Biochemistry 2003;42:4506–4519.
  71. Yao ZX, Brown RC, Teper G, Greeson J, Papadopoulos V: 22R-hydroxycholesterol protects neuronal cells from β-amyloid-induced cytotoxicity by binding to β-amyloid peptide. J Neurochem 2002;83:1–10.
  72. Lecanu L, Yao W, Teper GL, Greeson J, Papadopoulos V: Identification of naturally occurring spirostenols preventing beta-amyloid-induced neurotoxicity. Steroids 2004;69:1–16.
  73. Tillement L, Lecanu L, Yao W, et al: The spirostenol (22R,25R)-20α-spirost-5-en- 3β-yl hexanoate blocks mitochondrial uptake of Aβ in neuronal cells and prevents Aβ-induced impairment of mitochondrial function. Steroids 2006;71:725–735.
  74. Puglielli L, Tanzi RE, Kovacs DM: Alzheimer’s disease: the cholesterol connection. Nat Neurosci 2003;6:345–351.
  75. Saudou F, Finkbeiner S, Devys D, Greenberg ME: Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 1998;95:55–66.
  76. Valenza M, Cattaneo E: Cholesterol dysfunction in neurodegenerative diseases: is Huntington’s disease in the list? Prog Neurobiol 2006;80:165–176.
  77. Onuki Y, Morishita M, Chiba Y, Tokiwa S, Takayama K: Docosahexaenoic acid and eicosapentaenoic acid induce changes in the physical properties of a lipid bilayer model membrane. Chem Pharm Bull (Tokyo) 2006;54:68–71.
  78. Bosco DA, Fowler DM, Zhang Q, Nieva J, Powers ET, Wentworth P Jr, Lerner RA, Kelly JM: Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate alpha-synuclein fibrillization. Nat Chem Biol 2006;2:249–253.
  79. Prabhakara JPR, Feist G, Thomasson S, Thompson A, Schommer E, Ghribi O: Differential effects of 24-hydroxycholesterol and 27-hydroxycholesterol on tyrosine hydroxylase and α-synuclein in human neuroblastoma SH-SY5Y cells. J Neurochem 2008;107:1722–1729.
  80. Bar-On P, Crews L, Koob AO, Mizuno H, Adame A, Spencer B, Masliah E: Statins reduce neuronal alpha-synuclein aggregation in in vitro models of Parkinson’s disease. J Neurochem 2008;105:1656–1667.
  81. Huang X, Chen H, Miller MC, Mailman RB, Woodard JL, Chen PC, Xiang D, Murrow RW, Wang YZ, Poole C: Lower low-density lipoprotein cholesterol levels are associated with Parkinson’s disease. Mov Disord 2007;22:377–381.
  82. Biomel M, Grigoriadis N, Loourbopoulos A, Touloumi O, Rosenmann D, Abramsky O, Rosenmann H: Statins reduce the neurofibrillary tangle burden in a mouse model of tauopathy. J Neuropathol Exp Neurol 2009;68:314–325.
  83. Tsai SJ: Statins may act through increasing tissue plasminogen activator/plasmin activity to lower risk of Alzheimer’s disease. CNS Spectr 2009;14:234–235.
  84. Onyango IG, Khan SM: Oxidative stress, mitochondrial dysfunction, and stress signaling in Alzheimer disease. Curr Alzheimer Res 2006;3:339–349.
  85. Parihar MS, Brewer GJ: Mitoenergetic failure in Alzheimer disease. Am J Physiol Cell Physiol 2007;292:C8–C23.
  86. Dawson TM, Dawson VL: Molecular pathways of neurodegeneration in Parkinson’s disease. Science 2003;302:819–822.
  87. Cormier A, Morin C, Zini R, Tillement J-P: Nicotine protects rat brain mitochondria against experimental injuries. Neuropharmacology 2003;44:642–652.
  88. Morin D, Hauet T, Spedding M, Tillement J-P: Mitochondria as target for anti-ischemic drugs. Adv Drug Deliv Rev 2001;49:151–174.
  89. Papadopoulos V, Liu J, Culty M: Is there a mitochondrial signaling complex facilitating cholesterol import? Mol Cell Endocrinol 2007;265–266:59–64.
  90. Heneka MT, Landreth GE, Hull M: Drug insight: effects mediated by peroxisome proliferator-activated receptor-γ in CNS disorders. Nat Clin Pract 2007;3:496–504.
  91. Heneka MT, Sastre M, Dumitrescu-Ozimek L, Hanke A, Dewachter I, Kuiperi C, O’Banion K, Klockgether T, van Leuven F, Landreth GE: Acute treatment with the PPAR-γ agonist pioglitazone and ibuprofen reduces glial inflammation and Aβ1–42 levels in APPV717I transgenic mice. Brain 2005;128:1442–1453.
  92. Watson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR, Asthana S, Fishel MA, Kulstad JJ, Green PS, Cook DG, Kahn SE, Keeling ML, Craft S: Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am J Geriatr Psychiatry 2005;13:950–958.
  93. Risner ME, Saunders AM, Altman JF, Ormandy GC, Craft S, Foley IM, Zvartau-Hind ME, Hosford DA, Roses AD, Rosiglitazone in Alzheimer’s Disease Study Group: Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer’s disease. Pharmacogenomics J 2006;6:246–254.

 goto top of outline Author Contacts

Vassilios Papadopoulos
Research Institute, McGill University Health Centre
1650 Cedar Avenue, C10-148, Montreal, QC H3G 1A4 (Canada)
Tel. +1 514 934 1934, ext. 44580, Fax +1 514 934 8439
E-Mail vassilios.papadopoulos@mcgill.ca


 goto top of outline Article Information

Received: July 10, 2009
Published online: November 18, 2009
Number of Print Pages : 17
Number of Figures : 2, Number of Tables : 1, Number of References : 93


 goto top of outline Publication Details

Pharmacology (International Journal of Experimental and Clinical Pharmacology)

Vol. 85, No. 1, Year 2010 (Cover Date: January 2010)

Journal Editor: Donnerer J. (Graz), Billingsley M.L. (Hershey, Pa.), Maeyama K. (Matsuyama)
ISSN: 0031-7012 (Print), eISSN: 1423-0313 (Online)

For additional information: http://www.karger.com/PHA


Copyright / Drug Dosage / Disclaimer

Copyright: 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 or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
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 goverment 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.