Pharmakologie und klinische Pharmakologie der AT1-Rezeptorantagonisten

  • P. Dominiak
  • A. Dendorfer
Conference paper

Zusammenfassung

Seit 1980 standen mit den ACE-Hemmern (damals Captopril) erstmals Substanzen für die antihypertensive Therapie in Deutschland zur Verfügung, die ihre Angriffspunkte am Renin-Angiotensin-Aldosteron-System (RAAS) hatten und nicht, wie die bis zu diesem Zeitpunkt verfügbaren Antihypertensiva, die auf das sympathische System (zentral oder peripher), an der Niere oder auf die glatte Muskulatur wirkten. Auch ß-Adrenozeptoranta- gonisten beeinflussen das RAAS, indem sie die ß1-Adrenozeptoren am juxtaglomerulären Apparat der Niere blockieren und so zu einer verminderten Bildung und Freisetzung des Schlüsselenzyms für die Angiotensin (Ang)-II-Biosynthese, des Renins, beitragen, aber dies ist nicht ihre Hauptwirkung.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Literatur

  1. 1.
    Anderson GH, Jr, Streeten DHP, Dalakas TG (1977) Pressor responses to l-Sar-8-Ala-Ang II (saralasin) in hypertensive subjects. Circ Res 40: 243–250PubMedGoogle Scholar
  2. 2.
    Bader M, Zhao Y, Sander M, Lee MA, Bachmann MA, Bachmann S, Böhm M, Dyavidani B, Peters J, Mullins J, Ganten D (1992) The transgenic rats TGR(mREN2) 27: role of tissue renin in the pathophysiology of hypertension. Hypertension 19: 681–686PubMedGoogle Scholar
  3. 3.
    Bauer PH, Chiù AT, Garrison JC (1991) Effects of nonpeptide Ang II receptor antagonists on Ang II stimulated second messenger production in rat liver. FASEB J 5 (Part I): A870Google Scholar
  4. 4.
    Böhm M, Lee MA, Kreutz R et al. (1995) Angiotensin II receptor blockade in TGR(mREN2) 27: effects of renin-angiotensin-system gene expression and cardiovascular functions. J Hypertens 13: 891–9PubMedGoogle Scholar
  5. 5.
    Boucher R, Asselin JH, Genest J (1974) A new enzyme leading to direct formation of angiotensin II. Circ Res 34 (Suppl 1): 1203–1209Google Scholar
  6. 6.
    Bovee KC, Wong PC, Timmermanns PBMWM, Thoolen MJMC (1991) Effects of nonpeptide Ang II receptor antagonist DuP 753 on blood pressure and renal functions in spontaneously hypertensive PH dogs. Am J Hypertens 4 (Part 2): 327S-333SPubMedGoogle Scholar
  7. 7.
    Bovy PR, Olins GM (1992) Recent advances in nonpeptidic Ang II receptor antagonists. Current Drugs: Renin Angiotensin System. Current Patents Ltd., Middlesex House, London, pp B17-B34Google Scholar
  8. 8.
    Brasch H, Sieroslawski L, Dominiak P (1993) Ang II increases norepinephrine release from atria by acting on angiotensin subtype 1 receptors. Hypertension 22: 699–704PubMedGoogle Scholar
  9. 9.
    Brilla CG, Zhou G, Weber KT (1992) Ang II and collagen synthesis in cultured adult rat cardiac fibroblasts. J Hypertens 10 (Suppl 4): S125Google Scholar
  10. 10.
    Brooks DP DePalma PD, Ruffolo RR Jr (1992b) Effect of Captopril and the nonpeptide angiotensin II antagonists. SK&F 108566 and EXP3174, on renal funcdon in dogs with a renal artery stenosis. J Pharmacol Exp Ther 263: 422–7PubMedGoogle Scholar
  11. 11.
    Brooks DP, Frederickson TA, Kissinger JT et al. (1993) Blood pressure lowering activity of enalapril and the nonpeptide angiotensin II receptor antagonist, SK&F 108566, in furosemide-treated conscious cynomol- gus monkeys. Pharmacol Commun 2 (4): 331–7Google Scholar
  12. 12.
    Brooks DP, Fredrickson TA, Weinstock J et al. (1992a) Antihypertensive activity of the non-peptide angiotensin II receptor antagonist, SK&F 108566, in rats and dogs. Naunyn Schmiedebergs Arch Pharmacol 345: 673–8Google Scholar
  13. 13.
    Burnier M, Hagman M, Nussberger J, Biollaz J, Armagnac C, Brouard R, Weber B, Brunner HR (1995) Short-term and sustained renal effects of angiotensin II receptor blockade in healthy subjects. Hypertension 25: 602–609PubMedGoogle Scholar
  14. 14.
    Burnier M, Rutschmann B, Nussberger J et al. (1993) Salt-dependent renal effects of an Ang II antagonist in healthy subjects. Hypertension 22: 339–347PubMedGoogle Scholar
  15. 15.
    Busch U, Heinzel G, Roth W (1997) Animal pharmacokinetics of telmisartan and their applicadon to man [poster]. 1st Internadonal Symposium on Angiotensin II Antagonism; Sept. 28-Oct 1; LondonGoogle Scholar
  16. 16.
    Camargo MJF, Von Lutterotti N, Pecker MS et al. (1991) DuP 753 increases survival in spontaneously hypertensive stroke-prone rats fed a high sodium diet. Am J Hypertens 4/4, Part 2: 341S-345SGoogle Scholar
  17. 17.
    Cangiano JL, Rodriguez-Sargent C, Martinez-Maldonado M (1979) Effects of antihypertensive treatment on systolic blood pressure and renin in experimental hypertension in rat. J Pharmacol Exp Ther 208: 310–313PubMedGoogle Scholar
  18. 18.
    Captopril multicenter Research group (1983) A placebo-controlled trial of Captopril in refractionary chronic congestive heart failure. J Amer Coll Cardiol 2: 755–763Google Scholar
  19. 19.
    Case DB, Wallace JM, Larach JH (1979) Comparison between saralasin and converting enzyme inhibitor in hypertensive disease. Kidney Int 15: S107-S114Google Scholar
  20. 20.
    Cazaubon C, Gougat J, Guiraudou P, Broussier D, Lacour C, Rocon A, Galindo G, Barthélémy G, Gautret B, Nisato D (1992) In vitro and in vivo pharmacology of SR47436, an Ang II receptor antagonist. Am J Hypertens 5 (Part 2): 19A-20AGoogle Scholar
  21. 21.
    Chansel D, Czekalski S, Pham P et al. (1992) Characterization of Ang II receptor subtypes in human glomeruli and mesangial cells. Am J Physiol 262 (3): F432-F441PubMedGoogle Scholar
  22. 22.
    Chiù AT, McCall DE, Nguyen TT, Carini DJ, Duncia JV, Herblin WF, Wong PC, Wexler RR, Johnson AL, Timmermans PBMWM (1989) Discriminadon of Ang II receptor subtypes by dithiothreitol. Eur J Pharmacol 170:117–118PubMedGoogle Scholar
  23. 23.
    Chiù AT, McCall DE, Price WA, Wong PC, Carini DJ, Duncia JV, Wexler RR, Yoo SE, Johnson AL, Timmermans PBMWM (1990) Nonpeptide Ang II receptor antagonists. VII. Cellular and biochemical pharmacology of DuP753, on orally acdve antihypertensive agent. J Pharmacol Exp Ther 252: 711–718PubMedGoogle Scholar
  24. 24.
    Christ DD (1995) Human plasma protein binding of the Ang II receptor antagonist losartan potassium (DuP753/MK 954) and its pharmacologically active metabolite EXP3174. J Clin Pharmacol 35: 515–520PubMedGoogle Scholar
  25. 25.
    Christen Y, Waeber B, Nussberger J, Lee RJ, Timmermans PBMWM, Brunner HR (1991) Dose-response relationships following oral administration of DuP753 to normal humans. Am J Hypertens 4 (Part 2): 350S-353SPubMedGoogle Scholar
  26. 26.
    Christen Y, Waeber B, Nussberger J, Porchet M, Lee R, Maggon K, Shum L, Timmermans PBMWM, Brunner HR, Borland RM (1991) Oral administradon of DuP753, a specific angiotensin II antagonist, to normal male volunteers: inhibition of pressor response to exogenous angiotensin I and II. Circulation 83: 1333–1342PubMedGoogle Scholar
  27. 27.
    Chua CC, Chua BHL, Diglio CA, Siu BB (1992) Inducdon of endothelin-1 transcript by Ang II in rat heart endothelial cells. FASEB J 6: A1636Google Scholar
  28. 28.
    Cogan MG, Xie MH, Liu FY et al. (1991) Effects of DuP753 on proximal nephron and renal transport. Am JHypertens 4 (4):315S-320SGoogle Scholar
  29. 29.
    Crawford KW, Frey EA, Cote TE (1992) Ang II receptor recognized by DuP753 regulates two distinct guanine nucleotide-binding protein signaling pathways. Mol Pharmacol 41: 154–162PubMedGoogle Scholar
  30. 30.
    Criscione L, Bradley WA, Bühlmayer P, Whitebread S, Glazer R, Lloyd P, Mueller P, de Gasparo M (1995) Valsartan, Preclinical and clinical profile of an antihypertensive angiotensin-II antagonist. Cardiovasc Drug Rev 13: 230–250Google Scholar
  31. 31.
    Criscione L, de Gasparo M, Buehlmayer P, Whitebread S, Ramjoue HP, Wood JM (1993) Pharmacological profile of valsartan: A potent, orally active, nonpepdde antagonist of the Ang II AT,-receptor subtype. Br J Pharmacol 110:761–771PubMedCentralPubMedGoogle Scholar
  32. 32.
    Data on file, Bristol Myers Squibb/SanofiGoogle Scholar
  33. 33.
    Data on file, CibaGoogle Scholar
  34. 34.
    Data on file, Merck Sharp & DohmeGoogle Scholar
  35. 35.
    Data on file, SmithKline BeechamGoogle Scholar
  36. 36.
    De Gasparo M, Whitebread S (1995) Binding of valsartan to mammalian AT, receptors. Regul Pept 59: 303–311PubMedGoogle Scholar
  37. 37.
    DeLeon H, Bonhomme MC, Thibault G et al. (1993) Reassessment of ANF and ANG II receptors in rat mesenteric arteries. Abstr, Hypertension 22 (3): 424Google Scholar
  38. 38.
    de Zeeuw D, Remuzzi G, Kirch W (1997) Pharmacokinetics of candesartan cilexetil in patients with renal or hepatic impairment. J Hum Hypertens 11 (Suppl 2): S37–42PubMedGoogle Scholar
  39. 39.
    Delacrétaz E, Nussberger J, Biollaz J et al. (1995) Characterization of the angiotensin II receptor antagonist TCV-116 in healthy volunteers. Hypertension 14–21Google Scholar
  40. 40.
    Dendorfer A, Raasch W, Tempel K, Dominiak P (1998) Interactions between the renin-angiotensin system (RAS) and the sympathetic system. Basic Res Cardiol 93: Suppl 2, 24–29PubMedGoogle Scholar
  41. 41.
    Dendorfer A, Simon M, Dominiak P (1996) Herzwirksame Hormone: Bradykinin. Z Kardiol 85 (Suppl 6): 211–218PubMedGoogle Scholar
  42. 42.
    Deutsche Liga zur Bekämpfung des hohen Blutdruckes e.V., Deutsche Hypertonie Gesellschaft, Heidelberg: Empfehlungen zur Hochdruckbehandlung in der Praxis und zur Behandlung hypertensiver Notfälle. 12. Auflage, Stand November 1996Google Scholar
  43. 43.
    Dickstein K, Timmermans P, Segal R et al. (1998) Losartan: a selective angiotensin II Type 1 (AT,) receptor antagonist for treatment of heart failure. Exp Opin Invest Drugs 7: 1897–1914Google Scholar
  44. 44.
    Dominiak P, Blöchl A (1991) Does converting enzyme inhibition change the neuronal and extraneuronal uptake of catecholamines? Basic Res Cardiol 86 (Suppl 3): 149–156PubMedGoogle Scholar
  45. 45.
    Dominiak P, Bonner G (1996) ACE-Hemmer in Klinik und Praxis. Aktuelle Therapieprinzipien in Kardiologie und Angiologie. Springer, Berlin, HeidelbergGoogle Scholar
  46. 46.
    Dominiak P, Brenner P, Simon M, Blöchl A (1994) Angiotensin I increases adrenaline release and Ang II noradrenaline overflow in control and kininogen deficient Brown-Norway rats. Pharm Pharmacol Lett 4: 23–26Google Scholar
  47. 47.
    Dominiak P (1993) Modulation of sympathetic control by ACE inhibitors. Eur Heart J 14 (Suppl I): 169–172PubMedGoogle Scholar
  48. 48.
    Dominiak P (1955) Stand und Probleme der ACE-Hemmer-Behandlung. Was ist gesichert in der Therapie? ZAllg Med 71: 587–594Google Scholar
  49. 49.
    Drexler H, Lindpaintner K, Lu W, Schieffer B, Ganten D (1989) Transient increase in the expression of cardiac angiotensinogen in a rat model of myocardial infarction and failure. Circulation 80:11–450Google Scholar
  50. 50.
    Dzau VJ, Gonzalez D, Kaempfer C, Dubin D, Wintroub BU(1987) Human neutrophils release serine proteases capable of activating prorenin. Circ Res 60: 595–601Google Scholar
  51. 51.
    Dzau VJ, Sasamura H, Hein L (1993) Heterogeneity of angiotensin synthetic pathways and receptor subtypes: physiological and pharmacological implications. J Hypertens 11 (Suppl 3): S13-S18Google Scholar
  52. 52.
    Edwards RM, Aiyar N, Ohlstein EH, Weidley EE, Griffin E, Ezekiel M, Keenan RM, Ruffolo RR Jr, Weinstock J (1992) Pharmacological characterization of the nonpeptide Ang II receptor antagonist, SK&F108566. J Pharmacol Exp Ther 260: 175–181PubMedGoogle Scholar
  53. 53.
    Fauvel JP, Laville M, Maakel N et al. (1994) Effects of losartan on renal hemodynamic parameters in hypertensives (abstract). J Hypertens (Suppl 3) 12: S93Google Scholar
  54. 54.
    Fornes P, Richer C, Vacher E et al. (1993) Losartan‘s protective effects in stroke prone spontaneously hypertensive rats persist durably after treatment withdrawal. J Cardiovasc Pharmacol 22: 305–313PubMedGoogle Scholar
  55. 55.
    Fridman K, Wysocki M, Friberg P et al. (1998) Long-term effects of candesartan cilexetil on the systemic and renal haemodynamics in moderately hypertensive patients [abstract]. Am J Hypertens 11 (4 Pt2): 77AGoogle Scholar
  56. 56.
    Furakawa Y, Kishimoto S, Nishikawa K (1982) Hypotensive imidazole derivatives and hypotensive imidazole-5-acetic acid derivatives. Patents issued to Takeda Chemical Industries Ltd. on July 20,1982, and October 19, 1982, respectively, U.S. Patents 4,340,598 and 4,355,040, Osaka, JapanGoogle Scholar
  57. 57.
    Ganten D, Mulrow PJ (eds) (1990) Pharmacology of Antihypertensive Therapeutics. Handbook of Experimental Pharmacology, Vol 93. Springer, Berlin HeidelbergGoogle Scholar
  58. 58.
    Gillis JC, Markham A (1997) Irbesartan. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in the management of hypertension. Drugs 54: 885–902Google Scholar
  59. 59.
    Goa KL, Wagstaff AJ (1996) Losartan Potassium. A review of its pharmacology, clinical efficacy and tolerability in the management of hypertension. Drugs 51: 820–845PubMedGoogle Scholar
  60. 60.
    Hagino T, Abe K, Tsunoda K, Yoshinaga K (1992) Chronic effects of MK-954, a nonpeptide Ang II receptor antagonist, on 24-hour ambulatory blood pressure, renin angiotensin aldosterone system and renal function in essential hypertension. J Hypertens 10 (Suppl 4): 224Google Scholar
  61. 61.
    Hansson L, Lindholm LH, Niskanen L, Lauke J, Hedner T, Niklason A, Luomanmaki K, Dahlof B, de Faire V, Morlin C, Karlberg BE, Wester PO, Bjorck JE (1999) Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 20, 353: 611–616Google Scholar
  62. 62.
    Harding JW, Wright JW, Swanson GN, Hanesworth JM, Krebs LT (1994) AT4 receptors: specificity and distribution. Kidney Int 46: 1510–1512PubMedGoogle Scholar
  63. 63.
    Häuser W, Dendorfer A, Nguyen T, Dominiak P (1998) Effects of the AT 1 Antagonist HR 720 in Comparison to Losartan on Stimulated Sympathetic Outflow, Blood Pressure, and Heart Rate in Pithed Spontaneously Hypertensive Rats. Kidney Blodd Press Res 21: 29–35Google Scholar
  64. 64.
    Hübner R, Högemann AM, Sunzel M et al. (1997) Pharmacokinetics of candesartan after single and repeated doses of candesartan cilexetil in young and elderly healthy volunteers. J Hum Hypertens 11 (Suppl 2): 19–25Google Scholar
  65. 65.
    Ilson BE, Martin DE, Boike SC, Jorkasky DK (1998) The effects of eprosartan, an angiotensin II ATI receptor antagonist, on uric acid excredon in patients with mild to moderate essential hypertension. J Clin Pharmacol 38: 437–41PubMedGoogle Scholar
  66. 66.
    Inagami T, Murakami T, Higuchi K, Nakajo S (1991) Roles of renal and vascular renin in spontaneous hypertension and switching of mechanism upon nephrectomy: lack of hypotensive effects of inhibidon of renin, converting enzyme, Ang II receptor blocker after bilateral nephrectomy. Am J Hypertens 4: 15S-22SPubMedGoogle Scholar
  67. 67.
    Inoue Y, Nakamura N, Inagami T (1997) A review of mutagenesis studies of angiotensin II type 1 receptor, the three-dimensional receptor model in search of the agonist and antagonist binding site and the hypothesis of a receptor acdvadon mechanism. J Hypertens 15: 703–714PubMedGoogle Scholar
  68. 68.
    Kagoshima T, Masuda J, Sutani E et al. (1994) Angiotensin II receptor antagonist, TCV-116, prevents myocardial hypertrophy in spontaneously hypertensive rats. Blood Press 3 (Suppl 5): 89–93Google Scholar
  69. 69.
    Kanagy NL, Fink GD (1992) Losartan (DuP 753) prevents salt-induced hypertension in reduced renal mass rats. FASEB 16: A1810Google Scholar
  70. 70.
    Kebabian JW, Neumeyer JL (eds) (1994) The RBI Handbook of Receptor Classificadon. Research Bio- chemicals International, pp 10–11Google Scholar
  71. 71.
    Kessler-Icekson G, Schlesinger H, Cohen F (1992) Effect of Ang II and losartan on protein accumulation in cultured heart myocytes and nonmyocytes. FASEB J 6: A1872Google Scholar
  72. 72.
    Khairallah PhA (1972) Action of angiotensin on adrenergic nerve endings: inhibition of norepinephrine uptake. Fed Proc 31: 1351–1357PubMedGoogle Scholar
  73. 73.
    Kirby RF, Nanda A, Henry M, Johnson AK (1992) Preweanling losartan treatment reduces adult blood pressure in the spontaneously hypertensive rat. FASEB J 6: A1872Google Scholar
  74. 74.
    Kojima M, Shiojima I, Yamazaki T et al. (1994) Angiotensin II receptor antagonist TCV-116 induces regression of hypertensive left ventricular hypertrophy in vivo and inhibits the intracellular signaling pathway of stretch-mediated cardiomyocyte hypertrophy in vitro. Circuladon 89: 2204 -11Google Scholar
  75. 75.
    Lewis EJ, Hunsicker LG, Bain RP, Rohde RO (for the Collaboradve Study Group) (1993) The effect of angiotensin-converdng-enzyme inhibidon on diabetic nephropathy. New Engl J Med 329: 1456–1462PubMedGoogle Scholar
  76. 76.
    Linz W, Wiemer G, Gohlke P, Unger T, Schölkens BA (1995) Contribudon of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol Rev 47: 25–49PubMedGoogle Scholar
  77. 77.
    Liu YH, Yang XP, Sharov VG, Nass O, Sabbah HN, Peterson E, Carretero OA (1997) Effects of angiotensin- converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure. Role of kinins and angiotensin II type 2 receptors. J Clin Invest 99: 1926–35PubMedCentralPubMedGoogle Scholar
  78. 78.
    Lo MW, Goldberg MR, McCrea JB et al. (1995) Pharmacokinetics of losartan, an Ang II receptor antagonist, and its active metabolite EXP3174 in humans. Clin Pharmacol Ther 58: 641–649PubMedGoogle Scholar
  79. 79.
    Majewski H, Hedler L, Schurr C, Starke K (1984) Moduladon of noradrenaline release in the pithed rabbit: a role for Ang II. J Cardiovasc Pharmacol 6: 888–896PubMedGoogle Scholar
  80. 80.
    Markham A, Goa KL (1997) Valsartan. A Review of its Pharmacology and Therapeutic Use in Essendal Hypertension. Drug 54 (2): 299–311Google Scholar
  81. 81.
    Martin DE, Tompson D, Boike SC, Tenero D, Ilson B, Citerone D, Jorkasky DK (1997) Lack of effect of eprosartan on the single dose pharmacokinedcs of orally administered digoxin in healthy male volunteers. Br J Clin Pharmacol 43: 661–4Google Scholar
  82. 82.
    Martineau D, Yamaguchi N, Briand R (1995) Inhibidon by BMS 186295, a selecdve nonpepdde ATI antagonist, of adrenal catecholamine release induced by angiotensin II in the dog in vivo. Can J Physiol Pharmacol 73: 459–64PubMedGoogle Scholar
  83. 83.
    Mardnez F, Schmitt F, Savoiu C, Leenhardt AF, Brouard R, Peronnet P, Lacour B, Grünfeld JP (1994) Effect of SR 47436 (BMS-186295) on renal hemodynamics and on glomerular permselectivity in healthy humans. JAm Soc Nephrol 5: 607Google Scholar
  84. 84.
    Matsubara K, Brilla CG, Weber KT (1992) Ang Il-mediated inhibidon of collagenase activity in cultured cardiac fibroblasts. FASEB J 6: A941Google Scholar
  85. 85.
    McClellan KJ, Balfour JA (1998) Eprosartan. Drugs 55: 713–720Google Scholar
  86. 86.
    McClellan KJ, Goa KL (1998) Candesartan Cilexedl. A review of its Use in Essendal Hypertension. Drugs 56:847–869PubMedGoogle Scholar
  87. 87.
    McClellan KJ, Markham A (1998) Telmisartan. Drugs 56: 1039–1046PubMedGoogle Scholar
  88. 88.
    Mclnnes GT, O’Kane KPJ, Jonger J et al. (1997) The efficacy and tolerability of candesartan cilexetil in an elderly hypertensive population. J Hum Hypertens 11 (Suppl 2): S75–80Google Scholar
  89. 89.
    Meffert S, Stoll M, Steckelings UM, Bottari SP, Unger T (1996) The Ang II AT, receptor inhibits proliferation and promotes differentiation in PC12W cells. Mol Cell Endocrinol 122: 59–67PubMedGoogle Scholar
  90. 90.
    Meinecke I, Feltkamp H, Högemann A et al. (1997) Pharmacokinetics and pharmacodynamics of candesartan after administration of its pro-drug candesartan cilexetil in patients with mild to moderate essential hypertension - a population analysis. Eur J Clin Pharmacol 53: 221–8Google Scholar
  91. 91.
    Miwa K, Murakami H, Masaki K et al. (1997) In vitro metabolism of candesartan cilexetil [abstract]. In: 1st International Symposium on Angiotensin II Antagonism Sep 28-Oct 1; London, 1997Google Scholar
  92. 92.
    Mizuno K, Niimura S, Katoh K et al. (1994) TCV-116, a newly developed angiotensin II receptor antagonist, induces regression of cardiac hypertrophy through suppression of the tissue renin-angiotensin system in spontaneously hypertensive rats. Life Sci 54 (25): 1987–94PubMedGoogle Scholar
  93. 93.
    Morsing P, Brandt-Eliasson U, Abrahamsson T (1998) Candesartan, an insurmountable antagonist of angiotensin II mediated contractile effects in isolated vascular preparations: a comparison with irbesartan, losartan and its active metaboHte (EXP3174) [abstract]. Am J Hypertens 11 (4 Pt2): 37AGoogle Scholar
  94. 94.
    Morton JJ, Beattie EC, McPherson F (1991) Ang II receptor antagonist DuP753 reduces long-term post- treatment hypertension in the young spontaneously hypertensive rat: relation to vascular hypertrophy. Biophys J 59 (Part 2): 99AGoogle Scholar
  95. 95.
    Müller P, Cohen T, deGasparo M, Sioufi A, Racinepoon A, Howald H (1994) Ang II receptor blockade with single doses of valsartan in healthy, normotensive subjects. Eur J Clin Pharmacol 47: 231–245PubMedGoogle Scholar
  96. 96.
    Müller-Esterl W (1993) The realm of the kinins. Biomedical Progress 6: 49–53Google Scholar
  97. 97.
    Murphy DD, Shepard J, Smith SG III, Stephens GA (1992) Effects of the AT, receptor antagonist losartan on Ang II induced hypertrophy of rat cardiomyocytes. FASEB J 6: A1261Google Scholar
  98. 98.
    Nagano M, Higaki J, Mikami H et al. (1994) Role of renin-angiotensin system in hypertension in the elderly. Blood Press 3 (Suppl 5): 130–3Google Scholar
  99. 99.
    Nakashima M, Uematsu T, Kosuge K (1992) Pilot study of the uricosuric effect of DuP-753, a new Ang II receptor antagonist, in healthy subjects. Eur J Clin Pharmacol 42: 333–335PubMedGoogle Scholar
  100. 100.
    Neutel JM, Smith DHG (1998) Dose Response and Antihypertensive Efficacy of the AT, Receptor Antagonist Telmisartan in Patients with Mild to Moderate Hypertension. Advances in Therapy 15: 206–217Google Scholar
  101. 101.
    Nguyen T, Häuser W, Dominiak P (1995) Blockade von AT, -Rezeptoren mit S 4509 A reduziert die prä- und postsynaptische Antwort auf Ang II an spontan hypertensiven Ratten. Z Kardiol 84 (Suppl 1): 221–771Google Scholar
  102. 102.
    Nisato D, Cazaubon C, Lacour C, Gougat J, Guiraudou P, Bemhart C, Perreaut P, Breliere JC, LeFur G (1992) Pharmacological properties of SR 47436, a non-peptidic Ang II receptor antagonist. Br J Pharmacol 105: 84PGoogle Scholar
  103. 103.
    Nishikawa K, Inada Y, Shibouta Y et al. (1994) Pharmacological profile of a novel nonpeptide angiotensin II subtype 1 receptor antagonist. TCV-116. Blood Press 3 (Suppl 5): 7–14Google Scholar
  104. 104.
    Nishikawa K, Naka T, Chatani F, Yoshimura Y (1997) Candesartan cilexitil: a review of its preclinical pharmacology. J Hum Hypertension 11 (Suppl 2): S1-S7Google Scholar
  105. 105.
    Nishikimi T, Yamagishi H, Takeuchi K (1995) An angiotensin II receptor antagonist attenuates left ventricular dilatation after myocardial infarction in the hypertensive rat. Cardiovasc Res 29: 856–61PubMedGoogle Scholar
  106. 106.
    Nöda M, Fukuda R, Matsuo T et al. (1997) Effects of candesartan cilexetil (TCV-116) and enalapril in 5/6 nephrectomized rats. Kidney Int 52 (Suppl 63): SI36–139Google Scholar
  107. 107.
    Nöda M, Shibouta Y, Inada Y et al. (1993) Inhibition of rabbit aortic angiotensin II (All) receptor by CV-11974, a new nonpeptide All antagonist. Biochem Pharmacol 46: 311–8PubMedGoogle Scholar
  108. 108.
    Ohlstein EH, Brooks DP, Feuerstein GZ et al. (1997) Inhibition of sympathetic outflow by the angiotensin II receptor antagonist, eprosartan, but not by losartan, valsartan or irbesartan: relationship to differences in prejunctional angiotensin II receptor blockade. Pharmacology 55: 244–51PubMedGoogle Scholar
  109. 109.
    Ohtawa M, Takayama F, Saitoh K (1993) Pharmacokinetics and biochemical efficacy after single and multiple oral administration of losartan, an orally active nonpeptide Ang II receptor antagonist, in humans. Br J Clin Pharmacol 35: 290–297PubMedCentralPubMedGoogle Scholar
  110. 110.
    Ojima M, Inada Y, Shibouta Y et al. (1997) Candesartan (CV-11974) dissociates slowly from the angiotensin AT, receptor. Eur J Pharmacol 319: 137–46PubMedGoogle Scholar
  111. 111.
    Okada M, Kobayashi M, Satoh N et al. (1993) Effect of chronic treatment with losartan on development of hypertension in stroke prone spontaneously hypertensive rats (SHRSP): Comparative study with enalapril and hydralazine. Hypertens Res 16: 49–55Google Scholar
  112. 112.
    Okunishi H, Miyazaki M, Toda N (1984) Evidence for a putatively new Ang Il-generating enzyme in the vascular wall. J Hypertens 2: 277–284PubMedGoogle Scholar
  113. 113.
    Pals DT, Mascucci FD, Denning GS, Sipos F, Fessler DC (1971) Role of the pressor action of Ang II in experimental hypertension. Circ Res 29: 673–681PubMedGoogle Scholar
  114. 114.
    Peach MJ, Bumpus FM, Khairallah PhA (1971) Release of adrenal catecholamines by angiotensin I. J Pharmacol Exp Ther 176: 366–376PubMedGoogle Scholar
  115. 115.
    Peach MJ (1971) Adrenal medullary stimulaüon induced by angiotensin I, Ang II and analogues. Circ Res (Suppl II): 107–117Google Scholar
  116. 116.
    Peach MJ (1977) Renin-angiotensin system. Biochemistry and mechanism of acdon. Physiol Rev 57: 313–370PubMedGoogle Scholar
  117. 117.
    Price DA, De’Oliveira JM, Fisher ND, Hollenberg NK (1997) Renal hemodynamic response to an angiotensin II antagonist, eprosartan, in healthy men. Hypertension 30 (2 PT 1): 240–6PubMedGoogle Scholar
  118. 118.
    Quadri F, Badoer E, Stadler T, Unger Th (1991) Ang Il-induced noradrenaline release from anterior hypothalamus in conscious rats. A brain microdialysis study. Brain Res 563: 137–141Google Scholar
  119. 119.
    Raasch W, Häuser W, Dendorfer A, Schlecht T, Dominiak P (1996) Hypertrophieregression von Ventrikel und Aortenmedia an SHR: Beeinflussung des RAS auf verschiedenen Ebenen. Z Kardiol 85 (Suppl 2): 235–813Google Scholar
  120. 120.
    Reif M, White WB, Fagan TC, Oparil S, Flanagan TL, Edwards DT, Cushing DJ, Michelson EL (1998) Effects of Candesartan Cilexetil in Patients With Systemic Hypertension. Am J Cardiol 82: 961–965PubMedGoogle Scholar
  121. 121.
    Ribstein J, Sissmann J, Picard A, Bouroudian M, Mimran A (1994) Effects of the angiotensin II antagonist SR 47436 (BMS-186295) on the pressor response to exogenous angiotensin II and the renin-angiotensin system in sodium replete normal subjects. J Hypertens 12: 131Google Scholar
  122. 122.
    Riddell JG (1997) Bioavailability of candesartan is unaffected by food in healthy volunteers administered candesartan cilexedl. J Hum Hypertens 11 (Suppl 2): S29–30PubMedGoogle Scholar
  123. 123.
    Schieffer B, Wirger A, Meybrunn M, Seitz S, Holtz J, Riede UN, Drexler H (1994) Comparadve effects of chronic angiotensin-converting enzyme inhibition and Ang II type 1 receptor blockade on cardiac remodeling after myocardial infarcdon in the rat. Circulation 89: 2273–2282PubMedGoogle Scholar
  124. 124.
    Schierok H, Pairet M, Hauel N et al. (1997) Effects of telmisartan, a new angiotensin AT, receptor antagonist, on renal excretory funcdon in conscious dogs [abstract]. 1st Internadonal Symposium on Angiotensin II Antagonism; Sept 28-Oct 1: LondonGoogle Scholar
  125. 125.
    SHEP Cooperative Research Group (1991) Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 265: 3255–3264Google Scholar
  126. 126.
    Shibouta Y, Inada Y, Ojima M et al. (1993) Pharmacological profile of a highly potent and long- acting angiotensin II receptor antagonist. 2-ethoxy-l-[[2’-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]-lH- benzimidazole-7-carboxylic acid (CV-11974), and its prodrug, (±)-l-(cyclohexyloxycarbonyloxy)-ethyl 2-ethoxy-1 -[[2’-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1 H-benzimidazole-7-caraboxylate (TCV-116). J Pharmacol Exp Ther 266: 114–20PubMedGoogle Scholar
  127. 127.
    Sica DA, Lo MW, Shaw WC et al. (1995) The pharmacokinedcs of losartan in renal insufficiency. J Hypertens 13 (Suppl 1): S49-S52Google Scholar
  128. 128.
    Siegl PKS (1993) Discovery of losartan, the first specific non-peptide Ang II receptor antagonist. J Hypertens 11 (Suppl3):S19-S22Google Scholar
  129. 129.
    Sissmann J, Bouroudian M, Armagnac C, Donazollo Y, Latreille M, Panis R (1994) Angiotensin II blockade in healthy volunteers: Tolerability and impact on renin angiotensin system components of single and repeated doses of a new angiotensin II receptor antagonist SR 47436 (BMS-186295). J Hypertens 12: S92Google Scholar
  130. 130.
    Smith DHG, Morgenstern P (1998) Once-Daily Telmisartan Compared With Enalapril in the Treatment of Hypertension. Advances in Therapy 15: 229–240Google Scholar
  131. 131.
    Smith MC, Barrows S, Meibohm A et al. (1995) The effects of Ang II receptor blockade with losartan on systemic blood pressure and renal and extrarenal prostaglandin synthesis in women with essential hypertension. Am J Hypertens 8: 1177–1183PubMedGoogle Scholar
  132. 132.
    Stangier J, Schmid J, Türck D et al. (1997) Pharmacokinetics of [14C]-radiolabelled telmisartan, a potent angiotensin II antagonist, in healthy male subjects (poster). 1st International Symposium on Angiotensin II Antagonism; Sept 28-Oct 1; LondonGoogle Scholar
  133. 133.
    Starke K, Taube HD, Borowski E (1977) Presynaptic receptor systems in catecholaminergic transmission. Biochem Pharmacol 26: 259–268PubMedGoogle Scholar
  134. 134.
    Starke K (1971) Action of angiotensin on uptake, release and metabolism of [14C] noradrenaline by isolated rabbit hearts. Eur J Pharmacol 14: 112–113PubMedGoogle Scholar
  135. 135.
    Staszewska-Barczak J, Vane JR (1967) The release of catecholamines from the adrenal medulla by peptides. Br J Pharmacol Chemother 30: 655–667PubMedCentralPubMedGoogle Scholar
  136. 136.
    Stearns RA, Chakravarty PK, Chen R et al. (1995) Biotransformadon of losartan to its acdve carboxylic acid metabolite in human liver microsomes: role of cytochrome P4502C and 3 A subfamily members. Drug Metab Dispos 23: 207–215PubMedGoogle Scholar
  137. 137.
    Stearns RA, Miller RR, Doss GA et al. (1992) The metabolism of DuP753, a nonpepdde Ang II receptor antagonist, by rat, monkey, and human liver slices. Drug Metab Dispos 20: 281–287PubMedGoogle Scholar
  138. 138.
    Steckelings U, Obermüller N, Bottari SP, Quadri F, Veltmar A, Unger T (1992) Brain angiotensin: receptors, actions and possible role in hypertension. Pharmacol. Toxicol 70 (Suppl II): S23-S27PubMedGoogle Scholar
  139. 139.
    Stier CT Jr, Sim G, Mahboubi K et al. (1991) Prevention of stroke and hypertensive renal disease by the Ang II receptor antagonist DuP 753 in salt-loaded stroke-prone SHR. In: MacGregor GA, Sever PS (eds) Current advances in ACE inhibition 2. Churchill Livingstone, Edinburgh London Melbourne New York Tokyo, pp 252–255Google Scholar
  140. 140.
    Stoll M, Steckelings UM, Paul M, Bottari SP, Metzger R, Unger T (1995) The angiotensin AT.-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest 95: 651–657PubMedCentralPubMedGoogle Scholar
  141. 141.
    Sugimoto KI, Gotoh E, Takasaki I, Shionoiri H, Ishii M (1992) Effect of Ang II receptor antagonist on cardiac hypertrophy in Dahl salt sensitive rats. Hypertension 20: 419Google Scholar
  142. 142.
    Takeda K, Fujita H, Nakamura K et al. (1994) Effect of an angiotensin II receptor antagonists, TCV-116, on cardiac hypertrophy and coronary circulation in spontaneously hypertensive rats. Blood Press 3 (Suppl 5): 94–8Google Scholar
  143. 143.
    Tang SS, Loscalzo J, Dzau VJ (1989) Tissue plasminogen activator activates renin angiotensin in vitro. J Vase Med Biol 1:67–74Google Scholar
  144. 144.
    Tenero D, Martin D, Chapelsky M, Ilson B, Boike S, Patterson S, Keogh J, Rodriguez S, Jorkasky D (1998) Effect of hepatic disease on the pharmacokinetics and plasma protein binding of eprosartan. Pharmacotherapy 18: 42–50PubMedGoogle Scholar
  145. 145.
    Tenero D, Martin D, Ilson B, Jushchyshyn J, Boike S, Lundberg D, Zariffa N, Boyle D, Jorkasky D (1998) Pharmacokinetics of intravenously and orally administered eprosartan in healthy males: absolute bio- vailability and effect of food. Biopharm Drug Dispos 19: 351–6PubMedGoogle Scholar
  146. 146.
    Tenero DM, Martin DE, Miller AK, Ilson B, Boike SC, Zariffa N, Jorkasky DK (1998) Effect of age and gender on the pharmacokinetics of eprosartan. Br J Clin Pharmacol 46: 267–70PubMedCentralPubMedGoogle Scholar
  147. 147.
    The acute infarction ramipril efficacy (AIRE) study investigators (1993) Effect of ramipril on mortality and morbidity of survivors of acute mycardial infarction with clinical evidence of heart failure. Lancet 342: 821–828Google Scholar
  148. 148.
    The consensus trial study group (1987) Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med 316: 1429–1325Google Scholar
  149. 149.
    The studies of left ventricular dysfunction (SOLVD) investigators (1992) Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 327:685–691Google Scholar
  150. 150.
    Timmermans PBMWM, Smith RD (1996) Angiotensin-II-Rezeptoren: Physiologische und pharmakologische Bedeutung. In: Philipp Th, Schäfers RF (Hrsg) Angiotensin II - Antagonismus. Ein neuer Weg zur Hochdruckbehandlung. Springer, Berlin Heidelberg, S. 1–29Google Scholar
  151. 151.
    Timmermans PBMWM, Wong PC, Chiù AT, Herblin WF, Benfield P, Carini DJ, Lee RJ, Wexler RR, Saye JAM, Smith RD (1993) Ang II receptors and Ang II receptor antagonists. Parmacol Rev 45: 205–251Google Scholar
  152. 152.
    Tsunoda K, Abe K, Hagino T et al. (1993) Hypotensive effect of losartan, a nonpeptide Ang II receptor antagonist, in essential hypertension. Am J Hypertens 6: 28–32PubMedGoogle Scholar
  153. 153.
    Unger T, Chung O, Csikos T, Culman J, Gallinat S, Gohlke P, Höhle S, Meffert S, Stoll M, Stroth U, Zhu Y-Z (1996) Angiotensin receptors. J Hypertens 14 (Suppl 5): S95-S103Google Scholar
  154. 154.
    Unger T, Gohlke P, Gruber MG (1990) Converting enzyme inhibitors. In: Ganten D, Mulrow PJ (eds) Pharmacology of Antihypertensive Therapeutics. Handbook of Experimental Pharmacology, Vol 93. Springer, Berlin Heidelberg New York Tokyo, pp 739–481Google Scholar
  155. 155.
    Urata H, Healy B, Stewart RW, Bumpus FM, Husain A (1990) Ang Il-forming pathways in normal and failing human hearts. Circ Res 66: 883–890PubMedGoogle Scholar
  156. 156.
    Urata H, Kinoshita A, Misono KS, Bumpus FM, Husain A (1990) Identification of a highly specific chymase as the major angiotensin-II-forming enzyme in the human heart. J Biol Chem 265: 22348–22357PubMedGoogle Scholar
  157. 157.
    Van den Meiracker AH, Admiraal PJ, Janssen JA, Kroodsma JM, de Ronde WA, Boomsma F, Sissmann J, Blankestijn PJ, Mulder PG, Man In’t Veld AJ, Schalekamp MADH (1995) Hemodynamic and biochemical effects of the AT, receptor antagonist irbesartan in hypertension. Hypertension 25: 22–29PubMedGoogle Scholar
  158. 158.
    van Lier JJ, van Heiningen PNM, Sunzel M (1997) Absorption, metabolism and excretion of14C- candesartan and14C-candesartan cilexetil in healthy volunteers. J Hum Hypertens 11 (Suppl 2): S27–28PubMedGoogle Scholar
  159. 159.
    van Meel JCA, Hauel N, Entzeroth M et al. (1993) Antihypertensive effects of the angiotensin receptor antagonist, BIBR 277, in conscious renal hypertensive and spontaneously hypertensive rats [abstract] Br J Pharmacol 108 (Suppl): 191PGoogle Scholar
  160. 160.
    van Meel JCA, Redemann N, Haigh RM (1996) Hypotensive effects of the angiotensin II antagonist telmisartan in conscious cronically-instrumented transgenic rats. Arzneimittel Forschung 46: 755–9PubMedGoogle Scholar
  161. 161.
    Wada T, Inada Y, Shibouta Y, Ojima M, Kubo K, Kohara Y, Naka T, Nishikawa K (1992) Antihypertensive action of a nonpeptide Ang II (All) antagonist, TCV-116, in various hypertensive rats. J Hypertens 10 (Suppl 4): SI44Google Scholar
  162. 162.
    Wada T, Kanagawa R, Ishimura Y, Inada Y, Nishikawa K (1995) Role of angiotensin II in cerebrovascular and renal damage in deoxycorticosterone acetate-salt hypertensive rats. J Hypertens 13: 113–22PubMedGoogle Scholar
  163. 163.
    Weinstock J, Keenan RM, Samanen J, Hempel J, Finkelstein JA, Franz RG, Gaitanopoulos DE, Girard GR, Gleason JG, Hill DT, Morgan TM, Peishoff CE, Aiyar N, Brooks DP, Fredrickson TA, Ohlstein EH, Ruffolo RR Jr, Stack EJ, Sulpizio AC, Weidley EF, Edwards RM (1991) l-(Carboxybenzyl)imidazole-5-acrylic acids: potent and selective angiotensin II receptor antagonists. J Med Chem 34: 1514–1517Google Scholar
  164. 164.
    Wienen W, Entzeroth M, Diederen W et al. (1997) Pharmacology and antihypertensive effects of telmisartan, an AT,-selective angiotensin II receptor antagonist [poster] 1st International Symposium on Angiotensin II Antagonism. Sep 28-Oct 1; LondonGoogle Scholar
  165. 165.
    Wienen W, Hauel N, Van MJCA et al. (1993) Pharmacological characterization of the novel nonpepdde angiotensin II receptor antagonist. BIBR 277. Br J Pharmacol 110: 245–52PubMedCentralPubMedGoogle Scholar
  166. 166.
    Wikstrand J, Warnold I, Olsson G, Tuomilehto J, Elmfeldt D, Berglund G (1988) Primary prevendon with metoprolol in patients with hypertension. Mortality results from the MAPHY study. JAMA 259: 1976–1982PubMedGoogle Scholar
  167. 167.
    Williams GH (1988) Converting enzyme inhibitors in the treatment of hypertension. N Engl J Med 319 (23): 1517–1525PubMedGoogle Scholar
  168. 168.
    Winquist R, Panzenbeck M, Madwed J et al. (1994) The effects of BIBR 277, an angiotensin II type I (ATI) receptor antagonist in conscious monkeys [abstract]. FASEB J 8 (Pt 2): A882Google Scholar
  169. 169.
    Wintroub BU, Klickstein LB, Watt KW (1981) A human neutrophil dependent pathway for generadon of Ang IL J Clin Invest 68: 484–490Google Scholar
  170. 170.
    Wong PC, Hart SD, Chiù AT, Herblin WF, Carini DJ, Smith RD, Wexler RR, Timmermans PBMWM (1991) Pharmacology of DuP 532, a selective and noncompetitive AT, receptor antagonist. J Pharmacol Exp Ther 259: 861–870PubMedGoogle Scholar
  171. 171.
    Wong PC, Hart SD, Duncia JV et al. (1991) Nonpeptide Ang II receptor antagonists. XIII. Studies with DuP 753 and EXP 3174 in dogs. Eur J Pharmacol 202: 323–330PubMedGoogle Scholar
  172. 172.
    Wong PC, Price WA, Chiu AT, Duncia JV, Carini DJ, Wexler RR, Johnson AL, Timmermans PBMWM (1990) Nonpeptide Ang II receptor antagonists. XI. Pharmacology of EXP3174, an active metabolite of Dup 753 - an orally active antihypertensive agent. J Pharmacol Exp Ther 255: 211–217PubMedGoogle Scholar
  173. 173.
    Wong PC, Price WA, Chiù AT, Duncia JV, Carini DJ, Wexler RR, Johnson AL, Timmermans PBMWM (1990) Nonpepdde Ang II receptor antagonists. IX. Andhypertensive acdvity in rats of DuP 753, an orally acdve antihypertensive agent. J Pharmacol Exp Ther 252: 726–732PubMedGoogle Scholar
  174. 174.
    Wong PC, Price WA, Chiù AT, Duncia JV, Carini DJ, Wexler RR, Johnson AL, Timmermans PBMWM (1990) Nonpeptide Ang II receptor antagonists. VIII. Characterization of functional antagonism displayed by DuP 753, an orally acdve andhypertensive agent. J Pharmacol Exp Ther 252: 719–725PubMedGoogle Scholar
  175. 175.
    Wong PC, Tam SW, Herblin WF et al. (1991) Further studies on the selecdvity of DuP 753, a nonpepdde Ang II receptor antagonist. Eur J Pharmacol 196: 201–203PubMedGoogle Scholar
  176. 176.
    Wood JM, Schnell CR, Levens NR (1993) Kidney is an important target for the antihypertensive action of an Ang II receptor antagonist in spontaneously hypertensive rats. Hypertension 21: 1056–1061PubMedGoogle Scholar
  177. 177.
    Wright JW, Krebs LT, Stobb JW, Harding JW (1995) The angiotensin IV system: funcdonal implications. Front Neuroendocrinol 16: 23–52PubMedGoogle Scholar
  178. 178.
    Yoshiyama M, Kim S, Yamagishi H et al. (1994) Cardioprotecdve effect of the angiotensin II type I receptor antagonist TCV-116 on ischemia-reperfusion injury. Am Heart J 128: 1–6PubMedGoogle Scholar
  179. 179.
    Zierhut W, Studer R, Laurent D, Kästner S, Allegrini P, Whitebread S, Cumin F, Baum H, de Gasparo M, Drexler H (1996) Left ventricular wall stress and sarcoplasmic recdculum Ca2+-ATPase gene expression in renal hypertensive rats: dose-dependent effects of ACE inhibidon and AT,-receptor blockade. Cardiovasc Res 31: 758–768PubMedGoogle Scholar
  180. 180.
    Zimmerman BG (1978) Acdons of angiotensin on adrenergic nerve endings. Fed Proc 37: 199–202PubMedGoogle Scholar

Copyright information

© Dr. Dietrich Steinkopff Verlag GmbH & Co. KG, Darmstadt 1999

Authors and Affiliations

  • P. Dominiak
    • 1
  • A. Dendorfer
  1. 1.Institut für experimentelle und klinische Pharmakologie und ToxikologieMed. Universität zu LübeckLübeckDeutschland

Personalised recommendations