Klinische Pharmakologie -
Prof. Dr. Dr. Gerd Geisslinger

>

Expertise

• Neurobiologie und -pharmakologie von Schmerz und Entzündung
  
• Suche nach neuen Targets für die Schmerztherapie
  
• Antikarzinogene Wirkungen von Analgetika
  
• Untersuchung zur Thrombozytenfunktion und Hämostase
  
  

>

Methoden und Geräte

Labormethoden:

• Massenspektrometrie: LC/MS/MS, QTrap, GC, HPLC
  
• Real-time PCR (Taqman)
  
• Ermittlung genetischer Polymorphismen mittels Pyrosequencing und Kapillarelektrophorese
  
• Radioliganden-Bindungsassays
  
• [³⁵S]-GTPγS-Bindungsassays an humanem Gewebe und GVOs
  
• DNA-Sequenzierung, Klonierung, Transfektion/Transformation
  
• In-situ Hybridisierung
  
• 2D-Gelelektrophorese
  
• Immunhistochemie
  
• FACS-Analysen
  
• FRET-basiertes cAMP-Imaging (an Einzelzellen)
  
• Calcium-Imaging (an Einzelzellen)
  
• Enzymaktivitätsassays (COX, mPGES, PLA, SPT, CerS, DEGS)
  
• Proliferations-/Apoptoseassays
  
• Promotor-Reportergenassays
  
• Primärkultur (Neuronen, Glia)
  
• Transfektionen mit siRNA in vitro (knockdown- und Überexpressions-studien)

Tierexperimentelle Methoden:

• Nozizeptive Verhaltenstests: Formalintest, Hot-Plate-Test, inflammatorische Hyperalgesie, Pfotenödem (Plethysmometer)
  
• In vivo-Modelle zur Untersuchung von peripheren Nervenläsionen, Neuropathie, Entzündungs- und Knochenkrebsschmerzen
  
• Funktionelles Knockdown mittels siRNA
  
• Implantation intrathekaler Katheter zur direkten Applikation von Prüfsubstanzen in das Lumbalmark
  
• Implantation osmotischer Minipumpen zur kontinuierlichen Applikation von Prüfsubstanzen
  
• Stoffwechselanalyse (insbesondere Nierenfunktion)

Humane experimentelle Schmerzmodelle:

• Chemisch induzierter Schmerz: CO₂-Stimulation mit evozierten kortikalen Potenzialen und funktioneller Magnetresonanztomographie (fMRT)
  
• Kälte-Menthol-Modell
  
• Chemisch-thermisch induzierter Schmerz: Hitze-Capsaicin-Modell
  
• Entzündlicher Schmerz: „Freeze Lesion“, tonisch-nasaler Schmerz
  
• Elektrisch induzierter Schmerz: Sinuskurven-Modell
  
• Mechanisch induzierter Schmerz: stumpfer Druck, punktierter Schmerz
  
• Bewegungsinduzierter Muskelschmerz: DOMS-Modell

Sonstige Methoden:

• Mikrodialyse zur Bestimmung von Arzneistoffkonzentrationen in peripheren Geweben
  
• Pharmakokinetische Berechnungen, Pharmakokinetisch-pharmakodynamisches Modelling
  

>

Mitarbeiter

• Prof. Dr. Sebastian Harder (Klinische Studien, Thrombozytenfunktion und Hämostase)
  
• Prof. Dr. Irmgard Tegeder (Molekulare und tierexperimentelle Schmerzforschung)
  
• Prof Dr. Jörn Lötsch (Klinische Studien, pharmakokinetisch-pharmakodynamisches Modelling, Pharmakogenetik, fMRI)
  
• Prof. Dr. Rolf Nüsing (Pharmakologie der Prostanoide, Nephrologie)
  
• PD Dr. Sabine Grösch (Zellbiologie, antikarzinogene Wirkungen von Analgetika)
  
• PD Dr. Ellen Niederberger (Molekularbiologie, neue Targets für die Schmerztherapie)
  
• Dr. Helmut Schmidt (Analytik, LC-MS/MS)
  
• PD Dr. Klaus Scholich (Molekularbiologie, neue Targets für die Schmerztherapie)
  
• Dr. Dr. Achim Schmidtko (Molekulare und tierexperimentelle Schmerzforschung, neue Targets für die Schmerztherapie)
  
• Dr. Christian Brenneis (Calcium- und cAMP-Imaging, Molekularbiologie, neue Targets für die Schmerztherapie)
  
  

>

Publikationen

• Coste O, Brenneis C, Linke B, Pierre S, Maeurer C, Becker W, Schmidt H, Gao W, Geisslinger G, Scholich K: Sphingosine-1-phosphate modulates spinal nociceptive processing. J Biol Chem 2008; Epub ahead of print.
  
• Degousee N, Fazel S, Angoulvant D, Stefanski E, Pawelzik SC, Korotkova M, Arab S, Liu P, Lindsay TF, Zhuo S, Butany J, Li RK, Audoly L, Schmidt R, Angioni C, Geisslinger G, Jakobsson PJ, Rubin BB. Microsomal prostaglandin E2 synthase-1 deletion leads to adverse left ventricular remodeling after myocardial infarction. Circulation 2008; 117:1701-1710.
  
• Oertel BG, Preibisch C, Wallenhorst T, Hummel T, Geisslinger G, Lanfermann H, Lötsch J. Differential opioid action on sensory and affective cerebral pain processing. Clin Pharmacol Ther 2008; 83:577-588.
  
• Brenneis C, Coste O, Schmidt R, Angioni C, Popp L, Nüsing RM, Becker W, Scholich K, Geisslinger G. Consequences of altered eicosanoid patterns for nociceptive processing in mPGES-1-deficient mice. J Cell Mol Med 2008; 12:639-648.
  
• Oertel B, Lötsch J. Genetic mutations that prevent pain: implications for future pain medication. Pharmacogenomics 2008; 9:179-194.
  
• Coste O, Pierre S, Marian C, Brenneis C, Angioni C, Schmidt H, Popp L, Geisslinger G, Scholich K. Antinociceptive activity of the S1P-receptor agonist FTY720. J Cell Mol Med 2008; 12:995-1004.
  
• Tegeder I, Adolph J, Schmidt H, Woolf CJ, Geisslinger G, Lötsch J. Reduced hyperalgesia in homozygous carriers of a GTP cyclohydrolase 1 haplotype. Eur J Pain 2008; Mar 26.
  
• Niederberger E, Geisslinger G. Proteomics in neuropathic pain research. Anesthesiology 2008; 108:314-323.
  
• Schmidtko A, Gao W, Sausbier M, Rauhmeier I, Sausbier U, Niederberger E, Scholich K, Huber A, Neuhuber W, Allescher HD, Hofmann F, Tegeder I, Ruth P, Geisslinger G. Cysteine-rich protein 2, a novel downstream effector of cGMP/cGMP-dependent protein kinase I-mediated persistent inflammatory pain. J Neurosci 2008; 28:1320-1330.
  
• Graff J, von Hentig N, Kuczka K, Angioni C, Gute P, Klauke S, Babacan E, Harder S. Significant effects of tipranavir on platelet aggregation and thromboxane B2 formation in vitro and in vivo. J Antimicrob Chemother 2008; 61:394-399.
  
• Neddermeyer TJ, Flühr K, Lötsch J. Principle components analysis of pain thresholds to thermal, electrical, and mechanical stimuli suggests a predominant common source of variance. Pain 2008; Feb 1.
  
• Lötsch J, Reichmann H, Hummel T. Different odor tests contribute differently to the evaluation of olfactory loss. Chem Senses 2008; 33:17-21.
  
• Niederberger E, Schmidtko A, Gao W, Kühlein H, Ehnert C, Geisslinger G. Impaired acute and inflammatory nociception in mice lacking the p50 subunit of NF-kappaB. Eur J Pharmacol 2007; 559:55-60.
  
• Graff J, Skarke C, Klinkhardt U, Watzer B, Harder S, Seyberth H, Geisslinger G, Nüsing RM. Effects of selective COX-2 inhibition on prostanoids and platelet physiology in young healthy volunteers. J Thromb Haemost 2007; 5:2376-2385.
  
• Graff J, Arabmotlagh M, Cheung R, Geisslinger G, Harder S. Effects of parecoxib and dipyrone on platelet aggregation in patients undergoing meniscectomy: a double-blind, randomized, parallel-group study. Clin Ther 2007; 29:438-447.
  
• Graff J, von Hentig N, Misselwitz F, Kubitza D, Becka M, Breddin HK, Harder S. Effects of the oral, direct factor xa inhibitor rivaroxaban on platelet-induced thrombin generation and prothrombinase activity. J Clin Pharmacol 2007; 47:1398-1407.
  
• Nüsing RM, Schweer H, Fleming I, Zeldin DC, Wegmann M. Epoxyeicosatrienoic acids affect electrolyte transport in renal tubular epithelial cells: dependence on cyclooxygenase and cell polarity. Am J Physiol Renal Physiol 2007; 293:F288-298.
  
• Lötsch J, Geisslinger G. Current evidence for a modulation of nociception by human genetic polymorphisms. Pain 2007; 132:18-22.
  
• von Hentig N. Lopinavir/ritonavir: appraisal of its use in HIV therapy. Drugs Today (Barc) 2007; 43:221-247.
  
• Schuligoi R, Schmidt R, Geisslinger G, Kollroser M, Peskar BA, Heinemann A. PGD2 metabolism in plasma: kinetics and relationship with bioactivity on DP1 and CRTH2 receptors. Biochem Pharmacol 2007; 74:107-117.
  
• Lötsch J, Belfer I, Kirchhof A, Mishra BK, Max MB, Doehring A, Costigan M, Woolf CJ, Geisslinger G, Tegeder I. Reliable screening for a pain-protective haplotype in the GTP cyclohydrolase 1 gene (GCH1) through the use of 3 or fewer single nucleotide polymorphisms. Clin Chem 2007; 53:1010-1015
  
• Pierre SC, Schmidt R, Brenneis C, Michaelis M, Geisslinger G, Scholich K. Inhibition of cyclooxygenases by dipyrone. Br J Pharmacol 2007; 151:494-503.
  
• von Hentig N, Müller A, Rottmann C, Wolf T, Lutz T, Klauke S, Kurowski M, Oertel B, Dauer B, Harder S, Staszewski S. Pharmacokinetics of saquinavir, atazanavir, and ritonavir in a twice-daily boosted double-protease inhibitor regimen. Antimicrob Agents Chemother 2007; 51:1431-1439.
  
• Metzner J, Popp L, Marian C, Schmidt R, Manderscheid C, Renne C, Fisslthaler B, Fleming I, Busse R, Geisslinger G, Niederberger E. The effects of COX-2 selective and non-selective NSAIDs on the initiation and progression of atherosclerosis in ApoE-/- mice. J Mol Med 2007; 85:623-633.
  
• Daniel C, Sartory N, Zahn N, Geisslinger G, Radeke HH, Stein JM. FTY720 ameliorates Th1-mediated colitis in mice by directly affecting the functional activity of CD4+CD25+ regulatory T cells. J Immunol 2007; 178:2458-68.
  
• Schmidtko A, Burian M, Altis K, Hardt K, Angioni C, Schmidt R, Podda M, Geisslinger G. Pharmacological and histopathological characterization of a hyperalgesia model induced by freeze lesion. Pain 2007; 127:287-295.
  
• Oertel BG, Schneider A, Rohrbacher M, Schmidt H, Tegeder I, Geisslinger G, Lötsch J. The partial 5-hydroxytryptamine1A receptor agonist buspirone does not antagonize morphine-induced respiratory depression in humans. Clin Pharmacol Ther 2007; 81:59-68.
  
• Lötsch J, Skarke C, Schmidt H, Rohrbacher M, Hofmann U, Schwab M and Geisslinger G. Evidence for morphine-independent central nervous opioid effects after administration of codeine: contribution of other codeine metabolites. Clin Pharmacol Ther 2006; 79:35-48.
  
• Lötsch J, Skarke C, Wieting J, Oertel B, Schmidt H, Brockmöller J and Geisslinger G. Modulation of the central nervous effects of levomethadone by genetic polymorphisms potentially affecting its metabolism, distribution, and drug action. Clin Pharmacol Ther 2006; 79:72-89.
  
• Lötsch J and Geisslinger G. Relevance of frequent mu-opioid receptor polymorphisms for opioid activity in healthy volunteers. Pharmacogenomics J 2006; 6:200-210.
  
• Loibl S, von Minckwitz G, Gwyn K, Ellis P, Blohmer JU, Schlegelberger B, Keller M, Harder S, Theriault RL, Crivellari D, Klingebiel T, Louwen F, Kaufmann M. Breast carcinoma during pregnancy. Cancer 2006; 106:237-246.
  
• Lötsch J and Geisslinger G. Current evidence for a genetic modulation of the response to analgesics. Pain 2006; 121:1-5.
  
• Brenneis B, Maier T, Schmidt R, Hofacker A, Zulauf L, Jakobsson PJ, Scholich K, and Geisslinger G. Inhibition of prostaglandin E2 synthesis by SC-560 is independent of cyclo-oxygenase 1 inhibition FASEB J 2006; 20:1352-1360.
  
• Oertel BG, Schmidt R, Schneider A, Geisslinger G, and Lötsch J. The mu-opioid receptor gene polymorphism 118A>G depletes alfentanil induced analgesia and protects against respiratory depression in homozygous carriers. Pharmacogenet Genomics 2006; 16:625-636.
  
• Tegeder I and Geisslinger G. Cardiovascular risk with cyclooxygenase inhibitors: general problem with substance specific differences? Naunyn Schmiedebergs Arch Pharmacol 2006; 373:1-17.
  
• Schaible HG, Schmelz M and Tegeder I. Pathophysiology and treatment of pain in joint disease. Adv. Drug Del. Rev 2006; 58:323-342.
  
• Lötsch J and Geisslinger G. Misestimating the role of an active metabolite when modeling the effects after administration of the parent compound only. Clin Pharmacol Ther 2006; 80:95-97.
  
• Grösch S, Maier TJ, Schiffmann S, and Geisslinger G. COX-2-independent anticarcinogenic effects of selective COX-2 inhibitors. Journal of the National Cancer Institute 2006; 98:736-747.
  
• Schmidt R, Bremerich DH, and Geisslinger G. High sensitive determination of sufentanil in human plasma of parturients and neonates following patient-controlled epidural analgesia (PCEA). J Chromatogr B 2006; 836:98-107.
  
• Scholich K, Geisslinger G. Is mPGES-1 a promising target for pain therapy? Trends Pharmacol Sci. 2006; 27:399-401.
  
• Weigert A, Johann AM, von Knethen A, Schmidt H, Geisslinger G, and Brüne B. Apoptotic cells promote macrophage survival by releasing the anti-apoptotic mediator sphingosine-1-phosphate. Blood 2006; 108:1635-1642.
  
• Skarke C, Reus M, Schmidt R, Grundei I, Schuss P, Geisslinger G and Lötsch J. The cyclooxygenase-2 genetic variant -765G>C does not modulate the effects of celecoxib on prostaglandin E2 production. Clin Pharmacol Ther 2006; 80:621-632.
  
• Lötsch J, Dudziak R, Freynhagen R, Marschner J, and Geisslinger G. Fatal respiratory depression after multiple intravenous morphine injections. Clinical Pharmacokinetics 2006; 45:1051-1060.
  
• Tegeder I, Costigan M, Griffin RS, Abele A, Belfer I, Schmidt H, Ehnert C, Nejim J, Marian C, Scholz J, Wu T, Allchorne A, Diatchenko L, Binshtok AM, Goldman D, Adolph J, Sama S, Atlas SJ, Carlezon WA, Parsegian A,Lötsch J, Fillingim RB, Maixner W, Geisslinger G, Max MB and Woolf CJ. GTP-cyclohydrolase, the rate-limiting enzyme in tetrahydrobiopterin biosynthesis, regulates pain sensitivity and persistence. Nat Med 2006; 12:1269-1277.
  
• Lötsch J and Geisslinger G. Are mu-opioid receptor polymorphisms important for clinical opioid therapy? Trends Mol Med 2005; 11:82-89.
  
• Burian M, Geisslinger G. COX-dependent mechanisms involved in the antinociceptive action of NSAIDs at central and peripheral sites. Pharmacol Ther 2005; 107:139-154.
  
• Maier T, Janssen A, Schmidt R, Geisslinger G, and Grösch S. Targeting the beta-catenin/APC pathway: a novel mechanism to explain the cyclooxygenase-2-independent anticarcinogenic effects of celecoxib in human colon carcinoma cells. Faseb J 2005; 19:1353-1355.
  
• Schmidtko A, Del Turco D, Coste O, Ehnert C, Niederberger E, Ruth P, Deller T, Geisslinger G, Tegeder I. Essential role of the synaptic vesicle protein synapsin II in formalin-induced hyperalgesia and glutamate release in the spinal cord. Pain 2005; 115:171-181.
  
• Lötsch J, Skarke C, Schneider A, Hummel T, and Geisslinger G. The 5 HT4 receptor agonist mosapride does not antagonize morphine-induced respiratory depression. Clin Pharmacol Ther 2005; 78:278-287.
  
• Skarke C, Geisslinger G, Lötsch J. Is Morphine-3-Glucuronide of Therapeutic Relevance? Pain 2005; 116:177-180.
  
• Nüsing RM, Treude A, Weissenberger C, Jensen B, Bek M, Wagner C, Narumiya S, Seyberth HW. Dominant role of prostaglandin E2 EP4 receptor in furosemide-induced salt-losing tubulopathy: A model for Hyperprostaglandin E Syndrome/Antenatal Bartter Syndrome. J Am Soc Nephrol 2005; 16:2354-2362.
  
• Graff J, Harder S, Wahl O, Scheuermann EH, Gossmann J. Anti-inflammatory effects of clopidogrel intake in renal transplant patients: effects on platelet-leukocyte interactions, platelet CD40 ligand expression and pro-inflammatory biomarkers. Clin Pharmacol Ther 2005; 78:468-476.
  
• Hofacker A, Coste O, Nguyen H, Marian C, Scholich K, Geisslinger G. Downregulation of the cytosolic prostaglandin E2 synthase results in decreased nociceptive behavior in rats. J Neurosci 2005; 25:9005-9009.
  
• Tegeder I and Geisslinger G. Opioids as modulators of cell death and survival – unraveling mechanisms and revealing new indications. Pharmacological Reviews 2004; 56:351-369.
  
• Kunz S, Niederberger E, Ehnert C, Coste O, Pfenninger A, Kruip J, Wendrich TM, Schmidtko A, Tegeder I, Geisslinger G. The calpain inhibitor MDL 28170 prevents inflammation-induced neurofilament light chain (NFL) breakdown in the spinal cord and reduces thermal hyperalgesia. Pain 2004; 110:409-418.
  
• Pierre SC, Hausler J, Birod K, Geisslinger G, Scholich K. PAM mediates sustained inhibition of cAMP signaling by sphingosine-1-phosphate. EMBO J 2004; 23:3031-3040.
  
• Tegeder I, Del Turco D, Schmidtko A, Sausbier M, Feil R, Hofmann F, Deller T, Ruth P, and Geisslinger G. Reduced inflammatory hyperalgesia with preservation of acute thermal nociception in mice lacking cGMP-dependent protein kinase-I. PNAS 2004; 101:3253-3257.
  
• Tegeder I, Niederberger E, Schmidt R, Kunz S, Gühring H, Ritzeler O, Michaelis M, Geisslinger G. Specific inhibition of I-kappaB kinase (IKK) reduces hyperalgesia in inflammatory and neuropathic pain models in rats. J Neurosci 2004; 24:1637-1645.
  
• Burian M, Tegeder I, Seegel M, and Geisslinger G. Peripheral and central antihyperalgesic effects of diclofenac in a model of human inflammatory pain. Clin Pharmacol Ther 2003; 74:113-120.
  
• Grösch S, Tegeder I, Schilling K, Maier T, Niederberger E, Geisslinger G. Activation of c-Jun-N-terminal-kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers. FASEB J 2003; 17:1316-1318.
  
• Tegeder I, Grösch S, Schmidtko A, Häussler A, Schmidt H, Niederberger E, Scholich K, Geisslinger G. G-protein independent G1-cell cycle block and apoptosis with morphine in adenocarcinoma cells – involvement of p53 phosphorylation. Cancer Res 2003; 63:1846-1852.
  
• Tegeder I, Meier S, Burian M, Schmidt H, Geisslinger G, Lötsch J. Peripheral opioid analgesia in experimental human pain models. Brain 2003; 126:1092-1102.
  
• Niederberger E, Schmidtko A, Rothstein JD, Geisslinger G, Tegeder I. Modulation of spinal nociceptive processing through the glutamate transporter GLT-1. Neuroscience 2003; 116:81-87.
  
• Skarke C, Darimont J, Schmidt H, Geisslinger G, Lötsch J. Analgesic effects of morphine and morphine-6-glucuronide in a transcutaneous electrical pain model in healthy volunteers. Clin Pharmacol Ther 2003; 73:107-121.
  
• Klinkhardt U, Adams J, Graff J, Bauersachs R, Lindhoff-Last E, Harder S. Clopidogrel, but not Aspirin reduces formation of platelet-leukocyte conjugates and P-selectin ex-pression in patients with peripheral vascular disease. Clin Pharmacol Ther 2003; 73:232-241.
  
• Lötsch J, Skarke C, Grösch S, Darimont J, Schmidt H, Geisslinger G. The polymorphism A118G of the human mu-opioid receptor gene decreases the clinical activity of morphine-6-glucuronide but not that of morphine. Pharmacogenetics 2002; 12:3-9.
  
• Niederberger E, Tegeder I, Vetter G, Schmidtko A, Schmidt H, Euchenhofer C, Bräutigam L, Grösch S, Geisslinger G. Celecoxib loses its anti-inflammatory efficacy at high doses through activation of NF-kappaB. FASEB J 2001; 15:1622-1624.