AG Ulrich-Merzenich

Synergy Research and Experimental Medicine

Drug combination treatments have met for a considerable time with apprehensions regarding potentially negative interactions and the possible potentiation of adverse events. Today they are routinely applied in an increasing number of disciplines in medicine, particularly in oncology and rheumatology. Here, drug combinations and complex treatment regimes often achieve better results than single drug treatments. We could show that a combinatory treatment approach can cure the rare autoimmune disease Acquired Hemophilia [4]. But also phytopharmaceuticals can be considered a natural „model“ for combinatory treatments. These multi-component mixtures are often effective only in specific compositions and represent combined actions of single substances.

Our work group focuses on the assessment and determination of synergistic effects in combinatory treatments with an emphasis on combinations of drugs/small molecules/plant constituents with biologicals. Synergy means primarily an over-additive effect of two or more drugs or substances administered in combination. We undertake systematic screening of drug combinations and investigate combinatory treatments for synergistic effects based on different pharmacological definitions of „synergy“ with an emphasis on the combination index based on the combination index theorem of Chou and Talalay that has been derived from the median-effect equation and the mass-action law [17].

In the context of this research PD Dr. Gudrun Ulrich-Merzenich founded the Journal “Synergy” as the international platform for the dissemination, exchange and discourse of innovative research on the systematic development of combination therapies based on synergistic effects and the quantification of synergistic and/or antagonistic modes of action.

We investigate the molecular mechanisms how synergistic effects are brought about in the cell/ in patients by a system biology approach. We apply the “omic” technologies (transcriptomics, proteomics, metabolomics) with a special emphasis on immune modulation.

We screen with high throughput equipment, use different cell line panels and primary cells of healthy donors/patients (mainly immune competent cells) and assess the predictive value of these screening results for the development of a personalised medicine. Schork (Nature 2015,520:609-611) published an analysis documenting that the 10 highest-grossing drugs in the USA are only effective in one out of four to one out of 24 patients. It calls for clinical studies that do not focus on the statistical average response of patients to drugs, but on the individual response to a therapy. With our methodic approach we offer an option to integrate complex combinatory screening into clinical routine.

Our synergy research also covers assay and method development for the discovery and validation of synergistic drug interactions, including the dedicated application and development of suitable dispensing and liquid handling equipment as well as suitable laboratory automation.

Selected Projects:

• Vergleichende Untersuchungen der Lymphozytenpopulationen bei der erworbenen und der idiopathischen Hämophilie während der Immuntoleranzinduktion im Vergleich mit diversen schweren therapie-refraktären Autoimmunerkrankungen unter extrakorporaler Therapie (Novo Nordisk, Mainz, Germany) (gemeinsam mit Frau PD Dr. Zeitler)

• Genchipanalysen für Phytopharmaka I – VII
  Firma Steigerwald Arzneimittelwerk GmbH ,Darmstadt, Deutschland

• Gesamtprojekt: Identifizierung von Arzneipflanzen und pflanzlichen Stoffen – valide Referenzdaten und systembiologische Datenauswertung (Kennziffer: LZ 121.03/V/11788) (Prof. Knöss, BfArM, Prof. König, Universität Bonn) Teilprojekt „Genexpressionsanalysen“ ; BfArM

• Endocannabinoide in der Tumorbehandlung (Untersuchungen zur Signaltransduktion; Synergie-Screening) (DAAD, Bonfor, Karl und Veronika Carstens Stiftung, Essen, Deutschland,Dr. Ramy Ammar)

• Überprüfung der Dispensierfähigkeit ausgewählter Substanzen mit dem CERTUS FLEX8 Dispenser

• Omalizumab: in vitro/ex vivo investigations of its anti-inflammatory efficacy in Severe Asthma [Novartis Pharma GmbH] (gemeinsam mit Prof. Dr. Uwe Juergens)

Selected Publications

1. Ulrich-Merzenich G, Bhonde RR. Donor site, age, and health affect fibroblast growth in culture. In Vitro Cell Dev Biol Anim 1995 (7): 494-6.

2. Ulrich-Merzenich G, Kraft K, Singh LM. Rheumatic diseases in Ayurveda: a historical perspective. Arthritis Rheum 1999; 42(7):15553-5.

3. Ulrich-Merzenich G, Metzner C, Schiermeyer B, Vetter H. Vitamin C and vitamin E antagonistically modulate human vascular endothelial and smooth muscle cell DNA synthesis and proliferation. Eur J Nutr 2002; 41(1): 27-34.

4. Zeitler H*, Ulrich-Merzenich G*, Hess l, Konsek E, Unkrig C, Walger P, Vetter H, Brackmann HH. Treatment of acquired hemophilia by the Bonn-Malmo Protocoll: documentation of an in vivo modulating concept. Blood 2005;15:105(6):2287-93. (*both authors have contributed equally)

5. Ulrich-Merzenich G, Zeitler H, Jobst D, Panek D, Vetter H.Application of the „Omic“-technologies in phytomedicine. 2007;14(1):70-82. Reprint with permission: Journal for Natural Remedies 2007; 7:1-18, Revista de Fitoterapia 2007;7(2):115-129 (Applicación de las tecnologias ómicas a la Fitoterapia , in spanischer Sprache

6. Seidel M, Fiebich BL, Ulrich-Merzenich G, Candelario-Jalil E, Koch FW, Vetter H. Seretonin mediates PGE2 overexpression through 5-HT2A and 5-HT3 receptor subtypes in serum-free tissue culture of macrophage like synovial cells. Rheumatol Int 2008(10):1354-6.

7. Wagner H, Ulrich-Merzenich G. Synergy research: Approaching a new generation of phytopharmaceuticals. Phytomedicine 2009, 16(2-3): 97-110. Reprint with permission: Journal for Natural Remedies 2009, 9(2):121-141.) This paper has been quoted so far 437 times (Scopus).

8. Ulrich-Merzenich G, Zeitler H, Panek D, Wagner H, Vetter H. New perspectives for with the „omic“-technologies. Phytomedicine 2009;16(6-7):495-508

9. Müller N, Ellinger S, Alteheld B, Ulrich-Merzenich G, Berthold H, Vetter H, Stehle P. Bolus ingestions of white and green tea stabilizes plasma antioxidant capacity, but does not affect markers of oxidative stress in healthy adults. Mol Nutr Food Res. 2010; 54(11):1636-19.
10. Ulrich-Merzenich G, Koptina A, Kelber O, Freischmidt A, Heilmann J, Müller J, Sadeghlar F, Zeitler H, Wagner H. Gene expression profiles obtained in vivo for the prediction of adverse events exemplified for salicylate containing phytopharmaceuticals and the tricyclic antidepressant Imipramine. Phytomedicine 2012,19(3-4):322-9.Epub 2011Nov25.

11. Flower A, Witt C, Liu JP, Ulrich-Merzenich G, Muir K, Yu H, Prude M, Lewith G. GP-TCM Guidelines for randomized controlled trials investigating Chinese herbal medicine (CHM).(Excecutive Summary) J Ethnopharmacol 2012, 140(3):550-4.

12. Zeitler H, Goldmann G, Marquardt N, Ulrich-Merzenich G. Long term outcome of patients with acquired haemophilia. A monocentre interim analysis of 82 patients. Atherosclerosis Suppl 2013;14:223-228.

13. Orland A, Knapp K, König GM, Ulrich-Merzenich G, Knöss W. Combining Metabolomic Analysis and Microarray Gene Expression Analysis in the Characterization of the Medicinal Plant Chelidonii majus Phytomedicine 2014 .

14. Zacharski DM, Brandt S, Esch S, König S, Mormann M, Ulrich-Merzenich G, Hensel A. Xyloglucan from Tropaeolum majus Seeds Induces Cellular Differentiation of Human Keratinocytes by Inhibition of EGFR Phosphorylation and Decreased Activity of Transcription Factor CREB. Biomacromolecules. 2015 Jul 13;16(7):2157-67.

15. Ulrich-Merzenich GS. Combination screening of synthetic drugs and plant derived natural products – potential and challenges for drug development. Synergy 2014; 1(1): 2014: 59-69.

16. Abdel-Aziz H, Schneider M, Neuhuber W, Kassem AM, Khailah S, Müller J, Eldeen HG, Khairy A, Khayyal MT, Shcherbakova A, Efferth T, Ulrich-Merzenich G. GPR84 and TREM-1 signaling contribute to the pathogenesis of reflux esophagitis. Mol Med 2015; 21:1011-1024.  
17. Fu J, Zhang N, Chou JH, Dong HJ, Lin SF, Ulrich-Merzenich G, Chou TC. Drug combination in vivo using combination index method: Taxotere and T607 against colon carcinoma HCT-116 xenograft tumor in nude mice. Synergy 2016; 3 (3): 15-30.

Contact Information

AG Synergy Research and Experimental Medicine
PD Dr. rer. nat. Gudrun Ulrich-Merzenich

Phone (+49) (0)228 287 16288
Fax (+49) (0)228 287 13630
Mobile (+49) (0)151 7274718
Email gudrun.ulrich-merzenich@ukbonn.de

Universitätsklinikum Bonn
Medizinische Klinik III
AG Synergieforschung und Experimentelle Medizin
Gebäude 26, Labore UG 65/69
Venusberg-Campus 1
53127 Bonn

University Clinic Centre Bonn
Medical Clinic III
AG Synergy Research and Experimental Medicine
Building 26, Laboratories UG 65/69
Venusberg-Campus 1
D-53127 Bonn / Germany

More information about PD Dr. Gudrun Ulrich-Merzenich:
CV of PD Dr. Gudrun Ulrich-Merzenich and full list of publications