Botanical drugs, synergy, and network pharmacology: Forth and back to intelligent mixtures

Planta Medica

Volumn 77, Issue 11, 2011, Pages 1086-1098

  Gertsch, Jürg ^a  

^a UNIVERSITY OF BERN   (Switzerland)

Author keywords

drug discovery; evolution; herbal medicine; mixtures; network pharmacology; pharmacodynamics; phytotherapy; polypharmacology; synergism; synergy

Indexed keywords

ANTINEOPLASTIC AGENT; ARTEMISININ; CHINESE DRUG; CLAVULANIC ACID; CURARE; CURCUMIN; CURCUMINOID; GALLOCATECHIN; IBEROGAST; PENICILLIN G; PHY 906; PIPERINE; PLANT MEDICINAL PRODUCT; POLYPHENOL DERIVATIVE; RESIN; SINUPRET; TARIQUIDAR; TERPENE; TRYPTAMINE; UNCLASSIFIED DRUG; ZE 185; ZOSUQUIDAR;

AYURVEDA; BIOENGINEERING; CHINESE MEDICINE; DRUG ACTIVITY; DRUG BIOAVAILABILITY; DRUG EFFECT; DRUG EFFICACY; DRUG ISOLATION; DRUG METABOLISM; DRUG MIXTURE; DRUG POTENTIATION; DRUG RESEARCH; DRUG SAFETY; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TOLERABILITY; HUMAN; LOGANIACEAE; MALARIA; NETWORK PHARMACOLOGY; NONHUMAN; PHARMACODYNAMICS; PHYTOTHERAPY; REVIEW; STRYCHNOS; TRADITIONAL MEDICINE;

DRUG DISCOVERY; DRUG SYNERGISM; METABOLIC NETWORKS AND PATHWAYS; PHARMACOGNOSY; PHYTOTHERAPY; PLANT PREPARATIONS; PLANTS, MEDICINAL;

EID: 79960814507     PISSN: 00320943     EISSN: 14390221     Source Type: Journal    
DOI: 10.1055/s-0030-1270904     Document Type: Review

References (173)

1. Hopkins A L. Network pharmacology. Nat Biotechnol 2007 25 1110-1111 (Pubitemid 47538107)
2. Hopkins A L. Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol 2008 4 682-690
3. Altmann K H., Gertsch J. Anticancer drugs from naturenatural products as a unique source of new microtubule-stabilizing agents. Nat Prod Rep 2007 24 327-357 (Pubitemid 46504987)
4. Gertsch J, Meier S, Tschopp N, Altmann K H. New tubulin inhibitors from plants: A critical assessment. Chimia 2007 61 368-372
5. +)-activated ATPase. A biochemical link to digitalis-induced inotropy. Pharmacol Rev 1984 36 143-163 (Pubitemid 14014255)
6. Prassas I, Diamandis E P. Novel therapeutic applications of cardiac glycosides. Nat Rev Drug Discov 2008 7 926-935
7. Prevatt-Smith K M., Prisinzano T E. New therapeutic potential for psychoactive natural products. Nat Prod Rep 2010 27 23-31
8. Fozzard H A., Lipkind G M. The tetrodotoxin binding site is within the outer vestibule of the sodium channel. Mar Drugs 2010 8 219-234
9. Nicolai E A. Rezepte und Kurarten mit theoretisch-praktischen Anmerkungen, von D. Ernst Anton Nicolai, Hofrath und Professor zu Jena, Vol. 4. Jena Cröker 1788 567
10. Mann R D. From mithridatium to modern medicine: the management of drug safety. J R Soc Med 1988 81 725-728 (Pubitemid 19018258)
11. Catellani P, Console R. The rise and fall of mithridatium and theriac in pharmaceutical texts. Pharm Hist (Lond) 2007 37 2-9
12. Griffin J P. Venetian treacle and the foundation of medicines regulation. Br J Clin Pharmacol 2004 58 317-325 (Pubitemid 39213980)
13. Bosch F, Rosich L. The contributions of Paul Ehrlich to pharmacology: a tribute on the occasion of the centenary of his Nobel Prize. Pharmacology 2008 82 171-179
14. Triggle D J. Pharmacological receptors: a century of discovery and more. Pharm Acta Helv 2000 74 79-84 (Pubitemid 30182555)
15. Crews C M. Targeting the undruggable proteome: the small molecules of my dreams. Chem Biol 2010 17 551-555
16. Karczmar A G. The Otto Loewi Lecture. Loewi's discovery and the XXI century. Prog Brain Res 1996 109 1-27 (Pubitemid 27047070)
17. Hopkins A L., Mason J S., Overington J P. Can we rationally design promiscuous drugs? Curr Opin Struct Biol 2006 16 127-136 (Pubitemid 43221881)
18. Hunt J T. Discovery of ixabepilone. Mol Cancer Ther 2009 8 275-281
19. Möhler H. The rise of a new GABA pharmacology. Neuropharmacology
20. Sternbach L H. The benzodiazepine story. Prog Drug Res 1978 22 229-266
21. Andersson T, Weidolf L. Stereoselective disposition of proton pump inhibitors. Clin Drug Investig 2008 28 263-279 (Pubitemid 351521381)
22. Lurje G, Lenz H J. EGFR signaling and drug discovery. Oncology 2009 77 400-410
23. Morrow J K., Tian L, Zhang S. Molecular networks in drug discovery. Crit Rev Biomed Eng 2010 38 143-156
24. Chen B, Wild D, Guha R. PubChem as a source of polypharmacology. J Chem Inf Model 2009 49 2044-2055
25. Yang X, Huang Y, Crowson M, Li J, Maitland M L., Lussier Y A. Kinase inhibition-related adverse events predicted from in vitro kinome and clinical trial data. J Biomed Inform 2010 43 376-384
26. Knight Z A., Lin H, Shokat K M. Targeting the cancer kinome through polypharmacology. Nat Rev Cancer 2010 10 130-137
27. Merino A, Bronowska A K., Jackson D B., Cahill D J. Drug profiling: knowing where it hits. Drug Discov Today 2010 15 749-756
28. Brötz-Oesterhelt H, Brunner N A. How many modes of action should an antibiotic have? Curr Opin Pharmacol 2009 8 564-573
29. Kohanski M A., Dwyer D J., Collins J J. How antibiotics kill bacteria: from targets to networks. Nat Rev Microbiol 2010 8 423-435
30. Wagner H. Synergy research: approaching a new generation of phytopharmaceuticals. Fitoterapia 2011 82 34-37
31. Schmidt B M., Ribnicky D M., Lipsky P E., Raskin I. Revisiting the ancient concept of botanical therapeutics. Nat Chem Biol 2007 3 360-366 (Pubitemid 46956331)
32. Griffith F L. A medical papyrus from Egypt. Br Med J 1893 1 1172-1174
33. Goltz D. Mittelalterliche Pharmazie und Medizin: dargestellt an Geschichte und Inhalt des Antidotarium Nicolai: mit einem Nachdruck der Druckfassung von 1471. Stuttgart Wissenschaftliche Verlagsgesellschaft 1976 136
34. Qiu J. Traditional medicine: a culture in the balance. Nature 2007 448 126-128 (Pubitemid 47067352)
35. Kong D X., Li X J., Zhang H Y. Where is the hope for drug discovery? Let history tell the future. Drug Discov Today 2009 14 115-119
36. Touwaide A, Pollio A, Aliotta G, Piomelli D, De Santo N G. Medicinal plants for the treatment of urogenital tract pathologies according to Dioscorides' De Materia Medica. Am J Nephrol 1997 17 241-247 (Pubitemid 27246172)
37. Dowling H. Medicines for man. New York Knopf 1973
38. Shapiro A K. The placebo effect in the history of medical treatment: implications for psychiatry. Am J Psychiatry 1959 116 298-304
39. Patwardhan B, Vaidya D B., Chorghade M, Joshi S P. Reverse pharmacology and systems approaches for drug discovery and development. Curr Bioact Compd 2008 4 201-212
40. Leonti M, Casu L, Sanna F, Bonsignore L. A comparison of medicinal plant use in Sardinia and Sicily-De Materia Medica revisited? J Ethnopharmacol 2009 121 255-267
41. Thomas E, Vanderbroek I, Goetghebeur P. The relationship between plant use and plant diversity in the Bolivian Andes, with special reference to medicinal plant use. Hum Ecol 2008 36 861-879
42. Moerman D E. Symbols and selectivity: a statistical analysis of native American medical ethnobotany. J Ethnopharmacol 1979 1 111-119 (Pubitemid 10099460)
43. Moerman D E. An analysis of the food plants and drug plants of native North America. J Ethnopharmacol 1996 52 1-22 (Pubitemid 26134507)
44. De Vos P. European materia medica in historical texts: longevity of a tradition and implications for future use. J Ethnopharmacol 2010 132 28-47
45. Moerman D E., Jonas W B. Deconstructing the placebo effect and finding the meaning response. Ann Intern Med 2002 136 471-476 (Pubitemid 34233178)
46. Blanz M. [Placebos: aspects in medical history and approaches to definition]. Fortschr Neurol Psychiatr 1991 59 361-370
47. Howlett A C. Reverse pharmacology applied to the cannabinoid receptor. Trends Pharmacol Sci 1990 11 395-397 (Pubitemid 20344020)
48. Breinbauer R, Vetter I R., Waldmann H. From protein domains to drug candidates-natural products as guiding principles in the design and synthesis of compound libraries. Angew Chem Int Ed Engl 2002 41 2879-2890
49. Cragg G M., Newman D J., Snader K M. Natural products in drug discovery and development. J Nat Prod 1997 60 52-60 (Pubitemid 27052102)
50. La Clair J J. Natural product mode of action (MOA) studies: a link between natural and synthetic worlds. Nat Prod Rep 2010 27 969-995
51. Thornburg C C., Zabriskie T M., McPhail K L. Deep-sea hydrothermal vents: potential hot spots for natural products discovery? J Nat Prod 2010 73 489-499
52. Potterat O, Hamburger M. Drug discovery and development with plant-derived compounds. Prog Drug Res 2008 65 45-118
53. Etkin N L. Perspectives in ethnopharmacology: forging a closer link between bioscience and traditional empirical knowledge. J Ethnopharmacol 2001 76 177-182 (Pubitemid 32487625)
54. Adams M, Berset C, Kessler M, Hamburger M. Medicinal herbs for the treatment of rheumatic disordersa survey of European herbals from the 16th and 17th century. J Ethnopharmacol 2009 121 343-359
55. Verpoorte R, Crommelin D, Danhof M, Gilissen L J., Schuitmaker H, van der Greef J, Witkamp R F. Commentary: A systems view on the future of medicine: inspiration from Chinese medicine?. J Ethnopharmacol 2009 121 479-481
56. Sagen A L., Gertsch J, Becker R, Heilmann J, Sticher O. Quinolizidine alkaloids from the curare adjuvant Clathrotropis glaucophylla. Phytochemistry 2002 61 975-978 (Pubitemid 35447177)
57. Gratus C, Wilson S, Greenfield S M., Damery S L., Warmington S A., Grieve R, Steven N M., Routledge P. The use of herbal medicines by people with cancer: a qualitative study. BMC Complement Alternat Med 2009 9 14
58. Neldner K H. Complementary and alternative medicine. Dermatol Clin 2000 18 189-193 (Pubitemid 30013739)
59. World Health Organization. Traditional, complementary and alternative medicines and therapies. Washington DC WHO Regional Office for the Americas/Pan American Health Organization (Working group OPS/OMS) 1999
60. World Health Organization. Traditional medicine. Available at. http://www.who.int/mediacentre/factsheets/fs134/en/ Accessed January 15, 2010[nl]
61. Graziose R, Lila M A., Raskin I. Merging traditional Chinese medicine with modern drug discovery technologies to find novel drugs and functional foods. Curr Drug Discov Technol 2010 7 2-12
62. Eng C. Are herbal medicines ripe for the cancer clinic? Sci Transl Med 2010 2 45ps41
63. Lam W, Bussom S, Guan F, Jiang Z, Zhang W, Gullen E A., Liu S H., Cheng Y C. The four-herb Chinese medicine PHY906 reduces chemotherapy-induced gastrointestinal toxicity. Sci Transl Med 2010 2 45-59
64. Melzer J, Brignoli R, Diehm C, Reichling J, Do D D., Saller R. Treating intermittent claudication with Tibetan medicine Padma 28: does it work? Atherosclerosis 2006 189 39-46 (Pubitemid 44441295)
65. Melzer J, Schrader E, Brattström A, Schellenberg R, Saller R. Fixed herbal drug combination with and without butterbur (Ze 185) for the treatment of patients with somatoform disorders: randomized, placebo-controlled pharmaco-clinical trial. Phytother Res 2009 23 1303-1308
66. Rodd R. Snuff synergy: preparation, use and pharmacology of yopo and Banisteriopsis caapi among the Piaroa of southern Venezuela. J Psychoactive Drugs 2002 34 273-279 (Pubitemid 35204596)
67. Gable R S. Risk assessment of ritual use of oral dimethyltryptamine (DMT) and harmala alkaloids. Addiction 2007 102 24-34 (Pubitemid 46006468)
68. Nahrstedt A, Butterweck V. Lessons learned from herbal medicinal products: the example of St. John's Wort (perpendicular). J Nat Prod 2010 73 1015-1021
69. Ulrich-Merzenich G, Panek D, Zeitler H, Vetter H, Wagner H. Drug development from natural products: exploiting synergistic effects. Indian J Exp Biol 2010 48 208-219
70. Liu R H. Potential synergy of phytochemicals in cancer prevention: mechanism of action. J Nutr 2004 134 (Suppl.12) 3479S-3485S (Pubitemid 39587593)
71. Liao Z G., Liang X L., Zhu J Y., Zhao G W., Yang M, Wang G F., Jiang Q Y., Chen X L. Correlation between synergistic action of Radix Angelica dahurica extracts on analgesic effects of Corydalis alkaloid and plasma concentration of dl-THP. J Ethnopharmacol 2010 129 115-120
72. Wagner H. Synergy research: a new approach to evaluating the efficacy of herbal mono-drug extracts and their combinations. Nat Prod Commun 2009 4 303-304
73. Hellmann J K., Münter S, Wink M, Frischknecht F. Synergistic and additive effects of epigallocatechin gallate and digitonin on Plasmodium sporozoite survival and motility. PLoS One 2010 5 e8682
74. Wang L, Zhou G B., Liu P, Song J H., Liang Y, Yan X J., Xu F, Wang B S., Mao J H., Shen Z X., Chen S J., Chen Z. Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia. Proc Natl Acad Sci USA 2008 105 4826-4831 (Pubitemid 351753831)
75. Wang Y, Qin Q, Chen J, Kuang X, Xia J, Xie B, Wang F, Liang H, Qi Z. Synergistic effects of Isatis tinctoria L. and tacrolimus in the prevention of acute heart rejection in mice. Transpl Immunol 2009 22 5-11
76. Shi Q, Liu Z, Yang Y, Geng P, Zhu Y Y., Zhang Q, Bai F, Bai G. Identification of anti-asthmatic compounds in Pericarpium citri reticulatae and evaluation of their synergistic effects. Acta Pharmacol Sin 2009 30 567-575
77. Lin F M., Chen L R., Lin E H., Ke F C., Chen H Y., Tsai M J., Hsiao P W. Compounds from Wedelia chinensis synergistically suppress androgen activity and growth in prostate cancer cells. Carcinogenesis 2007 28 2521-2529
78. Ginsburg I, Sadovnik M, Sallon S, Milo-Goldzweig I, Mechoulam R, Breuer A, Gibbs D, Varani J, Roberts S, Cleator E, Singh N. 47PADMA-28, a traditional Tibetan herbal preparation inhibits the respiratory burst in human neutrophils, the killing of epithelial cells by mixtures of oxidants and pro-inflammatory agonists and peroxidation of lipids. Inflammopharmacology 1999 7 47-62 (Pubitemid 29274790)
79. Chicca A, Raduner S, Pellati F, Strompen T, Altmann K H., Schoop R, Gertsch J. Synergistic immunomopharmacological effects of N-alkylamides in Echinacea purpurea herbal extracts. Int Immunopharmacol 2009 9 850-858
80. HemaIswarya S, Doble M. Potential synergism of natural products in the treatment of cancer. Phytother Res 2006 20 239-249
81. Gathirwa J W., Rukunga G M., Mwitari P G., Mwikwabe N M., Kimani C W., Muthaura C N., Kiboi D M., Nyangacha R M., Omar S A. Traditional herbal antimalarial therapy in Kilifi District, Kenya. J Ethnopharmacol 2011 134 434-442
82. Fiebich B L., Knörle R, Appel K, Kammler T, Weiss G. Pharmacological studies in an herbal drug combination of St. John's Wort (Hypericum perforatum) and passion flower (Passiflora incarnata): In vitro and in vivo evidence of synergy between Hypericum and Passiflora in antidepressant pharmacological models. Fitoterapia 2011 82 474-480
83. Adams L S., Seeram N P., Hardy M L., Carpenter C, Heber D. Analysis of the interactions of botanical extract combinations against the viability of prostate cancer cell lines. Evid Based Complement Alternat Med 2006 3 117-124 (Pubitemid 43999659)
84. Berenbaum M C. What is synergy? Pharmacol Rev 1989 41 93-141
85. Hastings I. How artemisinin-containing combination therapies slow the spread of antimalarial drug resistance. Trends Parasitol 2011 27 67-72
86. Gatti A, Sabato E, Di Paolo A R., Mammucari M, Sabato A F. Oxycodone/paracetamol: a low-dose synergic combination useful in different types of pain. Clin Drug Investig 2010 30 3-14
87. MacPherson R D. The pharmacological basis of contemporary pain management. Pharmacol Ther 2000 88 163-185 (Pubitemid 32057138)
88. Bansal T, Akhtar N, Jaggi M, Khar R K., Talegaonkar S. Novel formulation approaches for optimising delivery of anticancer drugs based on P-glycoprotein modulation. Drug Discov Today 2009 14 1067-1074
89. Bebrone C, Lassaux P, Vercheval L, Sohier J S., Jehaes A, Sauvage E, Galleni M. Current challenges in antimicrobial chemotherapy: focus on beta-lactamase inhibition. Drugs 2010 70 651-679
90. Atal C K., Zutshi U, Rao P G. Scientific evidence on the role of Ayurvedic herbals on bioavailability of drugs. J Ethnopharmacol 1981 4 229-232 (Pubitemid 11014202)
91. Efferth T, Koch E. Complex interactions between phytochemicals. The multi-target therapeutic concept of phytotherapy. Curr Drug Targets 2011 12 122-132
92. Wang S P., Liu L, Wang L L., Jiang P, Zhang J Q., Zhang W D., Liu R H. Screening and analysis of the multiple absorbed bioactive components and metabolites in rat plasma after oral administration of Jitai tablets by high-performance liquid chromatography/diode-array detection coupled with electrospray ionization tandem mass spectrometry. Rapid Commun Mass Spectrom 2010 24 1641-1652
93. Atal C K., Dubey R K., Singh J. Biochemical basis of enhanced drug bioavailability by piperine: evidence that piperine is a potent inhibitor of drug metabolism. J Pharmacol Exp Ther 1985 232 258-262 (Pubitemid 15193683)
94. Anand P, Thomas S G., Kunnumakkara A B., Sundaram C, Harikumar K B., Sung B, Tharakan S T., Misra K, Priyadarsini I K., Rajasekharan K N., Aggarwal B B. Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature. Biochem Pharmacol 2008 76 1590-1611
95. Hu G, Baker S P. Trends in unintentional injury deaths, U.S., 1999-2005: age, gender, and racial/ethnic differences. Am J Prev Med 2009 37 188-194
96. Colalto C. Herbal interactions on absorption of drugs: Mechanisms of action and clinical risk assessment. Pharmacol Res 2010 62 207-227
97. Madabushi R, Frank B, Drewelow B, Derendorf H, Butterweck V. Hyperforin in St. John's wort drug interactions. Eur J Clin Pharmacol 2006 62 225-233 (Pubitemid 43357581)
98. Zhou S F., Xue C C., Yu X Q., Wang G. Metabolic activation of herbal and dietary constituents and its clinical and toxicological implications: an update. Curr Drug Metab 2007 8 526-553 (Pubitemid 47209094)
99. Zeng Z P., Jiang J G. Analysis of the adverse reactions induced by natural product-derived drugs. Br J Pharmacol 2010 159 1374-1391
100. Roeder E, Wiedenfeld H. Pyrrolizidine alkaloids in medicinal plants of Mongolia, Nepal and Tibet. Pharmazie 2009 64 699-716
101. Heinrich M, Chan J, Wanke S, Neinhuis C, Simmonds M S. Local uses of Aristolochia species and content of nephrotoxic aristolochic acid 1 and 2a global assessment based on bibliographic sources. J Ethnopharmacol 2009 125 108-144
102. Berenbaum M C. Synergy assessment with growth curves. J Infect Dis 1984 150 304
103. Berenbaum M C. Minor synergy and antagonism may be clinically important. J Antimicrob Chemother 1987 19 271-273 (Pubitemid 17019959)
104. Leão P N., Pereira A R., Liu W T., Ng J, Pevzner P A., Dorrestein P C., König G M., Vasconcelos V M., Gerwick W H. Synergistic allelochemicals from a freshwater cyanobacterium. Proc Natl Acad Sci USA 2010 107 11183-11188
105. Shiojiri K, Ozawa R, Kugimiya S, Uefune M, van Wijk M, Sabelis M W., Takabayashi J. Herbivore-specific, density-dependent induction of plant volatiles: honest or cry wolf signals? PLoS One 2010 5 e12161
106. Kessler A, Baldwin I T. Defensive function of herbivore-induced plant volatile emissions in nature. Science 2001 291 2141-2144 (Pubitemid 32224443)
107. Gertsch J, Tobler R T., Brun R, Sticher O, Heilmann J. Antifungal, antiprotozoal, cytotoxic and piscicidal properties of Justicidin B and a new arylnaphthalide lignan from Phyllanthus piscatorum. Planta Med 2003 69 420-424 (Pubitemid 36774181)
108. Corning P A. The synergism hypothesis: on the concept of synergy and it's role in the evolution of complex systems. J Soc Evol Syst 1998 21 133-172
109. McLean S, Duncan A J. Pharmacological perspectives on the detoxification of plant secondary metabolites: implications for ingestive behavior of herbivores. J Chem Ecol 2006 32 1213-1228 (Pubitemid 43892405)
110. Yang C S., Lambert J D., Sang S. Antioxidative and anti-carcinogenic activities of tea polyphenols. Arch Toxicol 2009 83 11-21
111. Zhang H Y., Chen L L., Li X J., Zhang J. Evolutionary inspirations for drug discovery. Trends Pharmacol Sci 2010 31 443-448
112. Firn R D., Jones C G. A Darwinian view of metabolism: molecular properties determine fitness. J Exp Bot 2009 60 719-726
113. Firn R D., Jones C G. Natural productsa simple model to explain chemical diversity. Nat Prod Rep 2003 20 382-391 (Pubitemid 37007962)
114. Ewers R M., Thorpe S, Didham R K. Synergistic interactions between edge and area effects in a heavily fragmented landscape. Ecology 2007 88 96-106 (Pubitemid 46596826)
115. Schoenian I, Spiteller M, Ghaste M, Wirth R, Herz H, Spiteller D. Chemical basis of the synergism and antagonism in microbial communities in the nests of leaf-cutting ants. Proc Natl Acad Sci USA [in press][nl]
116. Hu Y, Platzer E G., Bellier A, Aroian R V. Discovery of a highly synergistic anthelmintic combination that shows mutual hypersusceptibility. Proc Natl Acad Sci USA 2010 107 5955-5960
117. Firn R D., Jones C G. The evolution of secondary metabolism a unifying model. Mol Microbiol 2000 37 989-994
118. Cordell G A., Colvard M D. Some thoughts on the future of ethnopharmacology. J Ethnopharmacol 2005 100 5-14 (Pubitemid 41078736)
119. de Sá Alves F R., Barreiro E J., Fraga C A. From nature to drug discovery: the indole scaffold as a privileged structure. Mini Rev Med Chem 2009 9 782-793
120. Fischbach M A., Clardy J. One pathway, many products. Nat Chem Biol 2007 3 353-355 (Pubitemid 46956329)
121. Fischbach M A., Walsh C T., Clardy J. The evolution of gene collectives: How natural selection drives chemical innovation. Proc Natl Acad Sci USA 2008 105 4601-4608 (Pubitemid 351753784)
122. Gertsch J, Leonti M, Raduner S, Racz I, Chen J Z., Xie X Q., Altmann K H., Karsak M, Zimmer A. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci USA 2008 105 9099-9104
123. Moussaieff A, Mechoulam R. Boswellia resin: from religious ceremonies to medical uses; a review of in vitro, in vivo and clinical trials. J Pharm Pharmacol 2009 61 1281-1293
124. Perry N, Perry E. Aromatherapy in the management of psychiatric disorders: clinical and neuropharmacological perspectives. CNS Drugs 2006 20 257-280
125. Romics I, Siller G, Kohnen R, Mavrogenis S, Varga J, Holman E. A special terpene combination (Rowatinex) improves stone clearance after extracorporeal shockwave lithotripsy in urolithiasis patients: results of a placebo-controlled randomised controlled trial. Urol Int [in press][nl]
126. Kohlert C, van Rensen I, März R, Schindler G, Graefe E U., Veit M. Bioavailability and pharmacokinetics of natural volatile terpenes in animals and humans. Planta Med 2000 66 495-505 (Pubitemid 30626473)
127. Buckle J. Use of aromatherapy as a complementary treatment for chronic pain. Alternat Ther Health Med 1999 5 42-51
128. Wink M. Evolution of secondary metabolites from an ecological and molecular phylogenetic perspective. Phytochemistry 2003 64 3-19 (Pubitemid 37101790)
129. McFrederick Q S., Fuentes J D., Roulston T, Kathilankal J C., Lerdau M. Effects of air pollution on biogenic volatiles and ecological interactions. Oecologia 2009 160 411-420
130. Busch B, Hertweck C. Evolution of metabolic diversity in polyketide-derived pyrones: using the non-colinear aureothin assembly line as a model system. Phytochemistry 2009 70 1833-1840
131. Bode H B., Bethe B, Höfs R, Zeeck A. Big effects from small changes: possible ways to explore nature's chemical diversity. Chembiochem 2002 3 619-627 (Pubitemid 36004525)
132. Williamson E M. Synergy and other interactions in phytomedicines. Phytomedicine 2001 8 401-409 (Pubitemid 32983062)
133. Ulrich-Merzenich G, Panek D, Zeitler H, Wagner H, Vetter H. New perspectives for synergy research with the omic-technologies. Phytomedicine 2009 16 495-508
134. Tong A H. Y., Evangelista M, Parsons A B., Xu H, Bader G D., Pagé N, Robinson M, Raghibizadeh S, Hogue C W. V., Bussey H, Andrews B, Tyers M, Boone C. Systematic genetic analysis with ordered arrays of yeast deletion mutants. Science 2001 294 2364-2368 (Pubitemid 33140562)
135. Yeh P, Tschumi A I., Kishony R. Functional classification of drugs by properties of their pairwise interactions. Nat Genet 2006 38 489-494
136. Gertsch J, Viveros-Paredes J M., Taylor P. Plant immunostimulantsScientific paradigm or myth? J Ethnopharmacol
137. Ríos J L., Recio M C., Escandell J M., Andújar I. Inhibition of transcription factors by plant-derived compounds and their implications in inflammation and cancer. Curr Pharm Des 2009 15 1212-1237
138. Yeh P, Kishony R. Networks from drug-drug surfaces. Mol Syst Biol 2007 3 85
139. Fitzgerald J B., Schoeberl B, Nielsen U B., Sorger P K. Systems biology and combination therapy in the quest for clinical efficacy. Nat Chem Biol 2006 2 458-466 (Pubitemid 44266307)
140. Lehár J, Krueger A S., Avery W, Heilbut A M., Johansen L M., Price E R., Rickles R J., Short 3rd G F., Staunton J E., Jin X, Lee M S., Zimmermann G R., Borisy A A. Synergistic drug combinations tend to improve therapeutically relevant selectivity. Nat Biotechnol 2009 27 659-666
141. Rollinger J M., Schuster D, Danzl B, Schwaiger S, Markt P, Schmidtke M, Gertsch J, Raduner S, Wolber G, Langer T, Stuppner H. In silico target fishing for rationalized ligand discovery exemplified on constituents of Ruta graveolens. Planta Med 2009 75 195-204
142. Leonti M, Cabras S, Weckerle C S., Solinas M N., Casu L. The causal dependence of present plant knowledge on herbals contemporary medicinal plant use in Campania (Italy) compared to Matthioli (1568). J Ethnopharmacol 2010 130 379-391
143. Pollio A, De Natale A, Appetiti E, Aliotta G, Touwaide A. Continuity and change in the Mediterranean medical tradition: Ruta spp. (Rutaceae) in Hippocratic medicine and present practices. J Ethnopharmacol 2008 116 469-482
144. Minker E, Bartha C, Rózsa Z, Szendrei K, Reisch J. Antispasmogenic effect of rutamarin and arborinine on isolated smooth muscle organs. Planta Med 1979 37 156-160 (Pubitemid 10246504)
145. Golub T R. Mining the genome for combination therapies. Nat Med 2003 9 510-511 (Pubitemid 36597093)
146. Gao J L., He T C., Li Y B., Wang Y T. A traditional Chinese medicine formulation consisting of Rhizoma Corydalis and Rhizoma Curcumae exerts synergistic anti-tumor activity. Oncol Rep 2009 22 1077-1083
147. Gertsch J. How scientific is the science in ethnopharmacology? Historical perspectives and epistemological problems. J Ethnopharmacol 2009 122 177-183
148. Woelkart K, Feizlmayr E, Dittrich P, Beubler E, Pinl F, Suter A, Bauer R. Pharmacokinetics of bilobalide, ginkgolide A and B after administration of three different Ginkgo biloba L. preparations in humans. Phytother Res 2010 24 445-450
149. Woelkart K, Frye R F., Derendorf H, Bauer R, Butterweck V. Pharmacokinetics and tissue distribution of dodeca-2E,4E,8E,10E/Z-tetraenoic acid isobutylamides after oral administration in rats. Planta Med 2009 75 1306-1313
150. He S M., Li C G., Liu J P., Chan E, Duan W, Zhou S F. Disposition pathways and pharmacokinetics of herbal medicines in humans. Curr Med Chem 2010 17 4072-4113
151. Feng C, Liu M, Shi X, Yang W, Kong D, Duan K, Wang Q. Pharmacokinetic properties of paeoniflorin, albiflorin and oxypaeoniflorin after oral gavage of extracts of Radix Paeoniae Rubra and Radix Paeoniae Alba in rats. J Ethnopharmacol 2010 130 407-413
152. Butterweck V, Liefländer-Wulf U, Winterhoff H, Nahrstedt A. Plasma levels of hypericin in presence of procyanidin B2 and hyperoside: a pharmacokinetic study in rats. Planta Med 2003 69 189-192 (Pubitemid 36470120)
153. Xu F, Liu Y, Dong H, Song R, Zhang Z. Pharmacokinetic comparison in rats of six bioactive compounds between Da-Cheng-Qi decoction and its parent herbal medicines. Nat Prod Commun 2010 5 795-800
154. Wegener T, Wagner H. The active components and the pharmacological multi-target principle of STW 5 (Iberogast). Phytomedicine 2006 13 (Suppl.5) 20-35 (Pubitemid 44809868)
155. Wang X, Wang Z, Sun H, Lv H, Guan H, Meng X, Sun H, Zhang G, Cao H. Pharmacokinetics of cimifugin in rat plasma after oral administration of the extract of Saposhnikovia divaricatae root. Determination of cimifugin by high performance liquid chromatography coupled with solid phase extraction. Arzneimittelforschung 2008 58 445-450
156. Lv H, Sun H, Sun W, Liu L, Wang P, Wang X, Cao H. Pharmacokinetic studies of a Chinese triple herbal drug formula. Phytomedicine 2008 15 993-1001
157. Schmid B, Kötter I, Heide L. Pharmacokinetics of salicin after oral administration of a standardised willow bark extract. Eur J Clin Pharmacol 2001 57 387-391 (Pubitemid 33787189)
158. He S M., Li C G., Liu J P., Chan E, Duan W, Zhou S F. Disposition pathways and pharmacokinetics of herbal medicines in humans. Curr Med Chem [in press][nl]
159. López-Moreno C A. Poster O26 Phytotherapy of malignant and benign tumors with mixtures of extracts of angiosperms from arid zones of North of Mexico. Naples Natural Products in Cancer Therapy 2008
160. Schmidt B, Ribnicky D M., Poulev A, Logendra S, Cefalu W T., Raskin I. A natural history of botanical therapeutics. Metabolism 2008 57 S3-S9 (Pubitemid 351814695)
161. Kneifel W, Czech E, Kopp B. Microbial contamination of medicinal plantsa review. Planta Med 2002 68 5-15 (Pubitemid 34113580)
162. Hamburger M. New approaches in analyzing the pharmacological properties of herbal extracts. Proc West Pharmacol Soc 2007 50 156-161
163. Wolfender J L., Ndjoko K, Hostettmann K. Liquid chromatography with ultraviolet absorbance-mass spectrometric detection and with nuclear magnetic resonance spectroscopy: a powerful combination for the on-line structural investigation of plant metabolites. J Chromatogr A 2003 1000 437-455 (Pubitemid 36638469)
164. Wang J, van der Heijden R, Spijksma G, Reijmers T, Wang M, Xu G, Hankemeier T, van der Greef J. Alkaloid profiling of the Chinese herbal medicine Fuzi by combination of matrix-assisted laser desorption ionization mass spectrometry with liquid chromatography-mass spectrometry. J Chromatogr A 2009 1216 2169-2178
165. Wang J, van der Heijden R, Spruit S, Hankermeier T, Chan K, van der Greef J, Xu G, Wang M. Quality and safety of Chinese herbal medicines guided by a systems biology perspective. J Ethnopharmacol 2009 126 31-41
166. Yu W L., Guizzunti G, Foley T L., Burkart M D., La Clair J J. An optimized immunoaffinity fluorescent method for natural product target elucidation. J Nat Prod [in press][nl]
167. Rosén J, Gottfries J, Muresan S, Backlund A, Oprea T I. Novel chemical space exploration via natural products. J Med Chem 2009 52 1953-1962
168. Jaki B U., Franzblau S G., Chadwick L R., Lankin D C., Zhang F, Wang Y, Pauli G F. Purity-activity relationships of natural products: the case of anti-TB active ursolic acid. J Nat Prod 2008 71 1742-1748
169. Vornholt W, Hartmann M, Keusgen M. SPR studies of carbohydrate-lectin interactions as useful tool for screening on lectin sources. Biosens Bioelectron 2007 22 2983-2988 (Pubitemid 46754871)
170. Miyazaki I, Simizu S, Osada H. The application of the chemical array for biological study. Methods Mol Biol 2010 669 95-107
171. van Breemen R B., Li Y. Caco-2 cell permeability assays to measure drug absorption. Expert Opin Drug Metab Toxicol 2005 1 175-185
172. Bohlin L, Göransson U, Alsmark C, Wedén C, Backlund A. Natural products in modern life science. Phytochem Rev 2010 9 279-301
173. Larkins N, Wynn S. Pharmacognosy: phytomedicines and their mechanisms. Vet Clin North Am Small Anim Pract 2004 34 291-327 (Pubitemid 38145858)