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Abstract

There are 482 Hypericum species which grow naturally in different geographic origins of the world from equator zone to Scandinavian Countries. Those species have been used as folk remedy in world-wide in treatments of neuralgia, menstural disorders, sciatica, arthritis and stomach diseases for centuries. Of all Hypericum, the most popular and common one is Hypericum perforatum L. It has been studied extensively in clinical trials for the last three decades and used popularly in treatment of depression. Our country is an important centre for Hypericum species which are known as “kantaron, binbirdelik otu, kan otu, kılıç otu, yaraotu, kuzukıran”. There are 89 Hypericum species in our flora of which 43 are endemic. On the contrary of world literature, hovewer, there are only few scientific studies on those species, conducted in our contry. Besides, those species have been collected extensively from natural flora for commercial purposes. In this review, it was aimed to remark Hypericum species which are an inactive source currently for our country and to present detailed information to the relevants

Keywords

• Hypericum sp., St. John’s wort, medicinal plant, drug raw material, natural sources

Önemli Tıbbi Bitkiler Olarak Hypericum Türleri​

Öz

Ekvator kuşağından kuzeyde İskandinav ülkelerine kadar dünyanın farklı coğrafyalarında yayılış gösteren 482 Hypericum türü bulunmaktadır. Bu türler dünya genelinde halk ilacı olarak yüzyıllardan bu yana sinir hastalıkları, adet krampları, siyatik, eklem iltihabı ve midevi rahatsızlıklardan kaynaklanan ağrıların giderilmesinde ve bazı cilt hastalıklarının tedavisinde kullanılmaktadır. Hypericum türleri içerisinde en yaygın ve popüler olanı Hypericum perforatum L.’dur. Bu tür son 30 yıldan beri bitki klinik ve laboratuar şartlarında yoğun olarak çalışılmakta olup günümüzde bilhassa depresyon tedavisinde yoğun olarak kullanılmaktadır. Ülkemiz kantaron, binbirdelik otu, kan otu, kılıç otu, yaraotu, kuzukıran gibi yöresel adlarla bilinen Hypericum türleri bakımından önemli bir merkezdir ve mevcut 96 türün 46’sı endemiktir. Ancak dünya literatürünün aksine bu türler ile ilgili ülkemiz şartlarında yürütülen çalışmaların sayısı oldukça azdır. Ayrıca bu bitkiler tür ayrımı gözetmeksizin doğal floradan ihraç maksadıyla yoğun bir şekilde toplanmaktadır. Bu derlemede ülkemiz için atıl bir kaynak durumunda olan Hypericum türlerine dikkat çekmek ve konuyla ilgilenenler için derli toplu ve detaylı bilgi sunmak amaçlanmıştır

Anahtar Kelimeler

• Hypericum sp., kantaron, tıbbi bitki, ilaç hammaddesi, doğal kaynaklar

Kaynakça

1. Agnol, R.D., Ferraz, A., Bernardi, A.P., Albring, D., Nör, C., Sarmento, L., Lamb, L., Hass, M, Von Poser, G., Schapoval, E.E.S., 2003. Antimicrobial activity of some Hypericum species. Phytomedicine 10: 511-516.
2. Altun, M.L., Yılmaz, B.S., Orhan, İ.E., Citoglu, G.C., 2013. Assessment of cholinesterase and tyrosinase inhibitory and antioxidant effects of Hypericum perforatum L. (St. John's wort). Industrial Crops and Products. 43: 87-92.
3. Andrade, M.R., Almeida, E.X., Conserva, L.M., 1998. Alkyl chromone and other compounds from Clusia nemorosa. Phytochemistry 43, 1431–1433.
4. Apaydın, Ş., Zeybek, U., Ince, I., Elgin, G., Karamenderes, C., Ozturk, B., Tuglular, I., 1999. Hypericum triquetrifolium Turra. extract exhibits antinociceptive activity in the mouse. Journal of Ethnopharmacology 67: 307-312.
5. Barış, D., Kızıl, M., Aytekin, Ç., Kızıl, G., Yavuz, M., Çeken, B., Ertekin, S., 2011. In Vitro Antimicrobial and Antioxidant Activity of Ethanol Extract of Three Hypericum and ThreeAchillea Species From Turkey. International Journal of Food Properties. 14: 339-355.
6. Barros, F.M.C., Pipi, B., Dresch, R.R., Dauber, B., Luciano, S.C., Apel, M.A., Fuentefria, A.M., Von Poser, G.L., 2013. Antifungal and antichemotactic activities and quantification of phenolic compounds in lipophilic extracts of Hypericum spp. native to South Brazil. Industrial Crops and Products 44: 294-299.
7. Baytop, T., 1999. Türkiye’de Bitkilerle Tedavi. Nobel Tıp Yayınevi. 2. Baskı. İstanbul, s:256.
8. Behnke, K., Jensen, G.S., Graubaum, H.J., Gruenwald, J., 2002. Hypericumperforatum versus fluoxetine in the treatment of mild to moderate depression. Adv. Ther. 19, 43–52.

9. Berghöefer, R., Höelzl, J., 1989. Isolation of (amentoflavone) from Hypericumperforatum. Planta Medica 55, 91.
10. Bergmann, R., Nussner, H., Demling, J., 1993. Behandlung leichter bis mittelschwerer depressionen. Therapiewoche Neurol. Psychiatr. 7, 235–240.
11. Bjerkenstedt, L., Edman, G.V., Alken, R.G., Mannel, M., 2005. Hypericumextract LI 160 and fluoxetine in mild to moderate depression: a randomized, placebo- controlled multi-center study in outpatients. Eur. Arch. Psychiatry Clin. Neurosci. 255, 40–47.
12. Brenner, R., Azbel, V., Madhusoodanan, S., Pawlowska, M., 2000. Comparison of an extract of Hypericum(LI 160) and sertraline in the treatment of depression: a double- blind, randomized pilot study. Clin. Ther. 22, 411– 419.
13. Bystrov, N.S., Chernov, B.K., Dobrynin, V.N., Kolosov, M.N., 1975. The structure of hyperforin. Tetrahedron Letters. 32: 2791-2794.
14. Cakir, A., Kordali, S., Kilic, H., Kaya, E., 2005. Antifungal properties of essential oil and crude extracts of Hypericum linarioides Bosse. Biochemical Systematics and Ecology 33, 245-256.
15. Chatterjee, S.S., Noldner, M., Koch, E., Erdelmeier, C., 1998. Antidepressant activity of Hypericumperforatum and hyperforin: the neglected possibility. Pharmacopsychiatry 31 (Suppl. 1), 7–15.
16. Couladis, M., Chinou, I.B., Tzakou, O., Petrakis, P.V., 2003. Composition and antimicrobial activity of the essential oil of Hypericum rumeliacum subsp. apollinis (Boiss. & Heldr.). Phytotherapy Research 17, 152-154.
17. Crockett, S.L. and Robson, N.K.B., 2011. Taxonomy and Chemotaxonomy of the Genus Hypericum. Medicinal and Aromatic Plant Science and Biotechnology, 5 (Special Issue 1), 1-13.
18. Culpeper, N., 1652. The English Physician or an Astrologo- Physical Disclosure on the Vulgar Herbs of this Nation. Nathanial Brook, London, England.
19. Çamaş, N., Radusiene, J., Stanius, Z., Çalışkan, Ö., Çırak, C., 2012. Secondary metabolites of Hypericum leptophyllum Hochst., an endemic Turkish species. The Scientific World Journal. Vol. 2012, Article ID 501027, 4 pages, 2012. doi:10.1100/2012/501027.
20. Çamaş, N., Radusiene, J., Ivanauskas, L., Jakstas, V., Çırak, C., 2014a. Altitudinal changes in the content of bioactive substances in Hypericum orientale and Hypericum pallens. Acta Physiologia Plantarum, baskıda.
21. Çamaş, N., Radusiene, J., Ivanauskas, L., Jakstas, V., Kayıkçı, S., Çırak, C., 2014b. Chemical composition of Hypericum species from the Taeniocarpium and Drosanthe sections. Plant Systematic and Evolotion, baskıda.
22. Çırak, C., 2006. Hypericin in Hypericum lydium Boiss. growing in Turkey. Biochemical Systematics and Ecology 34: 897-899.
23. Çırak, C., Kevseroğlu, K. 2004. Kantaron bitkisinin eski çağlardan günümüze kullanım şekilleri ile modern tıptaki yeri ve önemi. OMÜ Ziraat Fakültesi Dergisi. 19:74-84.
24. Çırak, C., Ayan, A., Kevseroğlu, K., 2004. The effects of light and some presoaking treatments on germination rate of St. John’s wort (Hypericum perforatum L.) seeds. Pakistan Journal of Biological Sciences. 7:182-186.
25. Çırak, C., Sağlam, B., Ayan, A.K., Kevseroğlu, K., 2006. Morphogenetic and diurnal variation of hypericin in some Hypericum species from Turkey during the course of ontogenesis. Biochemical Systematics and Ecology. 34 : 1-13.
26. Çırak, C., Radusiene, J., Karabük, B., Janulis, V., Ivanauskas, L., 2007a. Variation of bioactive compounds in Hypericum perforatum growing in Turkey during its phenological cycle. Journal of Integrative Plant Biology. 49 (5): 615−620.
27. Çırak, C., Radusiene, J., Janulis, V., Ivanauskas, L., 2007b. Variation of bioactive secondary metabolites in Hypericum origanifolium during its phenological cycle. Acta Physiologia Plantarum, 29:197–203.
28. Çırak, C., Radusiene, J., Janulis, V., Ivanauskas, L., 2007c. Secondary metabolites in Hypericum perfoliatum: variation among plant parts and phenological stages. Botanica Helvetica. 117 (1):29-36.
29. Çırak, C., Radusiene, J., Janulis, V., Ivanauskas, L., 2007d. Chemical constituents of some Hypericum species growing in Turkey. Journal of Plant Biology. 50(6) : 632-635.
30. Çırak, C., Radusiene, J., Janulis, V., Ivanauskas, L., 2008a. Pseudohypericin and hyperforin in Hypericum perforatum from Northern of Turkey: variation among populations, plant parts and phenological stages. Journal of Integrative Plant Biology. 50 (5): 575–580.
31. Çırak, C., Radusiene, J., Sağlam, B., 2008b. Variation of bioactive substances in Hypericum montbretii during plant growth. Natural Product Research. 22(3): 246– 252.
32. Çırak, C., Radusiene, J., Janulis, V., Ivanauskas, L., 2009. Chemical constituents of Hypericum adenotrichum Spach, an endemic Turkish species. Natural Product Research. 23 (13): 1189–1195.
33. Çırak, C., Radusiene, J., Janulis, V., Ivanauskas, L., 2010. Secondary metabolites of Hypericum confertum and their possible chemotaxonomic significance. Natural Product Communications. 5(6): 897-898.
34. Çırak, C., Radusiene, J., Stanius, Z., Çamaş, N., Çalışkan, Ö., Odabaş, M.S., 2012. Secondary metabolites of Hypericum orientale L. growing in Turkey: variation among populations and plant parts. Acta Physiologia Plantarum. 34: 1313–1320.
35. Çırak, C., Radusiene, J., Çamaş, N., Çalışkan, Ö., Odabaş, M.S., 2013a. Changes in the contents of main secondary metabolites in two Turkish Hypericum species during plant development. Pharmaceutical Biology. 51(3): 391-399.
36. Çırak, C., Radusiene, J., Karpaviciene, B., Çamaş, N., Odabaş, M.S., 2013b. Changes in phenolic content of wild and greenhouse-grown Hypericum triquetrifolium during plant development. Turkish Journal of Agriculture and Forestry. 37: 307-314.
37. Deltito, J., Bayer, D., 1998. The scientific, quasi-scientific and populer literature on the use of St. John’s wort in the treatment of depression. J. Affect. Disort. 51:345-351.
38. Demirkiran, Ö., Mesaik, M.A., Beynek, H., Abbaskhan, A., Choudhary, M.I., 2009. Cellular reactive oxygen species inhibitory constituents of Hypericum thasium Griseb. Phytochemistry. 70: 244-249.
39. Devrim, C.Ö., Bilal, İ., Yusuf, Ö., Nilgün, Ö., İsmühan, P., Sagratini, G., Ricciutelli, M., Vittori, S., Maggi, F., 2011. New antidepressant drug candidate: Hypericum montbretti extract. Natural Product Research. 11: 1-4.
40. Duke, J.A., 1985. Handbook of Medicinal Herbs. CRC Press, Boca Raton, FL, pp. 242–243.
41. Dulger A, Gonuz B. 2005. Antibacterial activity of the endemic Hypericum kazdaghensis. Fitoterapia. 6:237-9.
42. Eckert, G.P., Muller, W.E., 2001. Effects of hyperforin on the fluidity of brain membranes. Department of Pharmacology, Biocenter Niederursel, University of Frankfurt, Frankfurt/Main, Germany. Pharmacopsychiatry 34, S22–S25.
43. ESCOP Monographs, 2003. The European Scientific Cooperative on Phytotherapy, 2nd edition. Exeter, United Kingdom
44. Fava, M., Alpert, J., Nierenberg, A.A., Mischoulon, D., Otto, M.W., Zajecka, J., Murck, H., Rosenbaum, J.F., 2005. A double-blind, randomized trial of St. John's wort, fluoxetine, and placebo in major depressive disorder. J. Clin. Psychopharmacol. 25, 441–447.
45. Felter, H.W. and J.U. Lloyd., 1898. King’s American Dispensatory, 18th ed., reprinted by Eclectic Medical Publications, Portland, OR.
46. Fenner, R., Sortino, M., Kuze Rates, S.M., Dall’Agnol, R., Ferraz, A., Bernardi, A.P., Albring, D., Nör, C., Von Poser, G., Schapoval, E., Zacchino, S., 2005. Antifungal activity of some Brazilian Hypericum species. Phytomedicine 12: 236-240.
47. Fuller, R.W., Blunt, J.W., Boswell, J.L., Cardellina, J.H., Boyd, M.R., 1999a. Guttiferone F, the first prednylated benzophenone from Allanblackia stuhlmannii. Journal of Natural Products 62 (1), 130–132.
48. Gastpar, M., Singer, A., Zeller, K., 2005. Efficacy and tolerability of Hypericumextract STW3 in long-term treatment with a oncedaily dosage in comparison with sertraline. Pharmacopsychiatry 38, 78–86.
49. Gastpar, M., Singer, A., Zeller, K., 2006. Comparative efficacy and safety of a once-daily dosage of Hypericumextract STW3-VI and citalopram in patients with moderate depression: a double-blind, randomised, multicentre, placebo-controlled study. Pharmacopsychiatry 39, 66–75.
50. Gerard, J., 1597. The Herballe or General History of Plantes. Imprinted by John Norton, London.
51. German Commission EMonographs, 1998. American Botanical Council. Boston, MA.
52. Ghasemi, Y., Khalaj, A., Mohagheghzadeh, A., Khosravi, A.R., Morowvat, M.H., 2007. Composition and antimicrobial activity of the essential oil and extract of Hypericum elongatum. Journal of Applied Sciences 7 (18), 2671-2675.
53. Greene, T., 1824. The Universal Herbal. Caxton Press, London.
54. Greeson, J., Sanford, B., Monti, D. A., 2001. St. John’s worth (Hypericum perforatum): a review of the current pharmacological, toxicological and clinical literature. Psychopharmacology. 153:402-414.
55. Griffith, R.E., 1847. Medical Botany. Lea & Blanchard, Philadelphia.
56. Gudzic, B., Djokovic, D., Vajs, V., Palic, R., Stojanovic, G., 2002. Composition and antimicrobial activity of the essential oil of Hypericum maculatum Crantz. Flavour and Fragrance Journal 17, 392-394.
57. Gunther, R.T., 1968. The Greek Herbal of Dioscorides. Hafner Publishing Company.
58. Gurevich, A.I., Dobrynin, V.N., Kolosov, M.N., Popravko, S.A., Riabova, I.D., 1971. Antibiotic hyperforin from Hypericumperforatum L. Antibiotiki 16, 510–513.
59. Güner, A., Aslan, S., Ekim, T., Vural, M., Babaç, M.T., (edlr.), (2012). Türkiye Bitkileri Listesi (Damarlı Bitkiler). Nezahat Gökyiğit Botanik Bahçesi ve Flora Araştırmaları Derneği Yayını. İstanbul.
60. Hakimoglu, F., Kızıl, G., Kanay, Z., Kızıl, M., Isı, H., 2007. The effect of ethanol extract of Hypericum lysimachioides on lipid profile in hypercholesterolemic rabbits and itsin vitro antioxidant activity. Atherosclerosis 192: 113-122.
61. Hammer, K.D., Hillwig, M.L., Solco, A.K., Dixon, P.M., Delate, K., Murphy, P.A., Wurtele, E.S., Birt, D.F., 2007. Inhibition of prostaglandin E(2) production by antiinflammatory hypericum perforatum extracts and constituents in RAW264.7 Mouse Macrophage Cells. J Agric Food Chem. 55(18):7323-31.
62. Hänsgen, K.D., Vesper, J., 1996. Antidepressive wirksamkeit eines hochdosierten Hypericum-extraktes. Münch. Med. Wochenschift 138, 29–33.
63. Harrer, G., Hubner, W.D., Podzuweit, H., 1994. Effectiveness and tolerance of the Hypericumextract LI 160 compared to maprotiline: a multicenter double-blind study. J. Geriatr. Psychiatry Neurol. 7 (Suppl 1), S24– S28.
64. Hill, J., 1808. The Family Herbal. C. Brightly & T. Kinnersley, Bungay.
65. Hostanska, K., Reichling, J., Bommer, S., Weber, M., Saller, R., 2003. Hyperforin a constituent of St John’s wort (Hypericumperforatum L.) extract induces apoptosis by triggering activation of caspases and with hypericin synergistically exerts cytotoxicity towards human malignant cell lines, Eur. J. Pharm. Biopharm. 56: 121–132.
66. Hölzl, J., Demisch, L., Gollnik, B., 1989. Investigation about antidepressive and moodchanging effects of Hypericumperforatum. Planta Medica 55, 643.
67. Hübner, W.D., Lande, S., Podzuweit, H., 1994. Hypericumtreatment of mild depressions with somatic symptoms. J Geriatr. Psychiatry Neurol. S1, S12–S14.
68. Hypericum Depression Trial Study Group, 2002. Effect of Hypericum perforatum (St John's wort) in major depressive disorder: a randomized controlled trial. JAMA 287, 1807–1814.
69. Ishiguro, K., Nagareya, N., Fukumoto, H., 1998. A phoroglucinol derivative from cell suspension cultures of Hypericum patulum. Phytochemistry 47, 1041– 1043.
70. Istikoqlou C, Mavreas V, Geroulanos G., 2010. History and therapeutic properties of Hypericum perforatum from antiquity until today. Psychiatriki. 21: 332-8.
71. Kaçar., O, Azkan, N., 2010. Tıbbi bitki olarak sarı kantaron (Hypericum perforatum L.) ve halk sağlığındaki yeri, Dünya Gıda Dergisi Mayıs, 82-89.
72. Kalb, R., Trautmann-Sponsel, R.D., Kieser, M., 2001. Efficacy and tolerability of Hypericum extract WS 5572 versus placebo in mildly to moderately depressed patients. A randomized doubleblind multicenter clinical trial. Pharmacopsychiatry 34, 96–103.
73. Kasper, S., Dienel, A., 2002. Cluster analysis of symptoms during antidepressant treatment with Hypericum extract in mildly to moderately depressed out-patients. A meta-analysis of data from three randomized, placebo-controlled trials. Psychopharmacology. 164: 301-308.
74. Kasper, S., Anghelescu, I.G., Szegedi, A., Dienel, A., Kieser, M., 2006. Superior efficacy of St John's wort extract WS 5570 compared to placebo in patients with major depression: a randomized, double-blind, placebo- controlled, multi-center trial [ISRCTN77277298]. BMC Med. 4, 14.
75. Kasper, S., Gastpar, M., Müller, W.E., Volz, H.P., Dienel, A., Kieser, M., Möller, H.J., 2008a. Efficacy of St. John's wort extract WS 5570 in acute treatment of mild depression: a reanalysis of data from controlled clinical trials. Eur. Arch. Psychiatr. Clin. Neurosci. 258, 59–63.
76. Kasper, S., Volz, H.P., Möller, H.J., Dienel, A., Kieser, M., 2008b. Continuation and long-term maintenance treatment with Hypericum extract WS 5570 after recovery from an acute episode of moderate depression—a double-blind, randomized, placebo controlled long-term trial. Eur. Neuropsychopharmacol. 18: 803-813.
77. Keles, O., Seyyal, A.K., Bakirel, T., Alpinar, K., 2001. Screening of some Turkish plants for antibacterial activity. Turkish Journal of Veterinary and Animal Sciences 25, 559–565.
78. Kızıl, G., Kızıl, M., Yavuz, M., Emen, S., Hakimoglu, F., 2008. Antioxidant activities of ethanol extracts of Hypericum triquetrifolium and Hypericum scabroides. Pharm. Biol. 46, 231–242.
79. King, K., 1876. The American Dispensatory, tenth ed. Wilstach, Baldwin & Company, Cincinnati.
80. Kintzios, S.E., 2006. Terrestrial Plant-Derived Anticancer Agents and Plant Species Used in Anticancer Research. Critical Reviews in Plant Sciences, 25:79– 113.
81. Kitanov, G.M., Blinova, K.F., 1987. Modern state of the chemical study of species of the genus Hypericum. Chemistry of Natural Compounds 23, 151–166.
82. Lasik, M., Nowak, J., Stachowiak, B., Czarnecki, Z., 2007. Evaluation of the antagonistic properties of natural antibacterial substances extracted from herbs: poster presentation. Eurobiotech 54, 10.
83. Lavagna, S.M., Secci, D., Chimenti, P., Bonsignore, L., Ottaviani, A., Bizzarri, B., 2001. Efficacy of Hypericum and Calendula oils in the epithelial reconstruction of surgical wounds in childbirth with caesarean section. Farmaco 56, 451–453.
84. Lavie, G., Mazur, Y., Lavie, D., Meruelo, D., 1995. The chemical and biological properties of hypericin – a compound with a broad spectrum of biological activities. Medicinal Research Reviews 15, 111– 119.
85. Lecrubier, Y., Clerc, G., Didi, R., Kieser, M., 2002. Efficacy of St. John's wort extract WS 5570 in major depression: a double-blind, placebo-controlled trial. Am. J. Psychiatry 159, 1361–1366.
86. Lehrl, S., Woelk, H., 1993. Ergebnisse von messungen der kognitiven leistungsfähigkeit bei patienten unter der therapie mit johanniskraut. Nervenheilkunde 12, 281– 284.
87. Linde, K., Berner, M.M., Kriston, L., 2008. St John's wort for major depression. Cochrane Database Syst. Rev. CD000448.
88. Maisenbacher, P., Kovar, K.A., 1992a. Adhyperforin: a homologue of hyperforin from Hypericumperforatum. Planta Medica 58, 291–293.
89. Maisenbacher, P., Kovar, K.A., 1992b. Analysis and stability of Hyperici oleum. Planta Medica 58, 351–354.
90. Martarellia, D., Martarellib, B., Pediconia, D., Nabissic, M.I, Perfumia, M, Pompei, P. 2004. Hypericumperforatum methanolic extract inhibits growth of human prostatic carcinoma cell line orthotopically implanted in nude mice. Cancer Letters 210: 27–33.
91. Mckee, T.C., Covington, C.D., Fuller, R.W., Bokesh, H.R., Young, S., Cardellina, J.H., Kadushin, M.R., Soejarto, D.D., Stevens, P.F., Cragg, G.M., Botd, M.R., 1998. Pyranocoumarins from tropical species of the genus Calophyllum: a chemotaxonomic study of extracts in the National Cancer Institute collection. Journal of Natural Products 61 (10), 1252–1256.
92. Meruelo, D., Lavie, G., Lavie, D., 1988. Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses: aromatic polycyclic diones hypericin and pseudohypericin. Proceedings of the National Academy of Sciences of the United States of America 85, 5230–5234.
93. Mevdudi, E. A., 1991. Kuran’ın Anlamı ve Tefsiri. İnsan yayınları. Cilt 3; sf:331-366.
94. Moerman, D.E., 1998. Native American Ethnobotany. Timber Press, Portland, OR, pp.272–273.
95. Moreno, R.A., Teng, C.T., Almeida, K.M., Tavares Junior, H., 2006. Hypericumperforatum versus fluoxetine in the treatment of mild to moderate depression: a randomized double-blind trial in a Brazilian sample. Rev. Bras. Psiquiatr. 28, 29–32.
96. Mukherjee, P.K., Verpoorte, R., Suresh, B., 2000. Evaluation of in vivo wound healing activity of Hypericum patulum (Family: Hypericaceae) leaf extract on different wound model in rats. Journal of Ethnopharmacology 70, 315–321.
97. Nahrstedt, A., Butterweck, V., 1997. Biologically active and other chemical constituents of the herb of Hypericumperforatum L. Pharmacopsychiatry 30, 129–134.
98. Newman, D.J., Cragg, G.M., 2007. Natural products as sources of new drugs over the last 25 years. J. Nat. Prod. 70, 461–477.
99. Noldner M, Schotz K. 2002. Rutin is essential for the antidepressant activity of Hypericumperforatum extracts in the forced swimming test. Planta Med. 68:577-80.
100. Öztürk Y, Aydin S, Beis R, Başer KHC, Berberoğlu H. 1996. Effects of Hypericum perforatum L. And Hypericum calycinum L. extracts on the Central Nervous System in mice. Phytomedicine. 3: 139-146.
101. Öztürk, N., Korkmaz, S., Öztürk, Y., 2007. Wound-healing activity of St. John’s Wort (L.)onchicken embryonic fibroblasts. Journal of Ethnopharmacology 111, 33–39.
102. Pabuçcuoglu, A, Konyalıoglu S, Baş M, Meral GE. 2003. The in vitro effects of Hypericum species on human leukocyte myeloperoxidase activity. Journal of Ethnopharmacology. 87: 89-92.
103. Panossian, A.G., Gabrielian, E., Manvelian, V., Jurcic, K., Wagner, H., 1996. Immunosuppressive effects of hypericin on stimulated human leukocytes: inhibition of the arachidonic acid release, leukotriene B4 and interleukin-1 alpha production, and activation of nitric oxide formation. Phytomedicine 3, 19–28.
104. Papakostas, G.I., Crawford, C.M., Scalia, M.J., Fava, M., 2007. Timing of clinical improvement and symptom resolution in the treatment of major depressive disorder. A replication of findings with the use of a double-blind, placebo-controlled trial of Hypericumperforatum versus fluoxetine. Neuropsychobiology 56, 132–137
105. Peeva-Naumovska, V., Panovski, N., Grdanovska, T., Fredro- Kumbaradzi, E., 2010. Formulations of St. John’s Wort oil ointment and evaluation of its antibacterial effect. Available from: www.amapseec.org/cmapseec. 1/Papers/pap p067.htm
106. Philipp, M., Kohnen, R., Hiller, K.O., 1999. Hypericumextract versus imipramine or placebo in patients with moderate depression: randomised multicenter study of treatment for eight weeks. BMJ 319, 1534–1538.
107. Qu, L., Widrlechner, M.P., Rigby, S.M. 2010. Analysis of breeding systems, ploidy, and the role of hexaploids in three Hypericum perforatum L. populations. Industrial Crops and Products. 32:1-6.
108. Rahimi, R., Nikfar, S., Abdollahi, M., 2009. Efficacy and tolerability of Hypericumperforatum in major depressive disorder in comparison with selective serotonin reuptake inhibitors: a meta-analysis. Prog. Neuropsychopharmacol. Biol. Psychiatry 33, 118–127.
109. Robson, N. K. B. 1981. Studies in the genus Hypericum L.(Guttiferae) 2. Characters of the genus. Bulletin of the British Museum (Natural History) Botany Series, 8, 55-226.
110. Robson, N. K. B., Adams, P., 1968. Chromosome number in Hypericum and related genera. Brittonia. 20:95-106.
111. Röder, C., Schaefer, M., Leucht, S., 2004. Meta-analysis of effectiveness and tolerability of treatment of mild to moderate depression with St. John's Wort. Fortschr Neurol Psychiatr. 72: 330-43.
112. Saljic, J,. 1975. Ointment for the treatment of burns, Ger. Offen. 2,406,452 (CL. A61K), 21 Aug 1975 (CA 83: 197797).
113. Sanchez-Mateo, CC, C.X. Bonkanka, M. Hernández-Pérez, R.M. Rabanal. 2006. Evaluation of the analgesic and topical anti-inflammatory effects of Hypericum reflexum L. fil.. Journal of Ethnopharmacology 107: 1- 6.
114. Tanaka, N., Takaishi, Y., 2006. Xanthones from Hypericum
115. Saroglou, V., Marin, P.D., Rancic, A., Veljic, M., Skaltsa, H., 2007. Composition and antimicrobial activity of the essential oil of six Hypericum species from Serbia. Biochemical Systematics and Ecology 35, 146-152.
116. Sarrell, E.M., Cohen, H.A., Kahan, E., 2003. Naturopathic treatment for ear pain in children. Pediatrics 111: 574- 579.
117. Schempp, C.M., Kirkin, V., Simon-Haarhaus, B., Kersten, A., Kiss, J., Termeer, C.C., Gilb, B., Kaufmann, T., Borner, C., Sleeman, J.P., Simon, J.C., 2002. Inhibition of tumour cell growth by hyperforin, a novel anticancer drug from St. John’s Wort that acts by induction of apoptosis. Oncogene 21, 1242–1250.
118. Schempp, C.M., Windeck, T., Hezel, S., Simon, J.C., 2003. Topical treatment of atopic dermatitis with St. John’s Wort cream – a randomized, placebo controlled, double blind half-side comparison. Phytomedicine 10, 31–37.
119. Schmitt, A.C., Ravazzolo, A.P., Von Poser, G.L., 2001. Investigation of some Hypericumspecies native to Southern of Brazil for antiviral activity. Journal of Ethnopharmacology. 77: 239–245.
120. Sezik, E., Yeşilada, E., Honda, G., Takaishi, Y., Takeda, Y., Tanaka, T., 2001. Traditional medicine in Turkey 10: Folk medicine in central Anatolia. Journal of Ethnopharmacology. Vol:75. P:95-115.
121. Smelcerovic, A., Zuehlke, S., Spiteller, M., Raabe, N., Özen, T., 2008. Phenolic constituents of 17 Hypericum species from Turkey. Biochem Syst Ecol 36: 316-319.
122. Solomon, D., Adams, J., Graves, N., 2013. Economic evaluation of St. John’s wort (Hypericum perforatum) for the treatment of mild to moderate depression. Journal of Affective Disorders 148: 228-234.
123. Sparenberg, B.L., Demisch, J., Holzl, J., 1993. Untersuchungen uber die antidepressiven Wirkstoffe von Johanniskraut. Pharm Ztg Wiss. 138, 239–254.
124. Süntar, I.P., Akkol, E.K., Yılmazer, D., Baykal, T., Kırmızıbekmez, H., Alper, M., Yesilada, E., 2010. Investigations on the in vivo wound healing potential of Ethnopharmacology 127: 468-477.
125. Szegedi, A., Kohnen, R., Dienel, A., Kieser, M., 2005. Acute treatment of moderate to severe depression with Hypericumextract WS 5570 (St John's wort): randomised controlled double blind non-inferiority trial versus paroxetine. BMJ 330, 503.
126. Şerbetci, T., Özsoy, N., Demirci, B., Can, A., Kültür, Ş., Baser, K.H.C., 2012. Chemical composition of the essential oil and antioxidant activity of methanolic extracts from fruits and flowers of Hypericum lydium Boiss. Industrial Crops and Products 36: 599-606. chinense. Phytochemistry. 67: 2146-51.
127. Toker, Z., Kızıl, G., Özen, H.Ç., Kızıl, M., Ertekin, S., 2006. Compositions and antimicrobial activities of the essential oils of two Hypericum species from Turkey. Fitoterapia. 77: 57-60.
128. Tolkunova, N.N., Cheuva, E.N., Bidyuk, A.Ya., 2002. Effect of medicinal plant extracts on microorganism development. Pishchevaya Promyshlennost 8, 70–71.
129. Van Gurp, G., Meterissian, G.B., Haiek, L.N., McCusker, J., Bellavance, F., 2002. St John's wort or sertraline Randomized controlled trial in primary care. Can. Fam. Physician 48, 905–912.
130. Uzun, F. 2009. Ontogenic changes in hypericin content of some Hypericum species in natural pastureland of Turkey. Bangladesh J. Bot. 38: 13-18.
131. Verotta, L., Appendino, G., Bombardelli, E., Brun, R., 2007. In vitro antimalarial activity of hyperforin, a prenylated acylphloroglucinol. A structure–activity study. Bioorganic & Medicinal Chemistry Letters 17, 1544–1548.
132. Vlietinck, A.J., De Bruyne, T., Apers, S., Pieters, L.A., 1998. Plant derived leading compounds chemotherapy of human immunodeficiency virus (HIV-1) infection. Planta Medica 64, 97–109.
133. Vorbach, E.U., Hubner, W.D., Arnoldt, K.H., 1994. Effectiveness and tolerance of the Hypericumextract LI 160 in comparison with imipramine: randomized double-blind study with 135 outpatients. J. Geriatr. Psychiatry Neurol. 7 (Suppl 1), S19–S23.
134. Westerhoff, K., Kaunzinger, A., Wurglics, M., Dressman, J., Schubert-Zsilavecz, M., 2002. Biorelevant dissolution testing of St John's wort products. J. Pharm. Pharmacol. 54, 1615–1621.
135. Wheatley, D., 1997. LI 160, an extract of St. John's wort, versus amitriptyline in mildly to moderately depressed outpatients—a controlled 6-week clinical trial. Pharmacopsychiatry 30 (Suppl 2), 77–80.
136. WHO,1999. World Health Organization Monographs on Selected Medicinal Plants, vol. 2, Geneva.
137. Withering, W., 1796. An arrangement of British plants third ed. Published by Swinney, London.
138. Woelk, H., 2000. Comparison of St John's wort and imipramine for treating depression: randomised controlled trial. BMJ 321, 536–539.
139. Xie, X., J.B. Hudson, E.S. Guns, 2001. Tumor-specific and photodependent cytotoxicity of hypericin in the human LNCaP prostate tumor model, Photochem. Photobiol. 74: 221–225.
140. Yesilada, E., Gürbüz, I., 1998. Evaluation of the anti- ulcerogenic effect of the flowering herbs of Hypericum perforatum. Journal of Faculty of Pharmacy of Gazi University 15, 25–31.
141. Yesilada, E., Honda, G., Sezik, E., Tabata, M., Fujita, T., Tanaka, T., Takeda, Y., Takaishi, Y., 1995. Traditional medicine in Turkey. V. Folk medicine in the inner Taurus Mountains. Journal of Ethnopharmacology 46, 133–152