Pharmaceutical Medicine

, Volume 22, Issue 2, pp 107–118 | Cite as

The Development of Herbal Medicinal Products

Quality, Safety and Efficacy as Key Factors
  • Salvador Cañigueral
  • Roger Tschopp
  • Lara Ambrosetti
  • Alberto Vignutelli
  • Francesco Scaglione
  • Orlando Petrini
Review Article

Abstract

Physicians are increasingly recommending the use of plant-derived products, partly because of a growing dissatisfaction among consumers with conventional medicines, but also because of the progress made in the chemical, pharmacological and clinical study of herbal medicinal products, the use of innovative galenical forms and the growing importance of self medication. Quality is a key issue in the development of herbal medicinal products that have consistent safety and efficacy, and quality can only be achieved if it is prioritized from the earliest stages of the development process. Problems in the development of herbal remedies include the frequent lack of standardized products (leading to a poor reproducibility of results and lack of batch-to-batch uniformity), a lack of toxicology, pharmacokinetic and pharmacodynamic data, as well as of dose-response and interaction studies. In addition, the placebo effect in trials with herbal remedies is often very high.

Research involving herbal medicinal products must progress from the use of traditional evidence and/or open, observational trials to randomized, double-blind, placebo-controlled trials, the ‘gold standard’ of clinical and scientific research. Over time, the development process for herbal medicinal products should become more closely aligned with the development of new chemical entities. Pharmacovigilance is also slowly becoming a standard tool to monitor the safety of herbal medicinal products. Yet we should not discard the legacy of traditional wisdom because ethnopharmacology and knowledge provided by existing clinical trials (be they open, observational studies or small, double-blind investigations) is a source of invaluable insight into the safety and efficacy of herbal remedies. Ideally, a registration dossier for any herbal medicinal product should include both the results of appropriate preclinical and clinical studies, and the wealth of knowledge that has accumulated from the traditional use of the product.

Notes

Acknowledgement

The preparation of this manuscript has been funded in full by Pharmaton SA, a company manufacturing herbal medicinal products. Drs Tschopp, Ambrosetti and Vignutelli are employees of Pharmaton SA. Drs Cañigueral, Scaglione and Petrini have acted or act as consultants to Pharmaton SA.

All authors have contributed in equal parts to the preparation of the manuscript.

References

  1. 1.
    Williamson EM. Synergy and other interactions in phytomedicines. Phytomedicine 2001 Sep; 8 (5): 401–9PubMedCrossRefGoogle Scholar
  2. 2.
    Attiso M, Bonati A, Concha JA, et al. Réunion OMS sur la sélection et caractérisation des plantes médicinales (drogues végétales). Document DPM/79.1. 1978 Oct 9-13; Geneva. Geneva: WHO, 1978Google Scholar
  3. 3.
    European Directorate for the Quality of Medicines. European pharmacopoeia. 6th ed. Strasbourg: Council of Europe, 2008Google Scholar
  4. 4.
    Directive 2004/24/EC of the European Parliament and of the Council of 31 March 2004 amending, as regards traditional herbal medicinal products, Directive 2001/83/EC on the Community code relating to medicinal products for human use (Official Journal L 136, 30/4/2004, p. 85-90) [online]. Available from URL: http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-1/dir_2004_24/dir_2004_24_en.pdf [Accessed 2008 Feb 27]
  5. 5.
    Herbal Medicinal Products Committee (HMPC). Guideline on specifications: test procedures and acceptance criteria for herbal substances, herbal preparations and herbal medicinal products/traditional herbal medicinal products. CPMP/ QWP/2820/00 Rev 1. London 2006 [online]. Available from URL: http://www.emea.europa.eu/pdfs/human/qwp/282000en.pdf [Accessed 2008 Feb 27]
  6. 6.
    Cañigueral S. Fitoterapia: una terapéutica para el tercer milenio? Revista Fitoterapia 2002; 2 (2): 101–21Google Scholar
  7. 7.
    Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. JAMA 1998 Nov 11; 280 (18): 1569–75PubMedCrossRefGoogle Scholar
  8. 8.
    World Health Organization. WHO monographs on selected medicinal plants. Volume 1. Geneva: World Health Organization, 1999 [online]. Available from URL: http://whqlibdoc.who.int/publications/1999/9241545178.pdf [Accessed 2008 Feb 12]Google Scholar
  9. 9.
    World Health Organization. WHO monographs on selected medicinal plants. Volume 2. Geneva: World Health Organization, 2002 [online]. Available from URL: http://whqlibdoc.who.int/publications/2002/9241545372.pdf [Accessed 2008 Feb 12]Google Scholar
  10. 10.
    World Health Organization. WHO monographs on selected medicinal plants. Volume 3. Geneva: World Health Organization. 2007 [online]. Available from URL: http://www.who.int/medicines/publications/traditional/MedPlantsMonograph3.pdf [Accessed 2008 Mar 6]Google Scholar
  11. 11.
    World Health Organization. WHO guidelines on good agricultural and collection practices (GACP) for medicinal plants. Geneva: World Health Organization, 2003 [online]. Available from URL: http://whqlibdoc.who.int/publications/2003/9241546271.pdf [Accessed 2008 Feb 12]Google Scholar
  12. 12.
    World Health Organization. Quality control methods for medicinal plant materials. Geneva: World Health Organization, 1998 [online]. Available from URL: http://whqlibdoc.who.int/publications/1998/9241545100.pdf [Accessed 2008 Feb 12]Google Scholar
  13. 13.
    World Health Organization. WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems. Geneva: World Health Organization, 2004Google Scholar
  14. 14.
    World Health Organization. General guidelines for methodologies on research and evaluation of traditional medicine. Geneva: World Health Organization, 2000 [online]. Available from URL: http://whqlibdoc.who.int/hq/2000/WHO_EDM_TRM_2000.1.pdf [Accessed 2008 Feb 12]Google Scholar
  15. 15.
    Herbal Medicinal Products Committee (HMPC). Guideline on good agricultural and collection practice (GACP) for starting materials of herbal origin. EMEA/ HMPC/246816/2005. London, 2006 [online]. Available from URL: http://www.emea.europa.eu/pdfs/human/hmpc/24681605en.pdf [Accessed 2008 Mar 6]Google Scholar
  16. 16.
    Working Party on Herbal Medicinal Products (HMPWP). Updated draft points to consider on the evidence of safety and efficacy required for well-established herbal medicinal products in bibliographic applications. EMEA/HMPWG/23/99. Draft 1999 Jan 21 [online]. Available from URL: http://www.emea.europa.eu/pdfs/human/hmpc/002399en.pdf [Accessed 2008 Mar 6]
  17. 17.
    Working Party on Herbal Medicinal Products. Final concept paper on the implementation of different levels of scientific evidence in core-data for herbal drugs. EMEA/HMPWP/1156/03. London 2004 [online]. Available from URL: http://www.emea.europa.eu/pdfs/human/hmpc/115603en.pdf [Accessed 2008 Feb 12]Google Scholar
  18. 18.
    European Scientific Cooperative on Phytotherapy (ESCOP). ESCOP monographs: the scientific foundation for herbal medicinal products. Stuttgart: Thieme, 2003Google Scholar
  19. 19.
    Bauer R. Quality criteria and standardization of phytopharmaceuticals: can acceptable drug standards be achieved. Drug Inf J 1998; 32: 101–10CrossRefGoogle Scholar
  20. 20.
    Bauer R, Tittel G. Quality assessment of herbal preparations as a precondition of pharmacological and clinical studies. Phytomedicine 1996; 2 (3): 193–8PubMedCrossRefGoogle Scholar
  21. 21.
    Busse W. The significance of quality for efficacy and safety of herbal medicinal products. Drug Inf J 2000; 34: 15–23CrossRefGoogle Scholar
  22. 22.
    Mrlianova M, Tekel’ova D, Felklova M, et al. The influence of the harvest cut height on the quality of the herbal drugs Melissae folium and Melissae herba. Planta Med 2002 Feb; 68 (2): 178–80PubMedCrossRefGoogle Scholar
  23. 23.
    Soldati F, Tanaka O. Panax ginseng: relation between age of plant and content of ginsenosides. Planta Med 1984 Aug; 50 (4): 351–2PubMedCrossRefGoogle Scholar
  24. 24.
    Sprecher E. Ginseng: miracle drug or phytopharmacon? Apoth J 1987; 9: 52–61Google Scholar
  25. 25.
    Kitagawa I, Taniyama T, Shibuya H, et al. Chemical studies on crude drug processing: V. On the constituents of ginseng radix rubra (2). Comparison of the constituents of white ginseng and red red ginseng prepared from the same Panax ginseng root. J Pharm Soc Jpn 1987; 107: 495–505Google Scholar
  26. 26.
    Lemli J, Cuveele J. Les transformations des hétérosides anthroniques pendant le séchage des feuilles de Cassia senna et de Rhamnus frangula. Planta Med 1978; 34: 311–8CrossRefGoogle Scholar
  27. 27.
    Stahl-Biskup E. Essential oil chemistry of the genus Thymus: a global view. In: Bussing A, editor. Medicinal and aromatic plants: industrial profiles. Amsterdam: Harwood Academic Publishers, 2002: 75–124Google Scholar
  28. 28.
    Stahl-Biskup E, Laakso I. Essential oil polymorphism in Finnish Thymus species. Planta Med 1990 Oct; 56 (5): 464–8PubMedCrossRefGoogle Scholar
  29. 29.
    DeFeudis FV. Ginkgo biloba extract (EGb 761): pharmacological activities and clinical applications. Amsterdam: Elsevier Science Publishers, 1991: 24Google Scholar
  30. 30.
    Kennedy DO, Scholey AB. Ginseng: potential for the enhancement of cognitive performance and mood. Pharmacol Biochem Behav 2003 Jun; 75 (3): 687–700PubMedCrossRefGoogle Scholar
  31. 31.
    Sünram-Lea SI, Birchall RJ, Wesnes KA, et al. The effect of acute administration of 400 mg of Panax ginseng on cognitive performance and mood in healthy young volunteers. Curr Top Nutraceut Res 2005; 3 (1): 65–74Google Scholar
  32. 32.
    Scaglione F, Pannacci M, Petrini O. The standardised G115 Panax ginseng C.A. Meyer extract: a review of its properties and usage. Evid Based Integr Med 2005; 2 (4): 195–206CrossRefGoogle Scholar
  33. 33.
    Van Schepdael P. Les effets du ginseng G115 sur la capacité physique de sportifs d’endurance. Acta Ther 1993; 19 (4): 337–47Google Scholar
  34. 34.
    Rosenfeld MS, Nachtajler SP, Schwartz GT, et al. Evaluation of the efficacy of a standardized ginseng extract in patients with psychophysical asthenia and neurological disorders. Semana Med 1989, 173 (9): 148–54Google Scholar
  35. 35.
    D’Angelo L, Grimaldi R, Caravaggi M, et al. A double-blind, placebo-controlled clinical study on the effect of a standardized Ginseng extract on psychomotor performance in healthy volunteers. J Ethnopharmacol 1986; 16 (1): 15–22PubMedCrossRefGoogle Scholar
  36. 36.
    Dörling E, Kirchdorfer AM, Rückert KH. Do ginsenosides influence the performance? Results of a double-blind study. Notabene Med 1980; 10 (5): 241–6Google Scholar
  37. 37.
    Fuzzati N, Gabetta B, Jayakar K, et al. Liquid chromatography-electrospray mass spectrometric identification of ginsenosides in Panax ginseng roots. J Chro-matogr A 1999 Aug 27; 854 (1–2): 69–79CrossRefGoogle Scholar
  38. 38.
    Soldati F. Panax ginseng: standardization and biological activity. In: Cutler SJ, Cutler HG, editors. Biologically active natural products: pharmaceuticals. Boca Raton (FL): CRC Press, 2000: 209–32Google Scholar
  39. 39.
    Shin JY, Song JY, Yun YS, et al. Immunostimulating effects of acidic polysaccharides extract of Panax ginseng on macrophage function. Immunopharmacol Immunotoxicol 2002; 24 (3): 469–82PubMedCrossRefGoogle Scholar
  40. 40.
    Song JY, Akhalaia M, Platonov A, et al. Effects of polysaccharide ginsan from Panax ginseng on liver function. Arch Pharm Res 2004; 27 (5): 531–8PubMedCrossRefGoogle Scholar
  41. 41.
    Mahady GB, Fabricant D, Chadwick LR, et al. Black cohosh: an alternative therapy for menopause? Nutr Clin Care 2002; 5: 283–9PubMedCrossRefGoogle Scholar
  42. 42.
    American Botanical Council. Ginseng evaluation program [online]. Available from URL:http://abc.herbalgram.org/site/DocServer/Ginseng_Evaluation_Program.pdf?docID=241 [Accessed 2008 Feb 20]
  43. 43.
    Hall T, Lu Z, Yat PN, et al. Evaluation of consistency of standardized Asian ginseng products in the Ginseng Evaluation Program. Herbalgram 2001; 52: 31–45Google Scholar
  44. 44.
    Ernst E. A reevaluation of kava. Br J Clin Pharmacol 2007; 64: 415–7PubMedCrossRefGoogle Scholar
  45. 45.
    Whittona PA, Laua A, Salisburyb A, et al. Kava lactones and the kava-kava controversy. Phytochemistry 2003; 64: 673–9CrossRefGoogle Scholar
  46. 46.
    Boerner RJ, Sommer H, Berger W, et al. Kava-Kava extract LI 150 is as effective as opipramol and buspirone in generalised anxiety disorder: an 8-week random-ized, double-blind, multi-centre clinical trial in 129 out-patients. Phytomedicine 2003; 10: 38–49PubMedCrossRefGoogle Scholar
  47. 47.
    Chan K. Some aspects of toxic contaminants in herbal medicines. Chemosphere 2003 Sep; 52 (9): 1361–71PubMedCrossRefGoogle Scholar
  48. 48.
    De Smet P. Overview of herbal quality control. Drug Inf J 1999; 33 (3): 717–24CrossRefGoogle Scholar
  49. 49.
    United States Pharmacopoeia [online]. Available from URL: http://www.usp.org/aboutUSP/contactUs.html [Accessed 2008 Feb 26]
  50. 50.
    World Health Organization, Regional Office for the Western Pacific, Manila. Research guidelines for evaluating the safety and efficacy of herbal medicines. 1993 [online]. Available from URL: http://www.wpro.who.int/publications/pub_9290611103.htm [Accessed 2008 Feb 12]Google Scholar
  51. 51.
    Committee on Herbal Medicinal Products. Guideline on non-clinical documentation for herbal medicinal products in applications for marketing authorization (bibliographical and mixed applications) and in applications for simplified registration. EMEA/HMPC/32116/2005. 2006 [online]. Available from URL: http://www.emea.europa.eu/pdfs/human/hmpc/3211605en.pdf [Accessed 2008 Feb 12]Google Scholar
  52. 52.
    Loew D, Kaszkin M. Approaching the problem of bioequivalence of herbal medicinal products. Phytoyher Res 2002; 16: 705–11CrossRefGoogle Scholar
  53. 53.
    Westerhoff K, Kaunzinger A, Wurglics M, et al. Biorelevant dissolution testing of St John’s wort products. J Pharm Pharmacol 2002 Dec; 54 (12): 1615–21PubMedCrossRefGoogle Scholar
  54. 54.
    Barnes J. Quality, efficacy and safety of complementary medicines: fashions, facts and the future: part I. Regulation and quality. Br J Clin Pharmacol 2003 Mar; 55 (3): 226–33PubMedCrossRefGoogle Scholar
  55. 55.
    Barnes J. Quality, efficacy and safety of complementary medicines: fashions, facts and the future: part II. Efficacy and safety. Br J Clin Pharmacol 2003 Apr; 55 (4): 331–40PubMedCrossRefGoogle Scholar
  56. 56.
    Schulz V, Hansel R, Blumenthal M, et al. Rational phytotherapy: a reference guide for physicians and pharmacists. 5th ed. Berlin: Springer Verlag, 2004Google Scholar
  57. 57.
    Ernst E. Jumping to conclusions. Phytomedicine 2003; 10 (8): 708–9PubMedCrossRefGoogle Scholar
  58. 58.
    Petrini O. Klinische Entwicklung von Phytopharmaka. Wien Med Wochenschr 2002; 152 (7–8): 204–8PubMedCrossRefGoogle Scholar
  59. 59.
    Szanto E, Gruber D, Sator M, et al. Placebo-controlled study of Melbrosia in treatment of climacteric symptoms [in German]. Wien Med Wochenschr 1994; 144 (7): 130–3PubMedGoogle Scholar
  60. 60.
    Kennedy DO, Scholey AB, Wesnes KA. Differential, dose dependent changes in cognitive performance following acute administration of a Ginkgo biloba/ Panax ginseng combination to healthy young volunteers. Nutr Neurosci 2001; 4 (5): 399–412PubMedGoogle Scholar
  61. 61.
    Kennedy DO, Scholey AB, Wesnes KA. Modulation of cognition and mood following administration of single doses of Ginkgo biloba, ginseng, and a ginkgo/ginseng combination to healthy young adults. Physiol Behav 2002 Apr 15; 75 (5): 739–51PubMedCrossRefGoogle Scholar
  62. 62.
    Reay JL, Kennedy DO, Scholey AB. Single doses of Panax ginseng (G115) reduce blood glucose levels and improve cognitive performance during sustained mental activity. J Psychopharmacol 2005 Jul; 19 (4): 357–65PubMedCrossRefGoogle Scholar
  63. 63.
    Reay JL, Kennedy DO, Scholey AB. The glycaemic effects of single doses of Panax ginseng in young healthy volunteers. Br J Nutr 2006 Oct; 96 (4): 639–42PubMedGoogle Scholar
  64. 64.
    Reay JL, Kennedy DO, Scholey AB. Effects of Panax ginseng, consumed with and without glucose, on blood glucose levels and cognitive performance during sustained ‘mentally demanding’ tasks. J Psychopharmacol 2006 Nov; 20 (6): 771–81PubMedCrossRefGoogle Scholar
  65. 65.
    Scaglione F, Cattaneo G, Alessandria M, et al. Efficacy and safety of the standardised ginseng extract G115 for potentiating vaccination against the influenza syndrome and protection against the common cold [corrected]. Drugs Exp Clin Res 1996; 22 (2): 65–72PubMedGoogle Scholar
  66. 66.
    Scaglione F, Cogo R, Cocuzza C, et al. Immunomodulatory effects of Panax ginseng C. A. Meyer(G 115) on alveolar macrophages from patients suffering with chronic bronchitis. Int J Immunother 1994; 10 (1): 21–4Google Scholar
  67. 67.
    Scaglione F, Ferrara F, Dugnani S, et al. Immunomodulatory effects of two extracts of Panax ginseng C.A. Meyer. Drugs Exp Clin Res 1990; 16 (10): 537–42PubMedGoogle Scholar
  68. 68.
    Scaglione F, Weiser K, Alessandria M. Effects of the standardised ginseng extract G115® in patients with chronic bronchitis: a nonblinded, randomised, compara-tive pilot study. Clin Drug Invest 2001; 21 (1): 41–5CrossRefGoogle Scholar
  69. 69.
    Scholey AB, Kennedy DO. Acute, dose-dependent cognitive effects of Ginkgo biloba, Panax ginseng and their combination in healthy young volunteers: differential interactions with cognitive demand. Hum Psychopharmacol 2002 Jan; 17 (1): 35–44PubMedCrossRefGoogle Scholar
  70. 70.
    Bars PLI, Katz MM, Berman N, et al. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. JAMA 1997; 278: 1327–32PubMedCrossRefGoogle Scholar
  71. 71.
    Bars PLI, Kieser M, Itil KZ. A 26-week analysis of a double-blind, placebocontrolled trial of the Ginkgo biloba extract EGb 761 in dementia. Dement Geriatr Cogn Disord 2000; 11: 230–7PubMedCrossRefGoogle Scholar
  72. 72.
    Bars PLI, Velasco FM, Ferguson JM, et al. Influence of the severity of cognitive impairment on the effect of the Ginkgo biloba extract EGb 761 in Alzheimer’s disease. Neuropsychobiology 2002; 45: 19–26PubMedCrossRefGoogle Scholar
  73. 73.
    Cockle SM, Kimber S, Hindmarch I. The effects of four months supplementation with Ginkgo biloba extract (LI 1370) on activities of daily living in an older population: a postal survey. Phytomedicine 2000; 7: 21CrossRefGoogle Scholar
  74. 74.
    Cohen AJ, Bartlik B. Ginkgo biloba for antidepressant-induced sexual dysfunction. J Sex Marital Ther 1998; 24: 139–43PubMedCrossRefGoogle Scholar
  75. 75.
    Dongen MV, Rossum EV, Kessels AGH, et al. The efficacy of ginkgo for elderly people with dementia and age-associated memory impairment: new results of a randomized clinical trial. J Am Geriatr Soc 2000; 48: 1183–94PubMedGoogle Scholar
  76. 76.
    Elsabagh S, Hartley DE, Ali O, et al. Effects of 6 weeks’ treatment with Ginkgo biloba on cognitive function and mood in a young healthy population. J Psychopharmacol 2003; 17: A61Google Scholar
  77. 77.
    Elsabagh S, Hartley DE, File SE. Limited cognitive benefits in stage +2 postmenopausal women after 6 weeks of treatment with Ginkgo biloba. J Psychopharmacol 2005; 19: 173–81PubMedCrossRefGoogle Scholar
  78. 78.
    Kanowski S, Herrmann WM, Stephan K, et al. Proof of efficacy of the Ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia. Pharmacopsychiatry 1996; 29: 47–56PubMedCrossRefGoogle Scholar
  79. 79.
    Kanowski S, Hoerr R. Ginkgo biloba extract EGb 761 in dementia: intent-to-treat analyses of a 24-week, multi-center, double-blind, placebo-controlled, randomized trial. Pharmacopsychiatry 2003; 36: 297–303PubMedCrossRefGoogle Scholar
  80. 80.
    Wesnes KA, Ward T, McGinty A, et al. The memory enhancing effects of a Ginkgo biloba/Panax ginseng combination in healthy middle-aged volunteers. Psychopharmacology 2000; 152: 353–61PubMedCrossRefGoogle Scholar
  81. 81.
    Schrader E. Equivalence of St John’s wort extract (Ze 117) and fluoxetine: a randomized, controlled study in mild-moderate depression. Int Clin Psychopharmacol 2000; 15: 61–8PubMedCrossRefGoogle Scholar
  82. 82.
    Sommer H. Improvement in psychovegetative symptoms by Hypericum in a multicenter double-blind study. Nervenheilkunde 1991; 10: 308–10Google Scholar
  83. 83.
    Taylor LV, Kobak KA. An open-label trial of St. John’s wort (Hypericum perforatum) in obsessive-compulsive disorder. J Clin Psychiatry 2000; 61: 575–8PubMedCrossRefGoogle Scholar
  84. 84.
    Vorbach EU, Huebner WD, Arnoldt KH. Effectiveness and tolerance of the hypericum extract LI 160 in comparison with imipramine: randomized double blind study with 135 out-patients. Nervenheilkunde 1993; 12: 290–6Google Scholar
  85. 85.
    Woelk H. Comparison of St John’s wort and imipramine for treating depression: randomised controlled trial. BMJ 2000; 321: 536–9PubMedCrossRefGoogle Scholar
  86. 86.
    Woelk H, Beneke M, Gebert I, et al. Hypericum extract Ze 117 versus imipramine: a randomised, controlled study in mild-moderate depression. Phytomedicine 2000; 7: 108Google Scholar
  87. 87.
    Birks J, Grimley EV, Van Dongen M. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev 2002; (4): CD003120PubMedGoogle Scholar
  88. 88.
    Ernst E. The risk-benefit profile of commonly used herbal therapies: ginkgo, St John’s wort, ginseng, echinacea, saw palmetto, and kava. Ann Intern Med 2002 Jan 1; 136 (1): 42–53PubMedGoogle Scholar
  89. 89.
    Ernst E, Pittler MH. Ginkgo biloba for dementia: a systematic review of doubleblind, placebo-controlled trials. Clinical Drug Invest 1999; 17 (4): 301–8CrossRefGoogle Scholar
  90. 90.
    Foster S. Black cohosh: Cimicifuga racemosa, a literature review. Herbalgram 1999; 45: 35–50Google Scholar
  91. 91.
    Kennedy DO, Scholey AB. The psychopharmacology of European herbs with cognition-enhancing properties. Curr Pharm Des 2006; 12 (35): 4613–23PubMedCrossRefGoogle Scholar
  92. 92.
    Oken BS, Storzbach DM, Kaye JA. The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease. Arch Neurol 1998 Nov; 55 (11): 1409–15PubMedCrossRefGoogle Scholar
  93. 93.
    Pittler MH, Vogler BK, Ernst E. Feverfew for preventing migraine. Cochrane Database Syst Rev 2000; (3): CD002286PubMedGoogle Scholar
  94. 94.
    Vogler BK, Pittler MH, Ernst E. The efficacy of ginseng: a systematic review of randomised clinical trials. Eur J Clin Pharmacol 1999 Oct; 55 (8): 567–75PubMedCrossRefGoogle Scholar
  95. 95.
    Whiskey E, Werneke U, Taylor D. A systematic review and meta-analysis of Hypericum perforatum in depression: a comprehensive clinical review. Int Clin Psychopharmacol 2001 Sep; 16 (5): 239–52PubMedCrossRefGoogle Scholar
  96. 96.
    Williams Jr JW, Mulrow CD, Chiquette E, et al. A systematic review of newer pharmacotherapies for depression in adults: evidence report summary. Ann Intern Med 2000 May 2; 132 (9): 743–56PubMedGoogle Scholar
  97. 97.
    Wilt TJ, Ishani A, Stark G, et al. Saw palmetto extracts for treatment of benign prostatic hyperplasia: a systematic review. JAMA 1998 Nov 11; 280 (18): 1604–9PubMedCrossRefGoogle Scholar
  98. 98.
    Wagner H. Futuro en la investigación en Fitoterapia: tendencias y retos. Revista Fitoterapia 2006; 6 (2): 101–17Google Scholar
  99. 99.
    De Smet PA. Herbal remedies. N Engl J Med 2002 Dec 19; 347 (25): 2046–56PubMedCrossRefGoogle Scholar
  100. 100.
    Newton KM, Reed SD, LaCroix AZ, et al. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Intern Med 2006 Dec 19; 145 (12): 869–79PubMedGoogle Scholar
  101. 101.
    Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288: 321–33PubMedCrossRefGoogle Scholar
  102. 102.
    Haynes B. Can it work? Does it work? Is it worth it? The testing of healthcare interventions is evolving. BMJ 1999 Sep 11; 319 (7211): 652–3PubMedCrossRefGoogle Scholar
  103. 103.
    Ernst E. Risks of herbal medicinal products. Pharmacoepidemiol Drug Saf 2004 Nov; 13 (11): 767–71PubMedCrossRefGoogle Scholar
  104. 104.
    Ernst E, Rand JI, Barnes J, et al. Adverse effects profile of the herbal antidepressant St. John’s wort (Hypericum perforatum L.). Eur J Clin Pharmacol 1998 Oct; 54 (8): 589–94PubMedCrossRefGoogle Scholar
  105. 105.
    James JS. St. John’s wort warning: do not combine with protease inhibitors, NNRTIs. AIDS Treat News 2000 Feb 18; 337: 3–5Google Scholar
  106. 106.
    Johne A, Brockmoller J, Bauer S, et al. Pharmacokinetic interaction of digoxin with an herbal extract from St John’s wort (Hypericum perforatum). Clin Pharmacol Ther 1999 Oct; 66 (4): 338–45PubMedCrossRefGoogle Scholar
  107. 107.
    Mai I, Kruger H, Budde K, et al. Hazardous pharmacokinetic interaction of Saint John’s wort (Hypericum perforatum) with the immunosuppressant cyclosporin. Int J Clin Pharmacol Ther 2000 Oct; 38 (10): 500–2PubMedGoogle Scholar
  108. 108.
    Castot A, Djezzar S, Deleau N, et al. Pharmacovigilance off the beaten track: herbal surveillance or pharmacovigilance of medicinal plants [in French]. Therapie 1997 Mar–Apr; 52 (2): 97–103PubMedGoogle Scholar
  109. 109.
    109.-Siegel RK. Ginseng abuse syndrome: problems with the panacea. JAMA 1979; 241: 1614–5PubMedCrossRefGoogle Scholar
  110. 110.
    Blumenthal M. Debunking the ginseng abuse syndrome. Whole Foods 1991 Mar: 89–92Google Scholar
  111. 111.
    Gilbert GJ. Ginkgo biloba. Neurology 1997; 48: 1137PubMedCrossRefGoogle Scholar
  112. 112.
    Lewis SL, Rowin J. Ginkgo biloba: reply from the authors. Neurology 1997; 48: 1137Google Scholar
  113. 113.
    Lewis SL, Rowin J. Ginkgo biloba: reply from the authors. Neurology 1997; 48: 789–90CrossRefGoogle Scholar
  114. 114.
    Lewis SL, Rowin J. Association of Ginkgo biloba with intracerebral hemorrhage: reply from the authors. Neurology 1998; 50: 1933–4CrossRefGoogle Scholar
  115. 115.
    Odawara M, Tamaoka A, Yamashita K. Ginkgo biloba. Neurology 1997; 48: 789PubMedCrossRefGoogle Scholar
  116. 116.
    Rosenblatt M, Mindel J. Spontaneous hyphema associated with ingestion of Ginkgo biloba extract. N Engl J Med 1997; 336: 1108PubMedCrossRefGoogle Scholar
  117. 117.
    Rowin J, Lewis SL. Spontaneous bilateral subdural hematomas associated with chronic Ginkgo biloba ingestion. Neurology 1996; 46: 1775–6PubMedCrossRefGoogle Scholar
  118. 118.
    Skogh M. Extracts of Ginkgo biloba and bleeding or haemorrhage. Lancet 1998; 352: 1145–6PubMedCrossRefGoogle Scholar
  119. 119.
    Vale S. Subarachnoid haemorrhage associated with Ginkgo biloba. Lancet 1998; 352: 36PubMedCrossRefGoogle Scholar
  120. 120.
    Vale S. Extracts of Ginkgo biloba and bleeding or haemorrhage. Lancet 1998; 352: 1146CrossRefGoogle Scholar
  121. 121.
    Nortier JL, Martinez M-CM, Schmeiser HH, et al. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med 2000; 342: 1686–92PubMedCrossRefGoogle Scholar
  122. 122.
    Bailey T, Klepser ME. Unsafe and potentially safe herbal therapies. Am J Health Syst Pharm 1999; 56: 125–38Google Scholar
  123. 123.
    Mahady GB. Ginkgo biloba: a review of quality, safety, and efficacy. Nutr Clin Care 2001; 4: 140–7CrossRefGoogle Scholar
  124. 124.
    Kaufman DW, Kelly JP, Rosenberg L, et al. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 2002 Jan 16; 287 (3): 337–44PubMedCrossRefGoogle Scholar
  125. 125.
    Cvetkovic RS, Goa KL. Lopinavir/ritonavir: a review of its use in the management of HIV infection. Drugs 2003; 63 (8): 769–802PubMedCrossRefGoogle Scholar
  126. 126.
    Henderson L, Yue QY, Bergquist C, et al. St John’s wort (Hypericum perforatum): drug interactions and clinical outcomes. Br J Clin Pharmacol 2002; 54(4): 349–56PubMedCrossRefGoogle Scholar
  127. 127.
    Markowitz JS, De Vane CL, Boulton DW, et al. Effect of St John’s wort (Hypericum perforatum) on cytochrome P-450 2D6 and 3A4 activity in healthy volunteers. Life Sci 2000; 66 (9): PL133–9PubMedCrossRefGoogle Scholar
  128. 128.
    Piscitelli S, Burstein A, Chaitt D, et al. Indinavir concentrations and St John’s wort. Lancet 2000; 355 (9203): 547–8PubMedCrossRefGoogle Scholar
  129. 129.
    Yue Q, Bergquist C, Gerdén B. Seven cases of decreased effect of warfarin during concomitant treatment with St John’s wort. Lancet 2000; 355 (9203): 576–7PubMedCrossRefGoogle Scholar
  130. 130.
    Arold G, Donath F, Maurer A, et al. No relevant interaction with alprazolam, caffeine, tolbutamide, and digoxin by treatment with a low-hyperforin St John’s wort extract. Planta Med 2005 Apr; 71 (4): 331–7PubMedCrossRefGoogle Scholar
  131. 131.
    Hohl K, Gaus W. Bibliography on herb-drug and food-drug interactions [online]. Available from URL: http://www.uni-ulm.de/uni/fak/medizin/biodok/v4/herb_drug_interactions.html [Accessed 2008 Feb 12]Google Scholar
  132. 132.
    Schmid EF, Smith DA, Ryder SW. Communicating the risks and benefits of medicines. Drug Disc Today 2007 May; 12 (9–10): 355–64CrossRefGoogle Scholar
  133. 133.
    Committee on Herbal Medicinal Products. Annex 1. Assessment of case reports connected to herbal medicinal products containing cimicifugae racemosae rhizome (black cohosh, root). London, 8 May 2007. Doc. Ref. EMEA/269258/ 2006 Rev 1 [online]. Available from URL: http://www.emea.europa.eu/pdfs/ human/hmpc/26925806en.pdf [Accessed 2008 Feb 12]Google Scholar
  134. 134.
    Vanaclocha B, Cañigueral S. Posible hepatotoxicidad del rizoma de cimicífuga. Revista Fitoterapia 2006; 6 (2): 129–35Google Scholar
  135. 135.
    ClinicalTrials.gov, US National Institute of Health [online]. Available from URL: http://clinicaltrials.gov/ct2/results?term=herbal+AND+herbals [Accessed 2008 Feb 27]Google Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  • Salvador Cañigueral
    • 1
  • Roger Tschopp
    • 2
  • Lara Ambrosetti
    • 2
  • Alberto Vignutelli
    • 2
  • Francesco Scaglione
    • 3
  • Orlando Petrini
    • 4
  1. 1.Unitat de Farmacologia i Farmacognòsia, Facultat de FarmàciaUniversitat de BarcelonaBarcelonaSpain
  2. 2.Pharmaton SABioggioSwitzerland
  3. 3.Department of Pharmacology, Chemotherapy and Toxicology, Faculty of MedicineUniversity of MilanMilanItaly
  4. 4.Cantonal Institute of MicrobiologyBellinzonaSwitzerland

Personalised recommendations