Eisenberg et al. added to low dose estrogen, might have resulted in an additive or synergistic effect powerful enough to alter the course of disease in men with advanced prostate cancer A second case of note involved the evaluation of the herb Echinacea echinacea angustifolia DC. )in the prevention of rhinovirus infection(i.e. the common cold). In this study, 437 volunteers were proactively infected with rhinovirus [15. Subjects were then randomized to four groups. Three of the groups received various preparations and doses of a commonly sold Echinacea extract and one group received a placebo. There were no significant differences across groups with regard to rates of infection, severity of symptoms or viral titers. as such. the trial was considered to have refuted claims of clinical effectiveness of Echinacea. Subsequently, the New England Journal of Medicine published criticisms of the study's design [16]. These included the suggestion that a different Echinacea species might have been preferable; that the dose used in the study was far too low(by a factor of 6 )and that a higher dose might have made this trial more clinically and cientifically relevant [16] a third study involved the evaluation of a popular over-the-counter preparation of the herb saw palmetto(Serenoa repens(w. BartramSmall) in the treatment of benign prostatic hypertrophy [17]. In this study, 225 subjects were randomized to two groups, one receiving a Saw Palmetto extract in the form of a popular over-the-counter supplement and the other group receiving a placebo. There were no significant differences observed between these two groups in terms of symptomatic improvement. An accompanying editorial [18] commented that the study authors had tested a single, commercially available preparation of saw palmetto, thereby leaving open the possibility that a different preparation might still be ffective. Furthermore, these authors contended that in the absence of a plausible mechanism of action, a fair comparison of this herb(or its constituents)to a more conventional FDA approved therapeutic drug, would be problematic if not impossible Lessons learned from these and other ambitious(and expensive)clinical trials suggest that uture human clinical trials involving herbal products must ensure the reproducibility and quality of the intervention materials; and, will require an understanding of mechanisms of action and dosing prior to the implementation of new, large scale(and expensive)Phase or Ill clinical trials. The current NIH guidelines involving candidate herbal therapies reflect many of these hard learned lessons [19] as do the Consort Guidelines for publications involving randomized controlled trials involving herbal interventions [201 In hindsight, these were methodological inadequacies uncovered by individuals skilled the design and conduct of clinical trials. They provided part of the rationale for the study described in this manuscript. What about methodological challenges from the vantage point of other relevant experts including researchers skilled in botany, chemistry, ethnobotany and drug discovery 4.2. Lessons learned from the vantage point of drug discovery and ethnobotany 933 The current place of natural products in modern drug discovery is inconsistent with their past performance and future potential. Natural products have made, and continue to make substantial contributions both to understanding basic biological processes and treating human disease. If we focus on cancer, natural products from plants have led to frontline therapies such as paclitaxel, vinblastine, camptothecin and etoposide [4]. If we look at the immediate future, geldanamycin analogs- to pick just one example-are being pursued in clinical trials [21, 22]. Thus there is a strong scientific argument for continuing to explore natural products in drug discovery -an argument that is largely unheeded as pharmaceutical companies cut back on, or eliminate, their natural product programs Authoadded to low dose estrogen, might have resulted in an additive or synergistic effect powerful enough to alter the course of disease in men with advanced prostate cancer. A second case of note involved the evaluation of the herb Echinacea (Echinacea angustifolia DC.) in the prevention of rhinovirus infection (i.e. the common cold). In this study, 437 volunteers were proactively infected with rhinovirus [15]. Subjects were then randomized to four groups. Three of the groups received various preparations and doses of a commonly sold Echinacea extract and one group received a placebo. There were no significant differences across groups with regard to rates of infection, severity of symptoms or viral titers. As such, the trial was considered to have refuted claims of clinical effectiveness of Echinacea. Subsequently, the New England Journal of Medicine published criticisms of the study’s design [16]. These included the suggestion that a different Echinacea species might have been preferable; that the dose used in the study was far too low (by a factor of 6) and that a higher dose might have made this trial more clinically and scientifically relevant [16]. A third study involved the evaluation of a popular over-the-counter preparation of the herb saw palmetto (Serenoa repens (W. Bartram) Small) in the treatment of benign prostatic hypertrophy [17]. In this study, 225 subjects were randomized to two groups, one receiving a Saw Palmetto extract in the form of a popular over-the-counter supplement and the other group receiving a placebo. There were no significant differences observed between these two groups in terms of symptomatic improvement. An accompanying editorial [18] commented that the study authors had tested a single, commercially available preparation of saw palmetto, thereby leaving open the possibility that a different preparation might still be effective. Furthermore, these authors contended that in the absence of a plausible mechanism of action, a fair comparison of this herb (or its constituents) to a more conventional FDA approved therapeutic drug, would be problematic if not impossible. Lessons learned from these and other ambitious (and expensive) clinical trials suggest that future human clinical trials involving herbal products must ensure the reproducibility and quality of the intervention materials; and, will require an understanding of mechanisms of action and dosing prior to the implementation of new, large scale (and expensive) Phase II or III clinical trials. The current NIH guidelines involving candidate herbal therapies reflect many of these hard learned lessons [19] as do the Consort Guidelines for publications involving randomized controlled trials involving herbal interventions [20]. In hindsight, these were methodological inadequacies uncovered by individuals skilled in the design and conduct of clinical trials. They provided part of the rationale for the study described in this manuscript. What about methodological challenges from the vantage point of other relevant experts including researchers skilled in botany, chemistry, ethnobotany and drug discovery? 4.2. Lessons learned from the vantage point of drug discovery and ethnobotany The current place of natural products in modern drug discovery is inconsistent with their past performance and future potential. Natural products have made, and continue to make, substantial contributions both to understanding basic biological processes and treating human disease. If we focus on cancer, natural products from plants have led to frontline therapies such as paclitaxel, vinblastine, camptothecin and etoposide [4]. If we look at the immediate future, geldanamycin analogs – to pick just one example – are being pursued in clinical trials [21,22]. Thus there is a strong scientific argument for continuing to explore natural products in drug discovery —an argument that is largely unheeded as pharmaceutical companies cut back on, or eliminate, their natural product programs. Eisenberg et al. Page 4 Fitoterapia. Author manuscript; available in PMC 2012 January 1. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript