Next month I will examine treatment of ‘the andropause’.
The genesis of a phyto-pharmaceutical industry (Mark II)
Version of Record online: 16 APR 2003
Volume 91, Issue 7, pages 721–722, May 2003
How to Cite
Wyllie, M. G. (2003), The genesis of a phyto-pharmaceutical industry (Mark II). BJU International, 91: 721–722. doi: 10.1046/j.1464-410X.2003.04212.x
- Issue online: 16 APR 2003
- Version of Record online: 16 APR 2003
To a large extent the use of natural products, and more specifically plant extracts, underpins the rise of the pharmaceutical industry. The roles of Penicillium notatum, Digitalis purpurea, Salix alba and Papaver somniferum, and extracts or derivatives thereof, in the well-being of the pharmaceutical industry are well known.
Until recently, at least within the pharmaceutical industry, there has been a general movement away from natural products into rational drug design and development. However, it would appear that we are entering an era where the clinical potential of natural products is increasingly under the spotlight. The rise in popularity of alternative preparations may be indicative of a general move away from traditional treatment algorithms. It may also be evidence of a greater awareness of the adverse effects of many pharmacological agents or a widening desire among patients for greater personal control over their health status. Quality-of-life issues, e.g. the effects of drugs on the ability of the patient to carry out activities of daily living, and their influence on sexual function, are of great importance to patients and, consequently, should also be of concern to their physicians. Particularly important is the high degree of comorbid LUTS and sexual dysfunction that has recently become apparent. Conventional treatments for BPH, e.g. tamsulosin and finasteride, have been linked to a variety of negative effects, particularly relating to sexual function, which may seriously affect patients’ quality of life. Issues of patient choice, which are likely to come to the fore as the general public becomes more informed about medicine in general and their own health in particular, may mean that perceived ‘natural’ options are preferable to synthetic alternatives. So what is the prospect with respect to phytotherapy for the urological patient, physician and healthcare provider? In recognition of the attention span of the reader, only the case history for BPH is described below.
It is only within the last decade that the medical management of LUTS associated with BPH, using either α-blockers and/or 5α-reductase inhibitors, has become well accepted and widely used. Over this period there has also been an increase in use of non-pharmacological, alternative and herbal therapies for a variety of conditions, including those of the prostate. Although this was initially perceived as a European phenomenon, it was calculated by the AUA, on surveying members in 2001, that more than half of patients arriving in the urologist's office may have tried herbal remedies. Apparently, over $3 billion of over-the-counter sales of saw palmetto (Serenoa repens) were generated in the USA in that year. Herbal therapies commonly used in the treatment of LUTS include S. repens, Pygeum africanum and Urtica dioica, among others.
Over the past 20 years, several brands of S. repens extract have become available in Europe. In particular Permixon® (Pierre-Fabre), which is a specific chemically-characterized, lipido-sterolic extract of S. repens, is the most commonly administered ‘alternative’ treatment for LUTS. There have been relatively few trials of so-called phyto-pharmaceuticals and correspondingly, in the present era of evidence-based medicine, until recently it had not been possible to attempt to define precisely the potential role of S. repens or indeed any other extract in the management of LUTS.
It is recognised that individual clinical trials may be conducted for a variety of reasons, including meeting marketing objectives. In determining the relative clinical potential of a series of drugs, ideally studies should include comparison agents and placebo, but this is rarely the case. In the absence of such data, in an attempt to create ‘a level playing field’ independent analysis of all clinical data using meta-analysis is considered to be the most reliable alternative. Boyle et al., in a meta-analysis based on 2859 patients involved in 13 clinical trials of S. repens, showed that the maximum urinary flow rate and measures of nocturia improved significantly with use of the drug compared to placebo. An updated study (to be presented at the AUA meeting in 2003) of all currently published data for S. repens by the same team, involved a further 1963 men from four randomized studies. The additional data allowed an examination of the effect of Permixon on the IPSS and showed that, in addition by improving peak flow, by a mean (sd) of 2.28 (0.29) mL/s over the placebo, and nocturia, by a mean of 1.01 (0.13) times/night over placebo, the drug also caused a significant decrease in the IPSS, of − 4.7 (0.41). The changes induced by Permixon are at least as great as those described in the equivalent meta-analyses for terazosin and finasteride.
However, there is an Orwellian caveat, in that not all brands of S. repens are equal. As the content of different brands differs significantly, it was suggested that there will be a corresponding effect on both biological and clinical activity. In this context, a recent study by Feifer et al. indicated that six randomly-selected brands of the lipido-sterolic extract of S. repens contain actual dosages of −97% to +140% of that stated. Three brands actually contained < 20% of the amount stated on the packaging. Clinical efficacy may be significantly compromised if the active elements of a medication are present in far higher or lower concentrations than stated. In addition, the perceptions of the patient and doctor about the reliability of a particular product may be influenced by such discrepancies. The International Consultation on BPH has therefore recommended that even products derived from the same source be submitted to separate and rigorous evaluation in both clinical and pharmacological trials.
It would appear however, based on individual studies, that S. repens is not only equivalent to finasteride but also to α-blockers in terms of efficacy, durability and speed of treatment effect. One area of clinical differential would appear to be sexual side-effects. In comparative studies, Permixon is apparently devoid of the negative effects of finasteride and tamsulosin on erectile and ejaculatory function, respectively. The high degree of comorbid sexual dysfunction in patients with LUTS has recently become apparent. Thus, the lack of sexual dysfunction induced by S. repens may have important implications for patient preference.
The major impetus for the ‘legitimisation’ of phytotherapy for treating urological disease (or at least LUTS) has been the investment by Pierre-Fabre into scientific and clinical research. Several smaller European companies are conducting clinical research in this area. Of these, Oxford Natural Products offers the advantage of being able to conduct clinical programmes with well-characterized extracts or mixtures of defined composition. This level of chemical definition will become mandatory for regulatory approval. The quality of the clinical data, coupled with the magnitude of the commercial opportunity, has not surprisingly created an increased level of interest in phyto-pharmaceuticals within the industry.