Natural bioactive compounds as therapeutic candidates for benign prostatic hypertrophy

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Summary: Naturamed have developed a stringent supply and extraction/purification process to produce phytotherapeutics with efficacy against well established targets for the treatment of benign prostatic hypertrophy (BPH). The BPH therapeutics market has progressed little over the past 10 years and is likely to remain focused on 5-a-reductase inhibitors for the foreseeable future. Despite the lack of movement therapeutically, the market is expanding in size and value along side growing awareness of BPH and population ageing. The BPH market is characterized by a general consumer and clinician acceptance for phytotherapeutics and indeed Permixon, an extract of saw palmetto with 5-a-reductase inhibitory activity holds a large share of the market. Hurdles to the phytotherapeutic sector are largely related to non-stringent extraction processes, quality control and variability in starting materials. Naturamed have overcome these obstacles in the standardization of their NABIA production process. NABIA fractions are able to both antagonize 5-a-reductase and block a-adrenoceptors with an efficacy similar to reference treatments. This dual approach offers an improved approach to BPH as well as additional therapeutic potential for the treatment of erectile dysfunction, a condition that is highly prevalent in the same population segment. Clinical trials are anticipated to commence in 2003 and corporate partners are now being sought to speed the development of NABIA fractions towards the market. Partners are likely to come from the drug development sector.

The etiology of benign prostatic hyperplasia (BPH) is unknown but may involve hormonal changes associated with aging. Multiple fibroadenomatous nodules occur in the periurethral region of the prostate gland, probably originating within the periurethral glands rather than in the true fibromuscular prostate, which is displaced peripherally by progressive growth of the nodules. The hyperplasia may involve the lateral walls of the prostate (lateral lobe hyperplasia) or tissue at the inferior margin of the vesical neck (middle lobe hyperplasia). Histologically, the tissue is glandular, with varying proportions of fibrous stroma interposed.

As the lumen of the prostatic urethra becomes compromised, urine outflow is progressively obstructed, accompanied by hypertrophy of the bladder detrusor, trabeculation, cellule formation, and diverticula. Incomplete bladder emptying causes stasis and predisposes to infection with secondary inflammatory changes in the bladder and the upper urinary tract. Urinary stasis predisposes to calculus formation. Prolonged obstruction, although incomplete, can produce hydronephrosis and compromise renal function. A more frequent complication of BPH is the development of bladder instability and voiding problems which are not only a problem with respect to quality of life, but in the elderly or immobile underlies a serious risk of injuries caused by falls. As a result, bladder instability is one of the major reasons for the elderly entering into care homes. BPH has recently been associated with premature ejaculation, which although is not a serious medical condition it can depreciate quality of life and is as common as erectile dysfunction.

The prevalence of BPH has been difficult to determine with accuracy due the lack of a common definition. Based on autopsy studies, the prevalence of histologically diagnosed BPH increases from 8% in men aged 31 to 40 years to 40 to 50% in men aged 51 to 60 years and more than 80% in men older than 80 years. However, based on clinical criteria in men aged 55 to 74 years without prostate cancer, the prevalence of BPH is 19% using the criteria of a prostate volume greater than 30 mL and a high International Prostate Symptom score. If further criteria of a maximal urinary flow rate less than 10 mL/sec, and a post-void residual urine volume greater than 50 mL are included this incidence drops to 4%. As shown from the figure to the right, hyperplasia, obstruction and symptoms are not mutually inclusive. In the absence of serious clinical problems therefore, actual prevalence of BPH in men who are troubled by symptoms is possibly a more important statistic than the prevalence of BPH per se. Data from the Baltimore Longitudinal Study of Ageing suggest that the prevalence of symptomatic BPH is around 14% in men in their 40s, 24% in men in their 50s, and 43% in men beyond the age of 60. Being troubled by symptoms can produce a range of life-style changes. About half of the men with evidence of obstructive BPH reported interference with one or more aspects of daily life. The frequency of BPH especially in the current climate of population aging and the effects of this condition, both with respect to life-style in the mobile and institutionalization in the less mobile suggests that an understanding of the etiology of BPH and the availability of effective treatments should be an important clinical objective.

Etiology and Pathophysiology of BPH: The etiology, pathophysiology, therapeutic targets and treatment option surrounding BPH will only be described in brief here on the assumption that most readers will be well versed in the field however a full report can be produced on request (Click here for more). Prostatic obstruction has its origin in two elements: the static and the dynamic. The static component is related to enlargement of both the stroma and the epithelium of the prostate gland. This phenomenon is related to the concentration of dihydrotestosterone (DHT). DHT is produced by reduction of testosterone catalyzed by the enzyme 5-a-reductase in the epithelial cells of prostate. As testosterone levels drop with the development of BPH, so to do estrogens levels increase. Estrogen is produced by the conversion of androgens to estrogen by aromatase and is elevated and concentrated in the stroma. This has a feed-forward effect on the epithelium contributing to the proliferative activity of the prostate. Gland enlargement results in compression of the urethra contributing to outlet obstruction, especially following enlargement of the periurethral prostate. The dynamic component is generated from the tension of the prostate and the bladder smooth muscle. Smooth muscle contraction in the urethra, prostatic stroma and bladder neck contribute to the symptoms of BPH. The tension of prostatic smooth muscle is controlled by high-affinity a-1-adrenergic receptors.

Treatment of BPH: When BPH is associated with urinary tract infection or kidney dysfunction, initial therapy should be medical, directed toward stabilizing renal function, discontinuing anticholinergic and sympathomimetic drugs, and eradicating infection. Urethral or suprapubic catheter drainage may be desirable in advanced bladder outlet obstruction. The most commonly used pharmacological approaches to BPH include the use a 5-a-reductase inhibitor such as finasteride to reduce DHT production to normal levels. 5-a-reductase inhibitors limit the static component of BPH thus reducing prostate size and as a result improving voiding over time (months), especially in patients with large glands. Likewise, for some patients with mild to moderate obstructive symptoms, a-adrenergic blockers such as terazosin may improve voiding. The prostatic stroma plays a major role in the development of BPH. As mentioned above, estrogens control stromal - epithelial interactions, which in return, regulate the proliferative activity of the prostate. Peripheral conversion of androgens to estrogen by aromatase may lead to stimulation of stromal-epithelial interaction, resulting in enlargement of the prostate. Using aromatase inhibitors may prevent this process however clinical data has not been promising. For example Radlmaier et al (1996) and Gingell et al (1995) both failed to observe a therapeutic effect of atamestane in BPH patients. These negative effects may be due to the estrogen reduction secondary to the use of aromatase inhibitors causing a rise of androgen precursors. Thus it has been suggested that dual aromatase/5-a-reductase may offer benefit however again this is not supported by data showing that this protocol causes an increase in testosterone and DHT levels and a concomitant increase in prostatic volume in canine spontaneous BPH (Suzuki et al, 1998). Definitive therapy is surgical. Although sexual potency and continence are usually retained, about 5 to 10% of patients will experience some postsurgical problems. Transurethral resection of the prostate (TURP) is preferred. Larger prostates may require open surgery using the suprapubic or retropubic approach. The incidence of impotence and incontinence is much higher than after TURP. All surgical methods require postoperative catheter drainage for 1 to 5 days. Alternative surgical approaches include intraurethral stents, microwave thermotherapy, high-intensity focused ultrasound thermotherapy, laser ablation, electrovaporization, and radio frequency vaporization.

Phytotherapeutics have received considerable attention from the pharmaceutical industry. In fact over 150 plant derived products are in development or on the market (click here to access table). With respect to the treatment of BPH, Novogen's Promensil (PO-4) which is a combination of phytoestrogens derived from red clover and developed to treat the symptoms of menopause is currently in phase II development for BPH. More advanced is Permixon (saw palmetto; Serenoa repens), which was launched in 1984 and is now considered the reference BPH phytotherapeutic. Permixon is a "regulated" formulation of saw palmetto, which is derived from the liposterolic extract of the berry of the plant Serenoa Repens (the American dwarf palm tree). Permixon has not been launched in the US and instead "non-regulated" sources of saw palmetto are frequently used. Despite the relative paucity of phytotherapeutic molecules in development for BPH compared to other indications, phytotherapy through OTC agents has become a popular treatment option among BPH sufferers. In addition to Permixon and other forms of saw palmetto, Pygeum africanum and beta-sitosterol are also used by many patients with BPH, either alone or in combination with saw palmetto.

Wilt et al (2003) have reviewed the clinical evidence to support the use of Permixon. Trials were eligible if they were randomized and if they included clinical outcomes such as urologic symptom scales, symptoms, or urodynamic measurements. In total, 3139 men from 21 randomized trials lasting 4 to 48 weeks were assessed. Compared with placebo, Permixon improved urinary symptom scores, symptoms, and flow measures. Compared with finasteride, Permixon produced similar improvements in urinary symptom scores and peak urine flow. Adverse effects due to Permixon were mild and infrequent. While Permixon has been shown to have an equivalent efficacy to finasteride in patients with BPH, fewer comparison of phytotherapy with a-adrenergic blockers. In another study Debruyne et al (2002) have assessed the equivalent efficacy of Permixon and tamsulosin a reference a-adrenergic blocker. This study demonstrated that Permixon and tamsulosin are equivalent in the medical treatment of lower urinary tract symptoms in men with BPH, during and up to 12 months of therapy.

The mechanism of action of Permixon is unclear, however it has been shown to be an effective inhibitor of both 5-a-reductase types I and II isoenzymes. Treatment with Permixon thus caused a statistically significant reduction in DHT levels in the periurethral region of prostate tissue taken from BPH sufferers (Di Silverio et al, 1998). Cells which had been treated with the drug demonstrated extensive accumulation of lipids in the cytoplasm and widespread damage of intracellular membranes, including mitochondrial and nuclear membranes (Bayne et al, 1999). Consistent with these cell damaging effects, Vacherot et al (2000) reported that it inhibited proliferation and induced cell death in both epithelium and stroma of prostate taken from BPH sufferers. Unlike other 5-a-reductase inhibitors, Permixon does not interfere with the cells' capacity to secrete PSA, thus permitting the continued use of PSA measurements for prostate cancer screening

Compared to men receiving placebo, Pygeum africanum, the extract of the African prune tree bark (Tadenan), also provided a moderately large improvement in the combined outcome of urologic symptoms and flow measures in men with BPH (Wilt et al, 2002). Men using Pygeum africanum were more than twice as likely to report an improvement in overall symptoms and nocturia was reduced by 19%, residual urine volume by 24% and peak urine flow was increased by 23%. Adverse effects due to Pygeum Africanum were mild and comparable to placebo. It should be noted however that studies were small in size, were of short duration, used varied doses and preparations and rarely reported outcomes using standardized validated measures of efficacy.

A significant limiting factor to our understanding of the use and effectiveness of phytotherapy is the lack of standardization of these products. Feifer et al (2002) found that commonly used nutritional supplements for prostate disease vary widely in measured dose. Saw palmetto demonstrated tremendous variability with some samples containing virtually no active ingredients. This is due to different extraction procedures used by the different manufacturers and variations of the raw products (plants) used. Hence in order to fully exploit the BPH phytotherapeutic market standardization must be improved. To date standardization has been largely restricted to Permixon. Furthermore although phytotherapeutic have generally been evaluated and marketed separately there remains considerable potential for formulations that combine multiple active ingredients and which target different aspects of BPH etiology, for example 5-a-reductase and a-adrenergic blockers.

To date Naturamed has passed a number of milestones depicted in the flow chart below and as a result NABIA fractions are now ready for clinical trial.

Development history of NABIA

Control of starting materials

Agro technological variation (for example differences in strain, climate, growth conditions) can cause considerable variation in the levels of bioactive material in raw material. This issue has been addressed by Naturamed so that the starting material used to produce NABIA fractions is standardized. Agro variable have been verified and validated in order to specify the best and most consistent quality of the raw material. Several species of the same plant were tested and the optimal species as well as the exact harvest conditions required have been validated. A reliable controlled source of raw materials has been found and availability established. Standard analytical methods have been developed to test specifications of raw material and limits have been set to determine acceptance criteria. In setting up these controls, Naturamed have therefore overcome one of the major obstacles to phytotherapeutic acceptance, source variation.

Standardization of extraction and purification process

Having standardized starting materials, Naturamed's extraction and purification process was also standardized. Each NABIA fraction was prepared from a single anatomical part of a single plant species. The process consists of an initial extraction by organic solvent and then a purification process. This purification process involves a unique and proprietary sequence of separation steps that produces a series of purified fractions. The whole process is highly controlled and is standardized by liquid chromatography. Batch-to-batch repetition have demonstrated that the process is very reproducible. The process has been scaled up and 150 kg of raw material have been processed with the same in vitro results as those obtained at the development stage. The isolation and chemical definition of active ingredients derived from these fractions has been achieved. As with the supply and extraction/purification process, analytical tools have also been standardized and together this rigorous approach can now guarantee the supply of fractions of reproducible quantity and quality.

Screening of fractions

Standard assays of a1 adrenoceptor antagonism, 5-a-reductase inhibition and aromatase inhibition have been established and used to characterize NABIA fractions.

Chemical characterization of NABIA fractions: Five separate NABIA fractions have been evaluated pharmacologically, NABIA A, B, D, E and G. Each of these has been analyzed using Gas Chromatography/Mass Spectrometry (GC-MS) and high performance liquid chromatography (HPLC). The composition of fractions D, E and G is given below.

5-a-reductase activity can be determined in a number of standard assays, each of which are routinely employed in house at Naturamed. These assays include a rat liver microsomal assay that measures type I and type II 5-a-reductase activity by determining the disappearance of NADPH photospectrophometrically from a reaction mixture containing testosterone as the substrate (Sun et al, 1998). A second assay is available that allows for the measurement of [1,2,6,7,-3H(N)]testosterone reduction by a reaction mixture containing human hypertrophic prostate tissue obtained at surgery. Steroids levels are determined by liquid scintillation spectrophotometry following their separation by TLC according to Brooks et al (1981). Prostate preferentially expresses type II 5-a-reductase. A third assay follows a similar protocol with the exception that human foreskin fibroblasts were used as a source of type I and type II 5-a-reductase (Evans et al, 1995). This third assay was used to demonstrate that three NABIA fractions exhibited similar activity to that of Saw Palmetto (Table 1) although it should be noted that finasteride does exhibit greater activity.

Table1. Comparison of IC₅₀ for different 5-a-reductase inhibitors (results from human foreskin fibroblasts model)
Drug/fraction	Finasteride	Saw Palmetto	NABIA D	NABIA G	NABIA F
IC₅₀, ng/ml	10	10000	40000	30000	25000

Aromatase activity can be assayed using human placental extract according to Thompson & Siiteri (1974). Enzyme activity was determined by measuring the appearance of tritiated water as a result of [1beta,2beta-³H(N)]-androst-4-ene-3,17-dione aromatization. Orimetene, an aromatase inhibitor used in the treatment of breast cancer was used as a reference compound. Various NABIA fractions demonstrated aromatase inhibition however fractions A and B contained the most potent activity and in particular NABIA A was more potent that Orimetene (Table 2).

Table 2. Comparison of IC₅₀ for different aromatase inhibitors.
Drug/fraction	Orimetene	NABIA A	NABIA B
IC₅₀, mkg/ml	70	58	200

a1 adrenoceptor antagonism was measured according to Catret et al (1998). Briefly this assay measures binding of [H³]prazosin to rat cerebral cortex a adrenoceptors. As shown in Table 3 only fractions D and E had appreciable affinity in this assay. In both cases affinity was similar to the reference terazosin, a reference a adrenoceptor blocker that has been used for the treatment of BPH

Table 1. Comparison of IC₅₀ from two groups of a-blockers.
Group	Synthetic a-blockers	Natural a-blockers
Drug/fraction	Terazosin	Saw Palmetto	Fraction D	Fraction E
IC₅₀	~10² ng/ml	~300 *10⁸ ng/ml	10³ ng/ml	5*10⁴ ng/ml

In summary therefore a mixture of NABIA D, E, F and G fractions may be expected to combine 5-a-reductase inhibitory and a1 adrenoceptor antagonist activity. This profile may be expected to reduce both prostatic hyperplasia and smooth muscle tone thereby offering a bimodal approach to BPH, contrasting with existing treatments which target only one aspect of this condition. Inclusion of NABIA A and/or B would add further aromatase inhibitory activity however proof of concept surrounding such an approach has not yet been established. Instead these fraction may represent a promising approach to breast cancer.

Drug Safety: Side effects are not expected under clinical conditions since the botanical raw material from which NABIA fractions are fractionated have been used safely for decades in folkloristic medicine. Furthermore the raw material is currently sold as food supplement and have been used culinary for hundreds of years in many parts of the world. Nevertheless, small mammal toxicity studies have been performed and to date these expectation have been substantiated since none of the fractions produced toxicity at doses up to 5,000mg/kg. Animal trials were carried out for: NABIA D, NABIA E, NABIA G and the mixture NABIA D+E+G. Acute systemic toxicity in standard and relevant organs including hair, liver and skin was assessed.

Clinical Human Studies: The "Helsinki Committee" (same as the IRB) of Western Galilee Hospital (Naharia) had approved a randomized, double blind, placebo controlled clinical trial of NABIA in patients with BPH. This trial will include 100 patients and is planned to commence during the first quarter of 2003 following final approval from the Israeli Ministry Of Health.

Market values and development trends: The annual global sales figures for pharmaceutical treatments of BPH has been estimated by Decision Resources to have been $0.9 billion in 1997 and predicted to rise to $1.3 billion by 2007. Other analysts predict an even more lucrative market with Lehman Brothers estimating that the worldwide market value for BPH grew by 12% between 1998-2001, and is expected to grow a further 15% between 2001-2005 (forecast to reach US$3.5 billion). Peak sales of the once-daily treatment Xatral (alfuzosin) are expected to reach £230 million

BPH is essentially an aging disease and consequently the incidence of this condition is likely to rise along side the aging population. From the table below it can be seen that treatment options and drugs in development are almost exclusively adrenoceptor antagonists or testosterone related. Furthermore from the trends analysis it can be seen that the number of drugs in development is dropping. This coupled with a reduction is research efforts (the number of publications relating to BPH has dropped by around 35% over the past 7 years) suggests that major advances and new pharmacological targets will be slow in coming. This has been the case for at least a decade, over which period no new drug principles have been added to the therapeutic armamentarium for the treatment of BPH. Mixed type 1 and type 2 5-a-reductase inhibitors such as dutasteride (AVODART) may offer improvements over the type 2 inhibitor, finasteride. Subtype selective adrenoceptor antagonists may be able to improve treatment, but convincing evidence is still lacking. Muscarinic receptor antagonists are currently being evaluated in BPH patients but their eventual place in therapy as a single treatment or in combination with adrenoceptor antagonists has to be established. Endothelin receptor antagonists, alone or together with adrenoceptor antagonists seem to offer a new attractive approach however, proof of concept studies are lacking. This general inertia would suggest that the most likely activity will focus on the improvement of established approaches.

Phytotherapy has become a popular treatment option among American men with BPH and indeed this indication has become one of the most commercially successful example of phytherapeutics. The most popular herbal agent is saw palmetto. Pygeum africanum and beta-sitosterol are also used by many patients with BPH, either alone or in combination with saw palmetto. A significant limiting factor to our understanding of the use and effectiveness of phytotherapy is the lack of standardization of these products. Despite this lack of standardization and the variation in results that may be seen with herbal products, there is growing evidence from well-conducted clinical trials that phytotherapeutic agents may lead to subjective and objective symptom improvement beyond a placebo effect in men with BPH (see introduction). In Europe, phytotherapeutic preparations have been prescribed for the treatment of symptomatic BPH for over 20 years. In these countries, phytotherapeutic preparations represent approximately 1/3 of total sales of all therapeutic agents sold for the treatment of BPH. In France, and other countries, phytotherapeutic preparations are the most widely used drugs for the treatment of BPH. In Asia, Africa, and India, phytotherapy is considered a first-line treatment for BPH and has been utilized effectively for centuries. In the US, the multimillion dollar sales of phytotherapeutic preparations for "the health of the prostate and bladder" attests to the widespread utilization of these agents although it should be noted that in the US phytotherapeutic approaches remain non-reimbursable and furthermore the FDA denied approval for saw palmetto (click here for denial letter; likewise click here for the related testimony from the American Urological Association). In 1996, extracts of the saw palmetto berry was the 9th most common herbal remedy sold in the US increasing to the 5th most common in 1997. Over $1 billion were spent on natural products and alternative medicine for BPH in the US in 2001 (Lowe, 2002) and it is anticipated that the use of alternative therapies for BPH will continue to increase substantially as the US male population continues to age.

The likely focus on established approaches to BPH combined with an acceptance of phytotherapeutics would suggest that new natural extracts that offer improvements over existing products, either in terms of production stringency or therapeutic efficacy may compete well in the current market place.

Drugs in development or on the market for BPH

Launched
alfuzosin	a1 adrenoceptor antagonist	Sanofi-Synthelabo
terazosin	a adrenoceptor antagonist	Abbott
tamsulosin	a1 adrenoceptor antagonist	Yamanouchi
Permixon	5-a-reductase inhibitor	bioMerieux-Pierre Fabre
oxendolone	a adrenoceptor antagonist	Takeda
naftopidil	a adrenoceptor antagonist	Hoffmann-La Roche
mepartricin	Membrane permeability enhancer	SPA
finasteride	5-a-reductase inhibitor	Merck & Co
doxazosin	a1 adrenoceptor antagonist	Pfizer
doxazosin-GITS	a1 adrenoceptor antagonist	Pfizer
alfuzosin	a1 adrenoceptor antagonist	Sanofi-Synthelabo
(Pre-)registration
osaterone acetate	Androgen antagonist	Teikoku Hormone
dutasteride	5-a-reductase inhibitor	GlaxoSmithKline
Phase III Clinical Trial
silodosin	a1 adrenoceptor antagonist	Kissei
tamsulosin	a1 adrenoceptor antagonist	Yamanouchi
dihydrotestosterone	Testosterone agonist	Solvay
Phase II Clinical Trial
tamsulosin	a1 adrenoceptor antagonist	Yamanouchi
UK-338003	a1 adrenoceptor antagonist	Pfizer
fiduxosin	a1 adrenoceptor antagonist	Abbott
Parvosin	a1 adrenoceptor antagonist	Ranbaxy
QLT-0074	Unidentified	QLT
P-04	Estrogen agonist	Novogen
hCG	Adenylate cyclase stimulant	Milkhaus
GYKI-16084	a1a adrenoceptor antagonist	IVAX
cetrorelix	LHRH antagonist	Zentaris
Phase I Clinical Trial
(S)-doxazosin	a1 adrenoceptor antagonist	Sepracor
BXL-628	Vitamin D receptor agonist	BioXell
pirfenidone	Fibroblast growth factor antagonist	MARNAC
Preclinical
CEP-2563 dihydrochloride	Tyrosine kinase inhibitor	Cephalon
R-1437	G protein inhibitor	Hoffmann-La Roche
NX-1207	Unidentified	Nymox
Unnamed	Unidentified	UroGene
Andarine	Androgen receptor ligand	GTx
micrin	Unidentified	Endocrine
AS-601811	5-a-reductase inhibitor	Serono
NCX-2111	NO donor/COX inhibitor	NicOx
PH-45	Unidentified	Pherin
XNA-3	5-a-reductase inhibitor	Xenna

Intellectual Property: Naturamed intellectual property is a key component in its corporate strategy. Naturamed plans to file patents to protect the NABIA bio-active fractions and Naturamed methods for the NABIA production process.

Collaborative opportunities: Having established a rigorous system to ensure the standardization of NABIA starting materials, extraction/purification processes and analytical tools, Naturamed have addressed one of the key issues surrounding the use of phytotherapeutics as a main-stream treatment of BPH. The process of extraction/purification has been up scaled and is now ready to address the demands of clinical trial. This market sector has received considerable acceptability for patients and products that can be delivered in a standardized fashion carry excellent therapeutic and commercial potential. This concept is validated by the success of Permixon, the product of reference for the phytotherapeutic treatment of BPH. In contrast to Permixon, NABIA products target multiple etiologies of BPH. Both treatments target 5-a-reductase and indeed the 3 of the NABIA fractions display activity equipotent with saw palmetto for this enzyme. In addition however, NABIA fractions are able to antagonize the a1 adrenoceptor with similar efficacy to that of standard treatments. Thus a mixture of NABIA fractions, in particular a mixture of NABIA D, E, F and G may be expected to have a significant therapeutic advantage over Permixon. Very recently, NABIA fractions have also been shown to block a2 adrenoceptor. In a recent dossier (click here to access) we have reported that mixed a1/2 adrenoceptor antagonists represent a target for the treatment of erectile dysfunction. This condition is related to BPH at multiple stages. Firstly, erectile dysfunction and BPH are both highly prevalent in the same segment of population. Secondly a common adverse effect of finasteride is erectile dysfunction. Finally, surgical treatment of BPH can cause erectile dysfunction in a significant number of patients. Thus the potential that NABIA extracts can prevent rather than contribute to erectile dysfunction may represent an important additional advantage.

NABIA A and B fractions contain aromatase activity and since blocking this enzyme is associated with questional therapeutic activity in BPH patients, Naturamed has limited the development of mixtures containing either or both of these fractions to the possible treatment of breast cancer. The next stage of development is to evaluate the efficacy of NABIA fractions and since preliminary toxicology studies have been completed and because the safety profile of NABIA raw materials is well accepted a randomized, double blind, placebo controlled clinical trial of NABIA in patients with BPH has been pre-approved. Clinical studies will evaluate the effects of a mixture of NABIA D, E, F and G fractions at the same ratio that they occur in the starting material. Naturamed are now seeking corporate partners with whom to collaborate on the further development of NABIA products.

Permixon has been approved for sale in Europe as a treatment of BPH however comment should be passed on the standpoint of the FDA. Although it was not banned, the FDA refused permission for saw palmetto to be sold as a therapy for the treatment of BPH. It should be noted that the FDA turned down saw palmetto NOT Permixon. Concerns were related to stringency of production and also lack of well controlled clinical trials. Naturamed have and will continue to address these issues during the development and therefore hope to avoid the problems related to saw palmetto. If successful NABIA fractions stand to become the first FDA-approved phytotherapeutic treatment of BPH.

Terms of collaboration are negotiable however mutually acceptable conditions are envisaged to involve the collaborating company contributing to the funding of an initial clinical trial during an evaluation period with an option to enter into a full license agreement upon completion of the trial. Down stream collaboration can include the design of small molecule mimics of the active components of NABIA fractions. In addition further development of NABIA fractions A and B is ongoing in order to facilitate their advancement as treatments of breast cancer and this activity represents a further licensing opportunity.