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Preclinical and clinical investigations as an approach to rational phytotherapy in prostate diseases

Weisskopf, Marianne. Preclinical and clinical investigations as an approach to rational phytotherapy in prostate diseases. 2004, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_6686

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Abstract

Phytotherapeuticals have gained widespread usage in the treatment of symptomatic
benign prostatic hyperplasia (BPH). Among these phytotherapeutics, the most
popular and extensively studied are extracts of the dried ripe fruit of Serenoa repens
(SRE). The commercially available hydroethanolic (96%) SRE, Me180, is already
used as a medical treatment of symptomatic BPH. However, this extract was so far
neither investigated in vitro nor in vivo. The other extracts tested herein, derived from
Vitex agnus-castus (VAC), are so far not described to be used for treatment of
prostatic diseases or tested on prostate cells.
In a first part of the present studies, an in vitro screening system was established,
representative for different prostate disease stages. BPH and prostate cancer (PCA)
are multifactorial disease processes. Both diseases are age-related proliferative
disorders of the human prostate and with disturbed homeostasis in both conditions by
upsetting the balance between prostate cell proliferation and apoptosis. Thus, the
inhibition of proliferation and the reversion of the imbalance of homoeostasis is a
desired therapeutic option in both diseases.
Three different cell lines (BPH-1, LNCaP, PC-3) were chosen, representing different
disease stages. To evaluate the potential effects of selected plant extracts in
proliferative prostate diseases, several methodological approaches were used:
Crystal violet staining and WST-8 (tetrazolium based assay) were conducted to
establish the effects on cell proliferation and viability. To further elucidate the
mechanisms of cell death, FACScan analysis was performed to detect effects on cell
cycle distribution and apoptosis. Apoptosis was further investigated by co-treatment
of the cells with a pan-caspase inhibitor Z-VAD-fmk and by DNA fragmentation
assays. In addition, cytotoxicity was determined by measurement of lactate
dehydrogenase (LDH) in cell supernatants.
Proliferation of BPH-1 and PC-3 cells was modestly inhibited by Serenoa repens
extract Me180 in a dose-dependent manner with IC50 values of 100μg/ml, whereas in
androgen-responsive LNCaP cells, lower IC50 values of 35μg/ml, indicated a
possible mechanism through androgen-receptors. Me180 exerted similar effects in
vitro as other SRE’s previously investigated. Additional SRE’s, which varied with
respect to ripeness conditions of the raw material and the choice of solvents (hexane or ethanol) displayed no crucial differences in potency of growth inhibitory activities.
Moreover, Me180 exhibited a dose-dependent apoptotic effect in LNCaP cells, with
additional low cytotoxic effects. A low apoptotic effect was found in BPH-1 cells
without a cytotoxic effect, whereas PC-3 cells were almost insensitive to the Me180
treatment.
In addition, using the same methodology, these preclinical investigations were the
first to examine the effects of VAC fruit and leaf extracts on prostate cell proliferation.
The two different VAC’s were found to be effective inhibitors in all three cell lines
(with IC50 values < 10μg/ml after exposure to fruit extract and < 20μg/ml for leaf
extract, respectively) inducing apoptosis, and a low cytotoxic effect. Our new results
suggest that extracts of VAC, by modulating the cell cycle and the apoptotic
machinery, may possess a potential for development as an agent for prevention
and/or therapy of benign and malign prostatic hyperplastic diseases. Additional
studies are however required to further clarify their mechanisms of action and to
investigate their effects in vivo.
The in vitro data indicate that the chosen screening model system is suitable for the
detection of growth inhibitory activities of plant extracts in human prostate cell lines
and may help to find new phytotherapeuticals for this field of indication.
The objective of the second part was a clinical pilot study to compare the
therapeutical effects, tolerability and safety of treatment with Serenoa repens extract
Me180 (SabCaps®) versus tamsulosin (Pradif®) in patients with obstructive BPH. Due
to stringent exclusion criteria and hence difficulties in patient recruitment, the planned
patient number of 70 could not be achieved within a reasonable time for the thesis.
Only 19 patients, aged 50-79 years, with obstructive BPH (mean Qmax < 10ml/s for a
voiding volume of 150ml or assessed by flow-pressure study) were therefore included
in the study. Patients were randomised with either 320mg Me180 or Tamsulosin
0.4mg, given over a scheduled treatment period of 26 weeks in a double-blind
manner. The primary outcome measures were the change in peak urinary flow rate
(Qmax) and International Prostate Symptom Score (IPSS) with quality-of-life score
during the treatment. The secondary outcome measures included average urinary
flow rate (Qave), post-void residual urine volume and prostate volume, assessed by
transabdominal ultrasound. In addition, the International Index of Erectile Function
(IIEF) score was determined and adverse events were recorded. No significant differences were found in baseline parameters between the two
treatment groups. The treatment over 26 weeks was completed by 18 patients. In the
tamsulosin group, one patient withdrew from the study because of continuous
dizziness. There was no significant difference between the two treatments over the
26 weeks of the study with respect to IPSS, Qmax, Qave, residual urine, prostate
volume, and IIEF. During this pilot study all participants had some improvements in
their symptoms of BPH, but there was no significant difference in the beneficial effect
of either medication over the 26-weeks treatment time. With respect to the overall
incidence of adverse effects, Me180 was found significantly superior to the
tamsulosin group (p = 0.013).
The present data describe for the first time clinical results obtained with Me180.
Based on this pilot study, future clinical trials with larger patient numbers and longer
periods of treatment will be needed to assert if Me180 is an efficacious alternative
medical therapy for men with obstructive BPH.
Advisors:Schaffner, Willi
Committee Members:Drewe, Jürgen and Sulser, Tullio
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmazeutische Biologie (Hamburger)
UniBasel Contributors:Drewe, Jürgen
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:6686
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:164
Language:English
Identification Number:
Last Modified:22 Apr 2018 04:30
Deposited On:13 Feb 2009 15:11

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