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151. Pygeum africanum extract for the treatment of
patients with benign prostatic hyperplasia: A review of 25
years of published experience
Andro M.-C.; Riffaud J.-P.
Laboratoires DEBAT, Medical Department, 153, Rue de
Buzenval,92380 Garches France
Current Therapeutic Research - Clinical and Experimental
(United States) 1995, 56/8 (796-817)
Pygeum africanum bark extract has been used to treat mild
and moderate symptomatic benign prostatic hyperplasia (BPH) in
France since 1969. The extract has several potentially
relevant pharmacologic properties: modulation of age-related
hypercontractility of the bladder detrusor muscle;
anti-inflammatory activity, including inhibition of
chemotactic activity of leukotrienes; inhibition of fibroblast
proliferation; and improvement of prostatic histology and
secretion. The constituents of the extract have a safe
toxicologic profile, and some of them have anticarcinogenic
and antimutagenic properties. Published clinical experience
includes 2262 patients, of whom 452 received the active
product in comparative studies. Global outcome scores
are rated as good or better in at least half the patients in
most studies. Objective parameters were measured in
some open-label and all comparative studies and included
maximum flow rate, voided volume, residual volume, nocturia,
daytime frequency, and other symptoms. The placebo effect on
these parameters was often large. Nonetheless, the majority of
placebo-controlled studies, which compared changes from
baseline in patients who received placebo versus patients who
received P africanum extract, showed a statistically
significant advantage for most objective parameters with the
active compound. This finding was particularly true of more
recent and larger studies. Clinical tolerability of the
extract was excellent, with most studies reporting the
complete absence of any adverse effects. Thus
published clinical data from 2262 patients during the last 25
years show that P africanum bark extract is an effective and
exceptionally well-tolerated treatment for mild and moderate
symptomatic BPH. P africanum extract has a pharmacologic
profile distinct from other classes of drugs now being
proposed for BPH treatment (alpha-adrenoceptor antagonists and
5-alpha-reductase inhibitors). The recent resurgence
of interest in nonsurgical treatments for this condition
should prompt a reappraisal of P africanum extract, perhaps in
comparative trials with these other drug classes.
152. Inhibition of bFGF and EGF-induced
proliferation of 3T3 fibroblasts by extract of Pygeum
africanum (Tadenan(R))
Paubert-Braquet M.; Monboisse J.C.; Servent-Saez N.; Serikoff
A.; Cave A. ; Hocquemiller R.; Dupont Ch.; Fourneau C.; Borel
J.P.
Bio-Inova, Laboratoire de Recherche, 48-52, rue de la
Gare,78370 Plaisir France
Biomedicine and Pharmacotherapy (France) 1994, 48/Suppl. 1
(43S-47S)
An extract of Pygeum africanum bark (Tadenan(R)) is
prescribed for older men suffering from micturitional
difficulties due to benign prostatic hyperplasia (BPH). Its
mechanism of action is not completely understood. Basic
fibroblast growth factor (bFGF) probably plays a role in the
development of BPH. We have examined the effects of P
africanum extract on basal cell proliferation and on the
proliferation induced by bFGF, epidermal growth factor (EGF)
and insulin-like growth factor-1 (IGF-1). The proliferation of
3T3 fibroblasts was measured by the incorporation of tritiated
methylthymidine and staining nuclei with crystal violet. P
africanum extract slightly inhibited the basal growth of
fibroblasts. However, it had a much larger inhibitory effect
on cell proliferation induced by bFGF with 0.5 mug/ml, and the
effect was significant at 1 mug/ml. Pygeum africanum extract
also inhibited cell proliferation induced with EGF, but to a
lesser extent. This suggests that the therapeutic
effect of P africanum extract may be partly due to inhibition
of cell growth induced by certain growth factors.
153. Quantitative-comparative histology of
prostatic adenomas in medically and surgically treated
patients
Dutkiewicz S.; Kalczak M.
Department of Urology, Ministry of Internal Affairs, Central
Clinical Hospital,Warsaw Poland
International Urology and Nephrology (Hungary) 1994, 26/4
(455-460)
Transvesical adenectomy was done in 60 men with prostatic
adenomas, including 40 pretreated medically (20 with prazosin,
20 with Tadenan). The resected material was sampled for
histologic examination. Glandular, smooth muscle and fibrotic
tissues as well as inflammatory foci were assessed
quantitatively by planimetry . No adenomas consisting solely
of glandular hyperplasia were found. In adenomas from patients
pretreated with prazosin smooth muscle tissue was predominant
and postinflammatory lesions were the least frequently
observed. In Tadenan-pretreated patients quantitative
predominance of glandular and fibrotic tissues was found and
smooth muscle constituted the smallest pair of the
adenomas. Patients who had undergone surgery only had
adenomas in which focal inflammation predominated.
154. Effect of Pygeum africanum extract on
A23187-stimulated production of lipoxygenase metabolites from
human polymorphonuclear cells
Paubert-Braquet M.; Cave A.; Hocquemiller R.; Delacroix D.;
Dupont C.; Hedef N.; Borgeat P.
BIO-INOVA Research Laboratories, 48-52 Rue de la Gare,F 78370
Plaisir France
Journal of Lipid Mediators and Cell Signalling (Netherlands)
1994, 9/3 (285-290)
Pygeum africanum extract has been used for more than 20
years in France in patients suffering from benign prostatic
hypertrophy (BPH). The extract displays anti-inflammatory
activity and inhibits bladder hyperreactivity during the above
conditions. However, the mechanism of action of P. africanum
extract has never been clearly resolved. It has been recently
demonstrated that infiltration by inflammatory cells may be
involved in the development of BPH. Certain of these cell
types, such as macrophages, are known to produce chemotactic
mediators including leukotrienes, and thus may contribute to
the development of the disease. In order to investigate the
potential effect of P. africanum extract on arachidonate
metabolism, we examined its effect in vitro on leukotriene
(LT) synthesis in human polymorphonuclear cells stimulated
with the calcium ionophore A23187. Two formulations of the
extract were tested, one dissolved in DMSO and one aqueous
solution obtained after alkalinization (0.1 N;
NaOH/acidification (0.1 N; HCl). Neither formulation had any
effect on cell viability which was above 95% in both cases. P.
africanum extract dissolved in DMSO significantly inhibited
the production of 5-lipoxygenase metabolites (5-HETE, 20-COOH
LTBinf 4, LTB4 and 20-OH LTBinf 4) at concentrations as low as
3 mug/ml (p < 0.01), while the same extract dissolved in
NaOH/HCl only exhibited an inhibitory effect at 10 mug/ml (p
< 0.01). This difference apparently reflects the greater
solubility of the active components in the extract in DMSO.
The ability of P. africanum to antagonize
5-lipoxygenase metabolite production may contribute, at least
in part, to its therapeutic activity in inflammatory component
of BPH.
155. Combined extracts of Urtica dioica and Pygeum
africanum in the treatment of benign prostatic hyperplasia:
Double-blind comparison of two doses
Krzeski T.; Kazon M.; Borkowski A.; Witeska A.; Kuczera
J.
Warsaw School of Medicine,Warsaw Poland
Clinical Therapeutics (United States) 1993, 15/6
(1011-1020)
The 134 patients (aged 53 to 84 years) with symptoms of
benign prostatic hyperplasia were drawn from two medical
centers in Warsaw. The patients were randomly assigned to
receive two capsules of the standard dose of an urtica/pygeum
preparation (300 mg of Urtica dioica root extract combined
with 25 mg of Pygeum africanum bark extract) or two capsules
containing half the standard dose twice daily for 8 weeks.
After 28 days' treatment, urine flow, residual urine, and
nycturia were significantly reduced in both treatment groups.
After 56 days' treatment, further significant decreases were
found in residual urine (half-dose group) and in nycturia
(both groups). There were no between-group differences in
these measures of efficacy. Five patients reported adverse
effects of treatment; treatment was not discontinued in any
patient because of side effects. It is concluded that half
doses of the urtica/pygeum extract are as safe and effective
as the recommended full doses.
156. Efficacy of Pygeum africanum extract in the
treatment of micturitional disorders due to benign prostatic
hyperplasia. Evaluation of objective and subjective parametes.
A multicentre, randomized, double-blind trial
Barlet A.; Albrecht J.; Aubert A.; Fischer M.; Grof F.;
Grothuesmann H.G. ; Masson J.-C.; Mazeman E.; Mermon R.;
Reichelt H.; Schonmetzler F.; Suhler A.
Laboratoires Debat, 60 Rue de Monceau,F-75008 Paris
France
Wiener Klinische Wochenschrift (Austria) 1990, 102/22
(667-673)
The efficacy of an extract of Pygeum africanum in the
treatment of micturitional disorders due to benign prostatic
hyperplasia was tested in a multicentre double-blind trial
versus placebo. Capsules containing 50 mg of Pygeum africanum
extract or placebo were administered at a dosage of 1 capsule
in the morning and 1 capsule in the evening over aperiod of 60
days. 263 patients were included in this study, which was
carried out in 8 centres in Germany, France, and Austria.
Evaluation was mainly based on quantitative parameters such as
residual urine, uroflowmetry and the precise monitoring of
diurnal and nocturnal pollakiuria. Treatment with the Pygeum
africanum extract led to a marked clinical improvement: a
comparison of the quantitative parameters showed a significant
difference between the Pygeum africanum group and the placebo
group with respect to therapeutic response. The characteristic
subjective symptoms of micturitional disorders, which were
evaluated by the patients in a qualitative manner, were also
significantly improved by administration of Pygeum africanum
extract. Overall assessment at the end of therapy, showed that
micturition improved in 66% of the patients treated with
Pygeum africanum extract, as compared with an improvement of
31% in the placebo group. The difference was significant at
the statistical level of p < 0.001. During therapy with
Pygeum africanum extract, gastrointestinal side effect
occurred in 5 patients. Treatment was discontinued in three of
those cases.
157. Binding of permixon, a new treatment for
prostatic benign hyperplasia, to the cytosolic androgen
receptor in the rat prostate
Carilla E.; Briley M.; Fauran F.; et al.
Centre de Recherches Pierre Fabre, 81106 Castres Cedex
France
Journal of Steroid Biochemistry (United Kingdom) 1984, 20/1
(521-523)
The benign hyperplasia of the prostate is a manifestation
of aging, involving the accumulation within the gland, of
dihydrotestosterone, the probable mediator of the hyperplasia.
Binding studies were performed on the cytosolic androgenic
receptor of the rat prostate using (sup 3H)methyltrienolone as
a ligand. The binding of (sup 3H)methyltrienolone at 5 nM, was
inhibited by various drugs, such as methyltrienolone and
cyproterone acetate. Permixon, a liposterolic extract of the
plant, Serenoa Repens B, inhibits competitively the binding to
the cytosolic receptor of the rat prostate. Various vegetable
and mineral oils, the plant steroid: beta sitosterol and the
antiprostatic drug: Tadenan, were all found to be inactive.
The antiprostatic activity of Permixon shown in animal studies
and controlled clinical trials, may thus result from a direct
action at the cytosolic receptor.
158. An urodynamic study of patients with benign
prostatic hypertrophy treated conservatively with phytotherapy
or testosterone
Flamm J.; Kiesswetter H.; Englisch M.
Urol. Abt., Wilhelminenspit., Wien Austria
Wiener Klinische Wochenschrift (Austria) 1979, 91/18
(622-627)
Conservative therapy of benign prostatic hypertrophy
comprises the administration of oestrogens, gestagens,
androgens and anti-androgens. Phytodrugs, which
contain an extract of Sabal serrulatum or Pygeum Africana as
active substance are without side effects and are, therefore,
being used increasingly. 74 patients with irritable
or obstructive bladder symptoms due to benign prostatic
hypertrophy were treated with a phytodrug (Sabal serrulatum)
or with testosterone throughout a period of three months. In
group one (20 patients given phytodrugs and 10 patients given
testosterone) clinical symptoms and measurements of residual
urine, residual urine quotient, bladder capacity, micturition
pressure and maximum urethral closure pressure were recorded
at the beginning and at the end of therapy. In group two 28
patients were treated with the phytodrug in the first and
third months with an intervening placebo trial lasting four
weeks and 16 patients were given testosterone. Clinical
symptoms and uroflow and residual urine only were charted in
this group. None of the patients in either group showed an
improvement in the urodynamic parameters of obstruction, but
all patients felt a subjective alleviation of their
symptoms.
159. Saw palmetto extracts potently and
noncompetitively inhibit human alpha1-adrenoceptors in
vitro.
Goepel M; Hecker U; Krege S; Rubben H; Michel MC
Department of Urology, University of Essen, Germany.
mark.goepel@uni-essen.de
Prostate (United States) Feb 15 1999, 38 (3)
p208-15
BACKGROUND: We wanted to test whether phytotherapeutic
agents used in the treatment of lower urinary tract symptoms
have alpha1-adrenoceptor antagonistic properties in vitro.
METHODS: Preparations of beta-sitosterol and extracts of
stinging nettle, medicinal pumpkin, and saw palmetto were
obtained from several pharmaceutical companies. They were
tested for their ability to inhibit [3H]tamsulosin binding to
human prostatic alpha1-adrenoceptors and [3H]prazosin binding
to cloned human alpha1A- and alpha1B-adrenoceptors. Inhibition
of phenylephrine-stimulated [3H]inositol phosphate formation
by cloned receptors was also investigated.
RESULTS: Up to the highest concentration which could be
tested, preparations of beta-sitosterol, stinging nettle, and
medicinal pumpkin were without consistent inhibitory effect in
all assays. In contrast, all tested saw palmetto extracts
inhibited radioligand binding to human alpha1-adrenoceptors
and agonist-induced [3H]inositol phosphate formation.
Saturation binding experiments in the presence of a single saw
palmetto extract concentration indicated a noncompetitive
antagonism. The relationship between active concentrations in
vitro and recommended therapeutic doses for the saw palmetto
extracts was slightly lower than that for several chemically
defined alpha1-adrenoceptor antagonists.
CONCLUSIONS: Saw palmetto extracts have
alpha1-adrenoceptor-inhibitory properties. If bioavailability
and other pharmacokinetic properties of these ingredients are
similar to those of the chemically defined alpha1-adrenoceptor
antagonists, alpha1-adrenoceptor antagonism might be involved
in the therapeutic effects of these extracts in patients with
lower urinary tract symptoms suggestive of benign prostatic
obstruction.
160. Urtica dioica L.
Bombardelli E.; Morazzoni P.
E. Bombardelli, Indena S.p.A., Scientific Department, Viale
Ortles 12, 20139 Milan Italy
Fitoterapia (Italy) 1997, 68/5 (387-402)
U. dioica L. was used as medicinal plant since ancient
times. Hydroalcoholic extract of the nettle root (Urticae
radix) are currently used in the therapy of micturition
disorders associated with slight and moderate BPH.
161. Aromatase inhibitors from Urtica dioica
roots
Gansser D.; Spiteller G.
Lehrstuhl Organische Chemie 1, Universitat Bayreuth, NW
I,
Universitatsstrasse 30,D-95440 Bayreuth Germany
Planta Medica (Germany) 1995, 61/2 (138-140)
Methanolic extracts of stinging nettle (Urtica dioica L.)
roots were investigated for aromatase inhibition. Enzyme
inhibition was detected only after appropriate chromatographic
separation. Inhibitory effects on aromatase could be
demonstrated in vitro for a variety of compounds belonging to
different classes. The following compounds developed weak to
moderate activity: secoisolariciresinol (1), oleanolic and
ursolic acid (2 and 3),
(9Z,11E)-13-hydroxy-9,11-octadecadienoic acid (4), and
14-octacosanol (5). Inhibitory effects on aromatase have been
known to date neither for pentacyclic triterpenes nor for
secondary fatty alcohols. The potential physiological
significance of the above findings is discussed. Compound 5 is
a previously unknown constituent of plants.
162. Effects of stinging nettle root extracts and
their steroidal components on the Nasup +,Ksup +-ATPase of the
benign prostatic hyperplasia
Hirano T.; Homma M.; Oka K.
Dept. of Clinical Pharmacology, Tokyo College of Pharmacy,
1432-1 Horinouchi,Hachioji, Tokyo 192-03 Japan
Planta Medica (Germany) 1994, 60/1 (30-33)
The effects of organic-solvent extracts of Urtica dioica
(Urticaceae) on the Nasup +,Ksup +-ATPase of the tissue of
benign prostatic hyperplasia (BPH) were investigated. The
membrane Nasup +,Ksup +-ATPase fraction was prepared from a
patient with BPH by a differential centrifugation of the
tissue homogenate. The enzyme activity was inhibited by 10sup
-sup 4-10sup -sup 5 M of ouabain. The hexane extract, the
ether extract, the ethyl acetate extract, and the butanol
extract of the roots caused 27.6-81.5% inhibition of the
enzyme activity at 0.1 mg/ml. In addition, a column extraction
of stinging nettle roots using benzene as an eluent afforded
efficient enzyme inhibiting activiry. Steroidal components in
stinging nettle roots, such as stigmast-4-en-3-one,
stigmasterol, and campesterol inhibited the enzyme activity by
23.0-67.0% at concentrations ranging from 10sup -sup 3-10sup
-sup 6 M. These results suggest that some hydrophobic
constituents such as steroids in the stinging nettle roots
inhibited the membrane Nasup +,Ksup +-ATPase activity of the
prostate, which may subsequently suppress prostate-cell
metabolism and growth.
163. Antiproliferative effect of Pygeum africanum
extract on rat prostatic fibroblasts
Yablonsky F; Nicolas V; Riffaud JP; Bellamy F
Laboratoires Debat, groupe Fournier, Garches, France.
J Urol; 157(6):2381-7 1997
[published erratum appears in J Urol 1997 Sep;158(3 Pt
1):889]
The effect of a Pygeum africanum extract (Tadenan) (Pa),
used in the treatment of micturition disorders associated with
BPH, has been examined on the proliferation of rat prostatic
stromal cells stimulated by different growth factors. EGF,
bFGF, and IGF-I but not KGF are mitogenic for prostatic
fibroblasts in culture. Pygeum africanum inhibits both basal
and stimulated growth with IC50 values of 4.5, 7.7 and 12.6
micrograms./ml. for EGF, IGF-I and bFGF, respectively,
compared to 14.4 micrograms./ml. for untreated cells, the
inhibition being stronger towards EGF. Pygeum africanum
inhibited the proliferation induced by TPA or PDBu in a
concentration-dependent manner with IC50 values of 12.4 and
8.1 micrograms./ml. respectively. The antiproliferative
effects of Pa were not ascribed to cytotoxicity. These results
show that Pygeum africanum is a potent inhibitor of rat
prostatic fibroblast proliferation in response to direct
activators of protein kinase C, the defined growth factors
bFGF, EGF and IGF-I, and the complex mixture of mitogens in
serum depending on the concentration used. PKC activation
appears to be an important growth factor-mediated signal
transduction for this agent. These data suggest that
therapeutic effect of Pygeum africanum may be due at least in
part to the inhibition of growth factors responsible for the
prostatic overgrowth in man.
164. Role of Mepartricin in the treatment of benign
prostatic adenoma
Casella G; Barbaro A
Clinica 'Villa S. Anna', Reggio Calabria, Italy
Arch Sci Med (Torino); 135(1):95-98 1978
A Chloroform extract of Pygeum africanum and mepartricin
were used to treat 22 patients with prostatic hypertrophy.
Both substances were active against urinary symptomatology,
and the polyene also induced a significant decrease in
prostate size. Excellent results were obtained in 77% of the
patients. (6 Refs)
165. Influence of V-1326 extract of
Pygeum-Africanum on pituitary gonadal adrenal axis of the
rat
Thieblot L, Grizard G, Boucher D
Therapie (Paris) 32 (1). 1977 99-110.
In castrated rats, an extract of P. africanum (V 1326)
stimulates the secretory activity of the prostate and seminals
vesicles but it appears as an antagonist of testosterone in
these organs. In castrated adrenalectomized rats, V 1326
stimulates the action of testosterone on target organs and
increases pituitary gonadotropin content. The action of V 1326
stimulates the adrenals and pituitary.
166. Soy, disease prevention, and prostate
cancer.
Moyad MA
Section of Urology, University of Michigan, Ann Arbor
48109-0330, USA.
Semin Urol Oncol 1999 May;17(2):97-102
Population-based studies from around the world support the
theory that soy products and their constituents, primarily the
isoflavones or phytoestrogens, are partly responsible for the
lower rates of certain chronic diseases in different areas of
the world. Cardiovascular disease and hormonally induced
cancers are just a few of the conditions lower in Asian
countries that consume large quantities of soy per average
person. Genistein, one of soy's individual phytoestrogens, has
been found to inhibit numerous breast and prostate cancer cell
lines. A limited amount of clinical evidence also points to a
beneficial role of soy in reducing hormonal levels and
exhibiting weak estrogen and antiestrogen-like qualities.
Other phytoestrogens found in nature, such as lignans, may
also have a future role in cancer. Collectively, these
phytoestrogens, like genistein, have enough evidence to
warrant their use in a number of clinical trials as a
potential chemopreventive agent or adjunct to prostate cancer
treatment.
167. Does high soy milk intake reduce prostate
cancer incidence? The Adventist Health Study.
Jacobsen BK, Knutsen SF, Fraser GE
Institute of Community Medicine, University of Tromso,
Norway.
Cancer Causes Control 1998 Dec;9(6):553-7
OBJECTIVES: Recent experimental studies have suggested that
isoflavones (such as genistein and daidzein) found in some soy
products may reduce the risk of cancer. The purpose of this
study was to evaluate the relationship between soy milk, a
beverage containing isoflavones, and prostate cancer
incidence.
METHODS: A prospective study with 225 incident cases of
prostate cancer in 12,395 California Seventh-Day Adventist men
who in 1976 stated how often they drank soy milk.
RESULTS: Frequent consumption (more than once a day) of soy
milk was associated with 70 per cent reduction of the risk of
prostate cancer (relative risk = 0.3, 95 percent confidence
interval 0.1-1.0, p-value for linear trend = 0.03). The
association was upheld when extensive adjustments were
performed.
CONCLUSIONS: Our study suggests that men with high
consumption of soy milk are at reduced risk of prostate
cancer. Possible associations between soy bean products,
isoflavones and prostate cancer risk should be further
investigated.
168. Genistein, a component of soy, inhibits the
expression of the EGF and ErbB2/Neu receptors in the rat
dorsolateral prostate.
Dalu A, Haskell JF, Coward L, Lamartiniere CA
Department of Pharmacology and Toxicology, University of
Alabama at Birmingham, 35294, USA.
Prostate 1998 Sep 15;37(1):36-43
BACKGROUND: Epidemiological reports suggest that Asians
consuming a diet high in soy have a low incidence of prostate
cancer. In animal models, soy and genistein have been
demonstrated to suppress the development of prostate cancer.
In this study, we investigate the mechanism of action,
bioavailability, and potential for toxicity of dietary
genistein in a rodent model.
METHODS: Lobund-Wistar rats were fed a 0.025-1.0-mg
genistein/g AIN-76A diet. The dorsolateral prostate was
subjected to Western blot analysis for expression of
tyrosine-phosphorylated proteins, and of the EGF and ErbB2/Neu
receptors. Genistein concentrations were measured from serum
and prostate using HPLC-mass spectrometry. Body and prostate
weights, and circulating testosterone levels, were
measured.
RESULTS: Increasing concentrations of genistein in the diet
inhibited tyrosine-phosphorylated proteins with molecular
weights of 170,000 and 85,000 in the dorsolateral prostate.
Western blot analysis revealed that the 1-mg genistein/g
AIN-76A diet inhibited by 50% the expression of the EGF
receptor and its phosphorylation. In rats fed this diet,
serum-free and total genistein concentrations were 137 and
2,712 pmol/ml, respectively. The free and total genistein IC50
values for the EGF receptor were 150 and 600 pmol/g prostate
tissue, respectively. Genistein in the diet also inhibited the
ErbB2/Neu receptor. Body and dorsolateral prostate weights,
and circulating testosterone concentrations, were not
adversely effected from exposure to genistein in the diet for
3 weeks.
CONCLUSIONS: We conclude that genistein in the diet can
downregulate the EGF and ErbB2/Neu receptors in the rat
prostate with no apparent adverse toxicity to the host. The
concentration needed to achieve a 50% reduction in EGF
receptor expression can be achieved by eating a diet high in
soy products or with genistein supplementation. Genistein
inhibition of the EGF signaling pathway suggests that this
phytoestrogen may be useful in both protecting against and
treating prostate cancer.
169. Genistein inhibits the growth of human-patient
BPH and prostate cancer in histoculture.
Geller J, Sionit L, Partido C, Li L, Tan X, Youngkin T,
Nachtsheim D, Hoffman RM
AntiCancer, Inc., San Diego, California 92111, USA.
Prostate 1998 Feb 1;34(2):75-9
BACKGROUND: There is strong epidemiological evidence that
prostate disease is significantly less prevalent in the
Orient, where the intake of soy products is very high, than in
the United States. We therefore undertook a study of the
effects of genistein, a major component of soy, on growth of
human-patient benign prostatic hypertrophy (BPH) and prostate
cancer tissue in three-dimensional collagen gel-supported
histoculture.
METHODS: Surgical specimens of human BPH and cancer were
histocultured for 5 days to study the effects of genistein on
growth, as measured by inhibition of 3H-thymidine
incorporation per microgram protein on day 5.
RESULTS: Genistein in doses of 1.25-10 micrograms/ml
decreased the growth of BPH tissue in histoculture in a
dose-dependent manner, with little additional effect at higher
doses. Prostate cancer tissue in histoculture was similarly
inhibited by these doses of genistein.
CONCLUSIONS: Genistein decreases the growth of both BPH and
prostate cancer tissue in histoculture. The data suggest that
genistein has potential as a therapeutic agent for BPH and
prostate cancer.
170. Genistein-induced apoptosis of prostate cancer
cells is preceded by a specific decrease in focal adhesion
kinase activity.
Kyle E, Neckers L, Takimoto C, Curt G, Bergan R
Clinical Pharmacology Branch, National Cancer Institute,
National Institutes of Health, Bethesda, Maryland 20892,
USA.
Mol Pharmacol 1997 Feb;51(2):193-200
Genistein (5,7,4'-trihydroxyisoflavone), an isoflavinoid
found in soy beans, has been identified as potentially causal
for the low incidence of metastatic prostate cancer (PCa) in
certain countries. Although genistein-induced PCa cell
adhesion has been identified as a possible causative
mechanism, direct growth inhibition by genistein has been
reported and also could be causal. If in vivo growth
inhibition was significant, then growth inhibition should
occur at concentrations attained with dietary consumption, the
mechanism of growth inhibition should be relevant to PCa, and
genistein (a broad-spectrum in vitro protein-tyrosine kinase
inhibitor) should have relatively specific kinase inhibitory
effects in vivo. These considerations were investigated by
measuring growth inhibitory activity in a variety of PCa cell
lines. Growth inhibitory effects were shown not to occur with
concentrations below the low micromolar range (i.e., 3 logs
above that attained in serum). In-depth mechanistic studies
with the PC3-M metastatic variant cell line demonstrated that
growth inhibition was independent of genistein's estrogenic
effects. Genistein was shown to decrease the viability of
nonadherent cells, suggesting a lack of dependence on cell
adhesion for growth inhibition. However, important molecular
and kinetic differences between genistein's effects on growth
in adherent versus nonadherent cells were identified. Specific
suppression of focal adhesion kinase activity (without global
decreases in phosphotyrosine) was shown to precede induction
of apoptosis, which was responsible for growth inhibition in
adherent cells. These findings do not support an in vivo
growth inhibitory role by genistein consumed in quantities
associated with a soy-based diet. They do, however, identify
genistein as a potential therapeutic agent for PCa and as a
tool with which to study the control of apoptosis in PCa.
171. Treatment with finasteride preserves
usefulness of prostate-specific antigen in the detection of
prostate cancer: results of a randomized, double-blind,
placebo-controlled clinical trial. PLESS Study Group. Proscar
Long-term Efficacy and Safety Study.
Andriole GL, Guess HA, Epstein JI, Wise H, Kadmon D, Crawford
ED, Hudson P, Jackson CL, Romas NA, Patterson L, Cook TJ,
Waldstreicher J
Division of Urology, Washington University School of
Medicine, St. Louis, Missouri 63110, USA.
Urology 1998 Aug;52(2):195-201; discussion 201-2
OBJECTIVES: To evaluate prostate cancer detection
and prostate-specific antigen (PSA) among men with benign
prostatic hyperplasia treated with finasteride.
METHODS: Three thousand forty men 45 to 78 years of age
with PSA less than 10 ng/mL and no history of prostate cancer
were randomized in a double-blind, placebo-controlled trial to
finasteride (n = 1524) or placebo (n = 1516) for up to 4
years. A prerandomization biopsy negative for prostate cancer
was obtained in 98% of patients with a screening PSA of 4.0
ng/mL or more, and an end-of-study biopsy was requested of all
such patients without a recent second negative biopsy or a
prostate cancer diagnosis.
RESULTS: Overall, 644 patients (21%) underwent biopsy and
201 (6.6%) underwent transurethral resection of the prostate.
Prostate cancer was diagnosed in 4.7% of men on finasteride
and 5.1% on placebo (P = 0.7). Elevated PSA prompted diagnosis
in 35% of cases on finasteride and 34% on placebo. The area
under the receiver operating characteristic curve for last PSA
was 0.84 on finasteride and 0.79 on placebo (P = 0.07). Use of
an upper limit of normal for last PSA of 2.0 ng/mL for
finasteride and 4.0 ng/mL for placebo yielded similar
sensitivity (66% versus 70%, P = 0.6), higher specificity (82%
versus 74%, P < 0.0001), and a higher likelihood ratio (3.6
versus 2.7, P < 0.05) for finasteride than for placebo.
CONCLUSIONS: In men treated with finasteride,
multiplying PSA by 2 and using normal ranges for untreated men
preserves the usefulness of PSA for prostate cancer
detection.
172. Differential effect of finasteride on the
tissue androgen concentrations in benign prostatic
hyperplasia.
Habib FK, Ross M, Tate R, Chisholm GD
University Department of Surgery (WGH), Western General
Hospital, Edinburgh, Scotland.
Clin Endocrinol (Oxf) 1997 Feb;46(2):137-44
OBJECTIVE: The 5 alpha-reductase inhibitor,
finasteride, provides a logical medical treatment for benign
prostatic hyperplasia (BPH). However, the effects of chronic
finasteride treatment on prostatic androgen levels, 5
alpha-reductase activity and tissue prostatic specific antigen
(PSA) have not been studied. We have examined prostate tissue
androgen concentrations and 5 alpha-reductase activity of the
gland in men with BPH treated with the drug for 3
months.
DESIGN AND PATIENTS: Twenty-eight patients with
clinically diagnosed BPH, awaiting transurethral resection of
the prostate, were entered in a double-blind placebo
controlled study. Nineteen patients were randomly allocated to
treatment with finasteride (5 mg daily) and 9 received placebo
for 3 months.
MEASUREMENTS: Prostate specimens were collected immediately
following surgery and analysed for testosterone,
dihydrotestosterone (DHT), androstenedione, 5 alpha-reductase
activity and PSA. Blood specimens obtained before the start
and immediately following treatment were also tested for
steroid hormone concentrations and PSA levels.
RESULTS: There was no significant difference in the median
levels of intraprostatic testosterone (P = 0.77), DHT (P =
0.46) and androstenedione (P = 0.09) between the finasteride
and placebo groups. However, the 5 alpha-reductase activity of
the placebo group (237.9 pmol DHT/g tissue/30 min) was
approximately 10 times that of the finasteride group (21.5
pmol DHT/g tissue/30 min; P = 0.0008). Although we were unable
to detect any differences in the PSA concentrations of the
prostate glands, there was a significant difference (P =
0.0002) in the median percentage change of serum PSA
concentrations for the two patient groups. Serum DHT levels
were also depleted (P = 0.038) whilst serum testosterone was
increased (P = 0.054) in the finasteride patients when
compared to the placebo group. Furthermore our study
demonstrated no correlation between the in vitro 5
alpha-reductase activity of the gland and tissue DHT
concentrations.
CONCLUSIONS: Whilst finasteride treatment induced a
reduction in serum dihydrotestosterone and prostatic specific
antigen levels with a concomittant increase in blood
testosterone concentrations, the impact of the drug on tissue
androgen concentrations varied considerably from one patient
to another. The differential effect of the drug on tissue
androgen concentrations suggests that in the human prostate
there are possibly more than one isoform of 5 alpha-reductase
responsible for the accumulation of DHT in the gland.
173. [Effect of finasteride on the percentage of
free PSA: implications in the early diagnosis of prostatic
cancer].
[Article in Spanish]
Morote J, Lorente JA, Raventos CX, Lopez MA, Encabo G, De
Torres I, Lopez M, De Torres JA
Servicio de Urologia, Hospital General Vall d'Hebron,
Universidad Autonoma, Barcelona.
Actas Urol Esp 1998 Nov-Dec;22(10):835-9
OBJECTIVE: To analyze the behaviour of free PSA
percentage in finasteride-treated patients and to evaluate
whether this ratio allows an increased PSA specificity in the
early diagnosis of prostate cancer.
MATERIAL AND METHODS: Evaluation of PSA serum levels and
free PSA ratio in 336 patients initially diagnosed with
prostate benign hyperplasia (PBH). A group of 82 patients were
treated with finasteride for 14 to 58 months. A second group
of 254 patients received no treatment. All patients were
within the same age range and had similar PSA serum levels. In
total, 141 prostate biopsies were performed: 19.5 (16/82) and
49.1 (125/254) respectively.
RESULTS: Median PSA level in PBH patients was 1.6 ng/mL
for the finasteride-treated group and 3.5 for the untreated
group, p < 0.0001. Free PSA ratio was 18.6 and 18.8%,
respectively, p > 0.05. Carcinoma detection rate was 25%
(4/16) for the finasteride group and 27.2% (34/125) for the
untreated group. If biopsy had been requested when PSA
percentage was below 25%, 17.7 and 19.8% respectively would
have been prevented and all carcinoma detected.
CONCLUSION: Long-term treatment with finasteride reduces
PSA serum concentration about 50% without changing the free
PSA ratio. Carcinoma detection rate was similar in
finasteride-treated and untreated patients. Free PSA
ratio allows to increase PSA specificity and avoid unnecessary
biopsied also in finasteride-treated patients.
174. Effect of finasteride and/or terazosin on
serum PSA: results of VA Cooperative Study #359.
Brawer MK, Lin DW, Williford WO, Jones K, Lepor H
Northwest Prostate Institute and Pacific Northwest Cancer
Foundation, Seattle, Washington 98133, USA.
Prostate 1999 Jun 1;39(4):234-9
BACKGROUND: Medical management of benign prostatic
hyperplasia (BPH) giving rise to lower urinary tract
symptomatology (LUTS) has emerged as the mainstay for
first-line therapy. Prostate-specific antigen (PSA) is
the most important method of detecting prostate carcinoma. The
effect of finasteride on PSA has been widely reported. Little
data exist with respect to alpha-adrenergic blocking therapy
in men treated for BPH. In the present investigation we set
out to evaluate the effect of these two forms of
therapy.
METHODS: Patients enrolled in the VA Cooperative Study #359
trial were evaluated. This study evaluated men with moderate
LUTS owing to BPH in four treatment groups: placebo (P),
finasteride (F), terazosin (T), and combination of finasteride
plus terazosin (C). Men were recruited at 31 VA medical
centers and had a baseline in 52-week PSA determination at the
respective sites.
RESULTS: There was no significant difference in baseline
PSA between four groups (mean range, 2.0-2.9 ng/ml).
Statistically significant reduction in PSA levels was observed
at 52 weeks in the F and C arms (P < 0.001), whereas
significant increases were observed in the T and P arms (P
< 0.01). Additionally, there was no significant
difference in PSA response between the T and P arms. Thirty
percent of men in the C or F arms had more than 40-60%
reduction of PSA. In contrast, the majority of men on
T or P had less than 40% change in PSA. Only 35% of men on F
or C had the expected 40-60% reduction in PSA level.
CONCLUSIONS: These data demonstrate no clinically
significant effect of T on PSA level. The heterogeneity of PSA
response to F may make monitoring patients for the development
of prostate cancer problematic.
175. Androgen metabolism in the prostate of the
finasteride-treated, adult rat: a possible explanation for the
differential action of testosterone and 5
alpha-dihydrotestosterone during development of the male
urogenital tract.
George FW
Department of Internal Medicine, University of Texas
Southwestern Medical Center, Dallas 75235-8857, USA.
george02@utsw.swmed.edu
Endocrinology 1997 Mar;138(3):871-7
Previous work has clearly demonstrated that inhibition of 5
alpha-dihydrotestosterone (DHT) formation in vivo is not as
effective as total androgen ablation (castration) in causing
involution of the prostate. It is likely that this is due to
the fact that testosterone is partially effective in
maintaining androgen action. To provide insight into this
observation, the androgenic metabolites of testosterone,
androstenedione, and 5 alpha-DHT, were measured in prostate
tissue and in blood of 5 alpha-reductase inhibitor
(finasteride)-treated adult male rats. Finasteride treatment
caused a significant decrease in prostatic DHT levels and a
profound increase in prostatic testosterone and
androstenedione levels. Similarly, circulating DHT levels were
decreased in finasteride-treated rats (0.02 ng/ml compared
with 0.05 ng/ml seen in control rats); and circulating
androstenedione and testosterone levels were significantly
elevated in finasteride-treated animals compared with
controls. The in vitro effects of finasteride were
assessed on the metabolism of [3H]testosterone in a
tissue-slice assays. In the prostate, the inhibition of 5
alpha-reductase activity resulted not only in the decreased
formation of 5 alpha-reduced metabolites (primarily DHT and 5
alpha-androstanedione), but also an increase in the 17-oxo
metabolite androstenedione. In contrast, the tissues derived
from the embryonic wolffian duct (seminal vesicle and
epididymis) formed relatively low amounts of 17-keto steroids.
Because DHT is a high affinity ligand for the androgen
receptor and androstenedione shows very little, if any,
affinity for the receptor, these studies suggest that 5
alpha-reduction of testosterone may be a mechanism to amplify
androgen action in urogenital tissues such as the prostate by
preventing catabolism of testosterone to the inactive
androgen, androstenedione, at the site of hormone
action.
176. [Benign prostatic hyperplasia--the outcome of
age-induced alteration of androgen-estrogen balance?]
Weisser H; Krieg M
Institut fur Klinische Chemie, Transfusions- und
Laboratoriumsmedizin, Berufsgenossenschaftliche Kliniken
Bergmannsheil, Universitatsklinik der Ruhr-Universitat,
Bochum.
Urologe A 1997 Jan;36(1):3-9
Although human benign prostatic hyperplasia (BPH) is the
most common tumor in men, its etiology is still unclear. At
present, it is only widely accepted that BPH is under the
endocrine control of the testes and strongly associated with
aging. Therefore, in the human prostate we describe
the impact of aging on the activity of various androgen
metabolizing enzymes as well as on the endogenous androgen and
estrogen levels. Moreover, the inhibition of 5 alpha-reductase
by finasteride (Proscar) will be reported. Among all androgen
metabolizing enzymes, within the human prostate 5
alpha-reductase is the most powerful one. Most of the androgen
metabolizing enzymes undergo a significant age-dependent
alteration. For distinct enzymes, the correlation with age is
either negative (e.g. 5 alpha-reductase), or positive. Despite
a complex pattern of age-dependent alterations, the dominance
of 5 alpha-reductase among all androgen metabolizing enzymes
is always maintained. This is underlined by a strong
accordance between the age-dependent 5 alpha-reductase
activity and the corresponding age-dependent endogenous DHT
level. In epithelium, both the 5 alpha-reductase activity and
the DHT level decrease with age, whereas in stroma not only
the 5 alpha-reductase activity is rather constant over the
whole age range but the DHT level as well. In
contrast to the relatively unaltered DHT content in the stroma
of the human prostate, the estrogen content follows an
age-dependent increase. On the other side, in epithelium such
a positive correlation between the estrogen level and age is
not found. Thus, the age-dependent decrease of the DHT
accumulation in epithelium and the concomitant increase of the
estrogen accumulation in stroma will lead to a tremendous
increase with age of the estrogen/androgen ratio in the human
prostate. This could be of pathogenetic importance
for BPH development if in fact a balanced androgen/estrogen
synergism is necessary for the integrity of the normal human
prostate. Finally, it is remarkable that the
inhibition of 5 alpha-reductase activity by
finasteride (Proscar) is significantly stronger in epithelium
than in stroma. Therefore, it is conceivable
that the global size-reduction of BPH under finasteride
treatment is primarily due to the regression of BPH
epithelium.
177. Influence of finasteride on free and total
serum prostate specific antigen levels in men with benign
prostatic hyperplasia.
Pannek J, Marks LS, Pearson JD, Rittenhouse HG, Chan DW,
Shery ED, Gormley GJ, Subong EN, Kelley CA, Stoner E, Partin
AW
James Buchanan Brady Urological Institute and the Department
of Clinical Chemistry, Johns Hopkins Medical Institution,
Baltimore, Maryland, USA.
J Urol 1998 Feb;159(2):449-53
PURPOSE: Finasteride therapy for benign prostatic
hyperplasia (BPH) results in a marked lowering of serum
prostate specific antigen (PSA) levels. However, little is
known about the effect of finasteride on unbound or free serum
levels of PSA. Such information would be important since
percent free PSA may substantially improve the cancer
specificity of PSA testing. Thus, we prospectively studied the
effect of finasteride therapy on total and free serum PSA
levels.
MATERIALS AND METHODS: In a randomized, placebo
controlled, double-blind trial 40 men with histologically
confirmed BPH (age range 52 to 78 years) were treated with
either 5 mg. finasteride daily (26 patients) for 9 months or
placebo (14) for 6 months. Prostate volume was assessed by
transrectal ultrasound. Serum levels of free and total PSA
were measured from archived serum samples stored at -70C at
baseline and for as long as 9 months of treatment.
RESULTS: In the finasteride group mean total PSA levels
declined from 3.0 ng./ml. at baseline to 1.5 ng./ml. after 6
months of treatment (50% decrease, p <0.01). In the placebo
group, with similar baseline levels, no significant change was
observed. PSA density declined significantly in finasteride
treated men (p <0.01) but not in men receiving placebo. The
mean percent free PSA (13 to 17% at baseline) was not altered
significantly by finasteride or placebo.
CONCLUSIONS: Total PSA serum levels decreased by an
average of 50% during finasteride therapy but percent free PSA
did not change significantly. This information is
potentially useful in the interpretation of PSA data used for
early detection of prostate cancer in men receiving
finasteride. However, further studies are required to
demonstrate the use of percent free PSA to detect the
development of cancer.
178. The effect of finasteride on the prostate
gland in men with elevated serum prostate-specific antigen
levels.
Cote RJ, Skinner EC, Salem CE, Mertes SJ, Stanczyk FZ,
Henderson BE, Pike MC, Ross RK
Department of Pathology, University of Southern
California/Norris Comprehensive Cancer Center, Los Angeles
90033, USA.
Br J Cancer 1998 Aug;78(3):413-8
Prostate cancer is a disease associated with androgens. It
has been hypothesized that reducing the conversion of
testosterone (T) to dihydrotestosterone (DHT) in the prostate
by the use of the drug finasteride, a 5alpha-reductase
inhibitor, will reduce the incidence of prostate cancer. We
investigated the chemopreventive potential of finasteride by
evaluating its effect on the prostate gland of men with
elevated serum prostate-specific antigen (PSA). Fifty-two men
with elevated PSA and prostate sextant biopsies negative for
cancer were randomized to receive finasteride 5 mg day(-1) (27
patients) or no medication (25 patients) for 12 months and
were rebiopsied at 12 months. The biopsies were evaluated for
the presence of cancer, the proportion of glandular and
hyperplastic tissue, and the presence of high-grade prostatic
intraepithelial neoplasia (PIN). Epithelial proliferation was
assessed in the prestudy and 12-month biopsies by
immunohistochemistry using antibody to proliferating cell
nuclear antigen (PCNA). Serum blood samples were drawn at
baseline and after 1, 3, 6 and 12 months of study. In the
control group, serum levels of PSA and T were unchanged
throughout the 12 months. In the finasteride group, PSA
decreased 48% (P < 0.001), DHT decreased 67% (P < 0.001)
and T increased 21% (P < 0.001). Histological evaluation of
prestudy and 12-month biopsy specimens revealed that the
finasteride group had a 30% reduction in the percentage of
hyperplastic epithelial tissue (P = 0.002), although this
decrease was not statistically significantly different between
the finasteride and control groups (P = 0.11). In
patients with PIN on prestudy biopsy, no change occurred in
the PIN lesions with finasteride treatment. Finasteride also
had no effect on the proliferation index of prostatic
epithelial cells. Of the 27 patients treated with finasteride,
eight (30%) had adenocarcinoma of the prostate detected on the
12-month biopsy, compared with one (4%) of the control
patients (P = 0.025). In the treatment group, six cancers
occurred in the eight patients with PIN on the prestudy
biopsy; in the observation group no cancers were detected in
the five patients with PIN on the prestudy biopsy (P = 0.021).
Two cancers occurred in the 19 men in the treatment group with
no evidence of PIN on the prestudy biopsy, compared with one
cancer in the 20 men in the observation group with no evidence
of PIN on the prestudy biopsy (P = 0.60). This study, using a
novel model for evaluating short-term efficacy of
chemopreventive or therapeutic agents in men at high risk
of prostate cancer, provides little evidence that
finasteride is an effective chemopreventive agent for prostate
cancer in men with elevated PSA.
179. Finasteride: A Clinical Review
Gormley G.J.
Merck Research Laboratories, PO Box 2000,Rahway, NJ
07065-0914 United States
Biomedicine and Pharmacotherapy (France) 1995, 49/7-8
(319-324)
Finasteride is the first of a new class of 5alpha-reductase
inhibitors which allows selective androgen deprivation
affecting dihydrotestosterone (DHT) levels in target organs
such as the prostate and scalp hair without effecting
circulating levels of testosterone thus preserving the desired
androgen mediated effects on muscle strength, bone density and
sexual function. Finasteride has been demonstrated to
produce significant effects in men with an enlarged prostate
gland. The long-term data now emerging suggests that
progression of benign prostatic hyperplasia (BPH) may be
arrested providing additional long term benefits.
Experimental uses in prostate cancer prevention and male
pattern baldness offer new and exciting possibilities for this
class of compounds.
180. Comparison of finasteride (Proscar(R)), a
5alpha reductase inhibitor, and various commercial plant
extracts in in vitro and in vivo 5alpha reductase
inhibition
Rhodes L.; Primka R.L.; Berman C.; Vergult G.; Gabriel M.;
Pierre-Malice M.; Gibelin B.
RY80Y-140, Merck Sharp and Dohme Research Lab, POB
2000,Rahway, NJ 07065 United States
Prostate (United States) 1993, 22/1 (43-51)
Human prostate was used as a source of 5alpha reductase.
Compounds were incubated with an enzyme preparation and (sup
3H)testosterone. (sup 3H)-dihydrotestosterone production was
measured to calculate 5alpha reductase activity. IC$D5inf 0
values (ng/ml) were finasteride = 1; Permixon = 5,600; Talso =
7,000; Strogen Forte = 31,000; Prostagutt = 40,000; and
Tadenan = 63,000. Bazoton and Harzol had no activity at
concentrations up to 500,000 ng/ml. In castrate rats
stimulated with testosterone (T) or dihydrotestosterone (DHT),
finasteride, but not Permixon or Bazoton, inhibited T
stimulated prostate growth, while none of the three compounds
inhibited DHT stimulated growth. These results demonstrate
that finasteride inhibits 5alpha reductase, while Permixon and
Bazoton have neither antiandrogen nor 5alpha reductase
inhibitory activity. In addition, in a 7 day human clinical
trial, finasteride, but not Permixon or placebo, decreased
serum DHT in men, further confirming the lack of 5alpha
reductase inhibition by Permixon. Finasteride and the plant
extracts listed above do not inhibit the binding of DHT to the
rat prostatic androgen receptor (concentrations to 100
mug/ml). Based on these results, it is unlikely that these
plant extracts would shrink the prostate by inhibiting
androgen action or 5alpha reductase.
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