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The role of flower pollen extract in managing patients affected by chronic prostatitis/chronic pelvic pain syndrome: a comprehensive analysis of all published clinical trials

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Background Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is still a challenge to manage for all physicians. We feel that a summary of the current literature and a systematic review to evaluate the therapeutic efficacy of flower pollen extract would be helpful for physicians who are considering a phytotherapeutic approach to treating patients with CP/CPPS. Methods A comprehensive search of the PubMed and Embase databases up to June 2016 was performed. This comprehensive analysis included both pre-clinical and clinical trials on the role of flower pollen extract in CP/CPPS patients. Moreover, a meta-analysis of available randomized controlled trials (RCTs) was performed. The NIH Chronic Prostatitis Symptom Index (NIH-CPSI) and Quality of Life related questionnaires (QoL) were the most commonly used tools to evaluate the therapeutic efficacy of pollen extract. Results Pre-clinical studies demonstrated the anti-inflammatory and anti-proliferative role of pollen extract. 6 clinical, non-controlled studies including 206 patients, and 4 RCTs including 384 patients were conducted. The mean response rate in non-controlled studies was 83.6% (62.2%-96.0%). The meta-analysis revealed that flower pollen extract could significantly improve patients’ quality of life [OR 0.52 (0.34-.0.81); p = 0.02]. No significant adverse events were reported. Conclusion Most of these studies presented encouraging results in terms of variations in NIH-CPSI and QoL scores. These studies suggest that the use of flower pollen extract for the management of CP/CPPS patients is beneficial. Future publications of robust evidence from additional RCTs and longer-term follow-up would provide more support encouraging the use of flower pollen extracts for CP/CPPS patients.
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R E S E A R C H A R T I C L E Open Access
The role of flower pollen extract in
managing patients affected by chronic
prostatitis/chronic pelvic pain syndrome: a
comprehensive analysis of all published
clinical trials
Tommaso Cai
1*
, Paolo Verze
2
, Roberto La Rocca
2
, Umberto Anceschi
1
, Cosimo De Nunzio
3
and Vincenzo Mirone
2
Abstract
Background: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is still a challenge to manage for all
physicians. We feel that a summary of the current literature and a systematic review to evaluate the therapeutic
efficacy of flower pollen extract would be helpful for physicians who are considering a phytotherapeutic approach
to treating patients with CP/CPPS.
Methods: A comprehensive search of the PubMed and Embase databases up to June 2016 was performed. This
comprehensive analysis included both pre-clinical and clinical trials on the role of flower pollen extract in CP/CPPS
patients. Moreover, a meta-analysis of available randomized controlled trials (RCTs) was performed. The NIH Chronic
Prostatitis Symptom Index (NIH-CPSI) and Quality of Life related questionnaires (QoL) were the most commonly
used tools to evaluate the therapeutic efficacy of pollen extract.
Results: Pre-clinical studies demonstrated the anti-inflammatory and anti-proliferative role of pollen extract. 6
clinical, non-controlled studies including 206 patients, and 4 RCTs including 384 patients were conducted. The
mean response rate in non-controlled studies was 83.6% (62.2%-96.0%). The meta-analysis revealed that flower
pollen extract could significantly improve patientsquality of life [OR 0.52 (0.34-.0.81); p= 0.02]. No significant
adverse events were reported.
Conclusion: Most of these studies presented encouraging results in terms of variations in NIH-CPSI and QoL scores.
These studies suggest that the use of flower pollen extract for the management of CP/CPPS patients is beneficial.
Future publications of robust evidence from additional RCTs and longer-term follow-up would provide more
support encouraging the use of flower pollen extracts for CP/CPPS patients.
Keywords: Chronic pelvic pain syndrome, Inflammatory chronic pelvic pain syndrome, Prostatitis syndrome,
Chronic prostatitis symptom index, Pollen extract
* Correspondence: ktommy@libero.it
1
Department of Urology, Santa Chiara Regional Hospital, Trento, Italy
Full list of author information is available at the end of the article
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Cai et al. BMC Urology (2017) 17:32
DOI 10.1186/s12894-017-0223-5
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Background
Chronic prostatitis has been described as one of the
most common illnesses in men aged <50 year [1] with
differing clinical presentations [2]. According to the clas-
sification of the National Institute of Health (NIH) [3],
class III chronic prostatitis/chronic pelvic pain syndrome
(CP/CPPS) is the most frequent category [4]. Symptoms
such as pelvic pain, painful voiding and ejaculation and
disturbed sexual functioning are common, often result-
ing in a significant impact on quality of life [5]. Recently,
it has been established that the annual cost of a patient
affected by prostatitis exceeds that of a patient with type
1 diabetes and that his quality of life is analogous to a
patient with a heart attack or acute Crohn's disease [5].
Available therapies for CP/CPPS are not highly effective
and require further in-depth analysis and consideration
of such alternate strategies [6]. The traditional treatment
of CP/CPPS is known as the three As: antibiotics, anti-
inflammatory medications, and alpha blockers. The use
of antibiotics remains controversial, especially due to the
fact that bacteria cannot be isolated from the urogenital
samples of CP/CPPS patients [7]. On the other hand,
even if anti-inflammatory medications, aspirin or other
NSAIDs such as ibuprofen can decrease pain, they can
only be taken for a limited period of time due to their
high prevalence of drug-related adverse effects. In other
words, the standard treatment for CP/CPPS has not yet
been definitively established [7]. In this scenario, even if
phytotherapeutics seems to be an interesting option be-
cause of their generally low side effects, demonstrated
efficacy, and high treatment compliance by patients, few
compounds have been subject to scientific scrutiny and
prospective controlled clinical trials [8, 9].
Over the last few years, interest in the use of flower
pollen extract in the management of CP/CPPS has in-
creased. Several clinical experiments show that flower
pollen extract preparations may allow for a durable and
marked symptom reduction in young men with CP/CPPS
with improvement in semen quality and a significant re-
duction in the National Institutes of Health-Chronic Pros-
tatitis Symptom Index (NIH-CPSI) score [1013]. The
most common pollen extracts used in clinical trials is
Graminex® (Graminex® LLC, 95 Midland Road, Saginaw,
MI 48638) that is a mixture of standardized extracts of rye
grass pollen (Secale cereal), corn pollen (Zea mays), and
timothy pollen (Phleum pretense). However, up to the
present no comprehensive analysis of the current litera-
ture has been made so as to evaluate the tolerability and
clinical efficacy of flower pollen extract in the manage-
ment of patients affected by CP/CPPS.
Aim of the present review
Herein we aim to analyse all published data on flower
pollen extracts role in the management of patients
affected by CP/CPPS both in a pre-clinical and clinical
setting, with particular attention given to the random-
ized clinical trials. Moreover, we aim to analyse all pub-
lished studies in order to identify all clinical, laboratory
and instrumental characteristics that are able to predict
patientsclinical response to the treatment.
Research questions
We put forth two research queries:
1. Is flower pollen extract able to obtain significant
pre-clinical data in order to justify its clinical use in
the management of patients affected by CP/CPPS?
2. Is flower pollen extract able to improve overall and
disease-specific quality of life of patients affected by
CP/CPPS?
Methods
Types of studies
We have included pre-clinical studies regarding the ef-
fects of flower pollen extracts as a background and nar-
rative review. Moreover, we have included clinical trials,
randomized controlled trials, cohort, and case-control
studies for our systematic review and meta-analysis. Edi-
torials, commentaries, and review articles were used only
for the background and the narrative review.
Outcome measures
The primary outcome of the study was the improvement
of disease-related quality of life in terms of clinical re-
sponse to the treatment as defined by the investigators.
Clinical response to the treatment was generally evalu-
ated in terms of NIH-CPSI and SF-36 questionnaires.
Moreover, the improvement of symptoms [urinary and
sexual symptoms, in terms of the International Prostatic
Symptoms Score (IPSS)] and other questionnaires were
also considered as outcome measures, if used by the
investigators.
Risk of bias assessment
The risk of bias was performed by using the Newcastle-
Ottawa Scale for risk of bias assessment [14].
Search strategy and research methods
We performed a search of literature up to June 2016
using the Medline computerized database of the US
National Library of Medicine. The Google Scholar data-
base was used, too. The Medline search was carried-out
using Medical Subject Headings and free text terms as
follows: pollen extract,orflower pollen extractand
prostate(exploded) were combined with the terms:
treatmentand therapy. Abstracts were not considered
when full articles focusing on the same studies were
available. Due to the limited number of pre-clinical
Cai et al. BMC Urology (2017) 17:32 Page 2 of 8
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studies published, we also included all non-English lan-
guage papers as well. In cases of non-English language
papers, the paper was included if the abstract was
written in English and informative. Overlapping ex-
periments have not been included because they were
considered redundant. We considered as background
information and as a comparative paper the latest re-
view about the role of flower pollen extract in CP/
CPPS patients by Wagenlehner FM published in 2011
[15]. From an initial literature search with pollen ex-
tract and prostatitis, a total of 23 extended papers
were screened and 15 were selected and included in
the present review. Finally, 10 clinical trials and 5
pre-clinical studies were analysed and are discussed in
this review (Fig. 1). The Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA) and
Meta-analyses of Observational studies in Epidemi-
ology (MOOSE) guidelines for the reporting of this
present study was used in order to perform an accur-
ate research check-list and report [16, 17]. The meta-
analysis was performed using Review Manager 5.3
(Copenhagen: The Nordic Cochrane Centre, The
Cochrane Collaboration, 2014) software. The inverse
variance technique for the meta-analysis of the hazard
ratios has been used. Due to the fact that the studies
heterogeneity cannot be explained, a random-effects
model has been employed which in fact involves an
assumption that the effects being estimated in the dif-
ferent studies are not identical.
Review methodology
Two authors performed the study selection independently
(TC and PV). All disagreements were resolved by the se-
nior author (VM). Titles and abstracts were used to screen
for initial study inclusion. Full-text review was used where
abstracts were insufficient to determine if the study met
Fig. 1 The figure shows the study flow chart in line with the PRISMA statement (http://www.prisma-statement.org/)
Cai et al. BMC Urology (2017) 17:32 Page 3 of 8
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inclusion or exclusion criteria. Two authors (TC and PV)
independently performed all data abstraction including
evaluation of study characteristics, risk of bias, and out-
come measures with independent verification performed
by the senior author (VM). The limited number of the
studies collected did not require any other authors.
Results
Pre-clinical evidence
Our literature search identified 5 pre-clinical studies
(Table 1). Three in vitro models[1820] and three ani-
mal models [12, 21, 22] were used. All the studies dem-
onstrated/confirmed that pollen extracts show two
important pharmacological effects: anti-inflammatory
and anti-proliferative. Loschen et al. demonstrated that
rye pollen is able to inhibit the synthesis of prostaglan-
din and leukotriene performing an anticongestive and
anti-inflammatory effect on the prostate tissue [20]. An-
other aspect to take into account is the possible effect of
pollen extract on other tissues that differ from those of
prostate glands. In fact, Wagenlehner highlighted an-
other pharmacological effect of pollen extract that
can be considered as a therapeutic mechanism of this
compound: its effect on smooth muscles [15]. In
conformity with Wagenlehner [15], Nagashima
demonstrated in an animal model that consecutive
administration of flower pollen extracts increased
significantly maximum pressure during micturition to
promote micturition reflex [22].
Anti-inflammatory effect
It was concluded that pollen extracts are able to inhibit
prostaglandin and leukotriene synthesis and this effect is
comparable to that of diclofenac and indomethacin and
approximately 10 times higher than that of aspirin [20].
Anti-proliferative effects
Several animal models showed that pollen extract has a
possible effect on the prostate via the androgen metabol-
ism [21]. Talpur and co-workers demonstrated that pollen
extract decreased the size of the prostate in androgen-
induced prostatic enlargement in rats [21]. The effect of
pollen extract on prostate enlargement is due to the fact
that a fraction of this compound is a powerful mitogenic
inhibitor of fibroblastic and epithelial proliferation [15].
Moreover, Kamijo and co-workers found that pollen ex-
tract protects acinar epithelial cells and inhibits stromal
proliferation in association with enhanced apoptosis [12].
Finally, several in vitro studies demonstrated that pollen
extract is able to inhibit prostate cancer cell growth, as
found by Habib [18]. This effect is even more pronounced
in hormone-independent models, suggesting that there
might be a place for pollen extract in the control of abnor-
mal growth of hormone-insensitive cells [18].
Clinical evidence and meta-analysis
We identified 10 clinical studies (Table 2) and selected 6
clinical non randomized trials [10, 11, 2326] and 4
RCTs [13, 2729]. All trials demonstrated that pollen ex-
tracts significantly improved total symptoms, pain, and
QoL in patients with inflammatory CP/CPPS without se-
vere side-effects. Cai et al. used Graminex® (Graminex®
LLC, 95 Midland Road, Saginaw, MI 48638) in associ-
ation with B vitamins for the treatment of inflammatory
and non-inflammatory CP/CPPS [11, 27]. Wagenlehner
used Cernilton for the treatment of inflammatory CP/
CPPS [13], while Elist used Prostat/Poltit that contains
Table 1 Summary of all pre-clinical studies
Author, year [reference] Study type Model Compound used Main study finding
Habib FK, 1990 [18] In vitro study Human prostate
cancer cell line
pollen extract - pollen extract is able to inhibit
the prostate cancer cell growth
(hormone-independent model)
Habib FK, 1995 [19] In vitro study Human prostate
cancer cell line (DU145)
pollen extract - pollen extract V-7 fraction is able
to inhibit the prostate cancer cell
growth
Kamijo T, 2001 [12] Animal model Rats pollen extract - pollen extract protects acinar
epithelial cells and inhibits stromal
proliferation in association with
enhanced apoptosis
Loschen G, 1991 [20] In vitro study Microsomes (RBL-1 cells) pollen extract - pollen extract shows an
anti-inflammatory and
anti-proliferative therapeutic effect
Talpur N, 2003 [21] Animal model Rats pollen extract vs serenoa repens - pollen extract is able to influence
prostatic hyperplasia via effects on
androgen metabolism
Nagashima A, 1998 [22] Animal model Rats pollen extract - pollen extract increases the maximum
pressure during urination to promote
the urination reflex
Cai et al. BMC Urology (2017) 17:32 Page 4 of 8
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74 mg of highly defined extract of pollen from selected
Graminae species [28]. Finally, Iwamura used an associ-
ation of Cernitin T60 and Cernitin GBX [29].
Non-RCTs
As reported in Table 2, 6 clinical, non randomized trials
including 206 patients were selected. The mean response
rate in non-controlled studies was 83.6% (62.2%-96.0%).
Cai and co-workers in a non-randomized clinical study re-
ported a clinical response rate of 90%, demonstrating that
pollen extract in association with vitamins significantly
improved total symptoms, pain, and QoL in patients with
non-inflammatory CP/CPPS without severe side effects
[11]. The same results, in terms of clinical efficacy, were
reported by Rugendorff [10] and Buck [23] in two non-
randomized trials which reported a clinical response rate
of 62.2% and 86.6%, respectively. Moreover, three studies
by Japanese researchers demonstrated a high clinical re-
sponse rate to pollen extract treatment in patients with
both class IIIa and class IIIb CP/CPPS [2426].
Table 2 Summary of all clinical studies
Author, year
[reference]
Study design Patients number
(response rate)
Controls Number
(response rate)
Comparator Outcomes measured
Buck AC. 1989 [23] Prospective trial
(phase II)
15 (86.6) - - - pollen extract effective in the
treatment of chronic prostatitis
and prostatodynia.
Cai T. 2013 [11] Prospective trial
(phase II)
20 (90.0) - - - pollen extract significantly
improved total symptoms, pain,
and QoL in patients with
non-inflammatory CP/CPPS
without severe side effects.
Cai T, 2014 [27] Randomized
controlled trial
41 (75.6) 46 (41.3) ibuprofen - pollen extract significantly
improved quality of life of
patients when compared with
those treated with ibuprofen
(treatment difference in the
NIH-CPSI pain domain,
-2.14 ± 0.51, P < 0.001;
QoL scores, P = 0.002).
Elist J. 2006 [28] Randomized
controlled trial
30 (73.3) 28 (64.2) Placebo - pollen extract is superior to
placebo in providing
symptomatic relief in men
with chronic nonbacterial
prostatitis/chronic pelvic pain
syndrome.
Iwamura H, 2015 [29] Randomized placebo-
controlled trial
50 (78.1) 50 (88.2) Eviprostat
(phytotherapeutic
agent)
- pollen extract significantly
reduced the symptoms of
category III CP/CPPS without
any adverse events, in terms
of NIH-CPSI, IPSS, and QoL.
Jodai A, 1988 [24] Prospective trial
(phase II)
32 (75.0) - - - pollen extract significantly
reduced the symptoms in
75.0% of all treated patients.
Monden K. 2002 [25] Prospective trial
(phase II)
24 (91.6) - - - pollen extract significantly
reduced the symptoms of
chronic prostatitis group
Rugendorff EW. 1993 [10] Prospective trial
(phase II)
90 (62.2) - - - pollen extract significantly
reduced the symptoms of
category III CP/CPPS without
any adverse events, in terms
of urinary symptoms and QoL.
Suzuki T. 1992 [26] Prospective trial
(phase II)
25 (96.0) - - - pollen extract significantly
reduced the symptoms of
prostatitis patients without
any adverse events.
Wagenlehner FM. 2009 [13] Randomized
controlled trial
70 (70.6) 69 (49.3) Placebo - pollen extract significantly
improved total symptoms,
pain, and QoL in patients with
inflammatory CP/CPPS without
severe side-effects.
Cai et al. BMC Urology (2017) 17:32 Page 5 of 8
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RCTs and meta-analysis
The mean response rate in RCTs was 74.4% (70.6%-
78.1%). The latest RCT carried out by Iwamura and co-
workers demonstrated a response rate of 78.1% in 50
patients affected by CP/CPPS after 8 weeks of treatment
[29]. The authors defined the clinical response as a de-
crease in the NIH-CPSI total score by at least 25% [29].
They did not observe severe adverse events in any pa-
tients in their study [29]. On the other hand, Cai and
co-workers, in a cohort of patients randomized to pollen
extract or ibuprofen, reported a response rate of 75.6%
in the flower pollen extract group [27]. Both class IIIa
and class IIIb CP/CPPS patients were enrolled and,
moreover, it was reported that adverse events were less
frequent in the pollen extract group than in the ibupro-
fen group [27]. In the largest study, Wagenlehner and
co-workers demonstrated a clinical response rate of
70.6% [13] in 139 patients affected by inflammatory CP/
CPPS and treated for 12 weeks with flower pollen ex-
tract. They concluded that the beneficial effect continued
to improve after 12 weekstreatment showing that pollen
extract can be recommended for patients with inflamma-
tory CP-CPPS for long-term treatment [13]. In 2006 Elist,
by carrying out a double-blind study which included 60
patients with class IIIa or class IIIb CP/CPPS who were
treated with flower pollen extract for 6 months, reported
an overall clinical response of 73% [28]. All these 4 RCTs
were used for the/included in our meta-analysis. We in-
cluded 384 patients from 4 studies. The meta-analysis re-
vealed that flower pollen extract could significantly
improve patientsquality of life [OR 0.52 (0.34-.0.81); p=
0.02]. Figure 2 shows the forest plot of the effect of pollen
extract on CP/CPPS patients in terms of clinical response
rate, as defined by the investigators.
Sub-analysis on the basis of CP/CPPS type (class III a or b)
The analysis of the 4 RCT studies did not permit us to
clearly identify which CP/CPPS sub-type was the best
candidate to treat with the pollen extract. In this sense,
the CP/CPPS class type is not able to predict patients
clinical response to the treatment. Only one out of four
studies enrolled inflammatory CP/CPPS (class A) [13],
while the other three studies enrolled both class III a
and b [2729]. Cai and co-workers enrolled 25 patients
with inflammatory CP/CPPS (type IIIa) and 62 type IIIb
[27]. They found that in the pollen extract group pa-
tients affected by type IIIb CP/CPPS showed higher QoL
results and a lower pain level following treatment in
terms of the NIH-CPSI score (the NIH-CPSI score was
24.8 ± 1.8 at the enrolment versus 11.7 ± 1.7 at the
follow-up visit; P < 0.001) when compared with type IIIa
CP/CPPS patients [27]. Iwamura and co-workers en-
rolled 20 participents with class IIIa and 19 with class
IIIb, without any reference to the difference between the
two groups [29]. Finally, Elist did not report the results
stratified by the CP/CPPS class [28]. In the two studies
in which in which a data stratification according to class
IIIa or b, 84 class A CP/CPPS and 30 class b had been
treated with pollen extracts, while 80 class A CP/CPPS
and 32 class b were considered as controls. The lack of
data did not allow a significant analysis.
Risk of bias assessment
The 4 RCTs included showed few risk of bias. Three
studies contained both class IIIa and IIIb CP/CPPS pa-
tients, thus introducing the risk of a selection bias.
Moreover, the RCT by Elist showed an important risk of
a selection bias due to the fact that in this study patients
between 20 and 60 years were included.
Discussion
Main findings
Pollen extract is a mixture of natural components, such
as amino acids, carbohydrates, lipids, vitamins, phytos-
terols and minerals that have been introduced in uro-
logical practice for the treatment of CP/CPPS patients
[15]. In this review and meta-analysis of 4 RCTs with
low-to-moderate risk of bias, we found that the use of
flower pollen extracts in the management of CP/CPPS
patients is associated with a high rate of clinical re-
sponse without any significant adverse events. Moreover,
we found that in both class IIIa and class IIIb the use of
pollen extract is able to obtain significant improvements
in a patientsQoL. These findings allow us to discuss
Fig. 2 The figure shows forest plot of the effect of pollen extract on CP/CPPS patients in terms of clinical response rate
Cai et al. BMC Urology (2017) 17:32 Page 6 of 8
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several beneficial aspects of the role of pollen extract in
the management of CP/CPPS patients. Firstly, upon con-
sideration of the high clinical response rate of all in-
cluded papers it was found that the mean response rate
was high in both non-controlled [83.6% (62.2%-96.0%)]
and in RCTs studies [74.4% (70.6%-78.1%)]. In analysing
the reported encouraging results in terms of variations
in NIH-CPSI and QoL scores, the following consider-
ations should be taken into account:
- the proven anti-inflammatory, anti-proliferative effect
of pollen extract
- the low rate of adverse events
All pre-clinical studies demonstrated that pollen ex-
tracts show an important anti-inflammatory effect due
to the inhibition of prostaglandin and leukotriene syn-
thesis [20]. Moreover, the dose-dependent, anti-
inflammatory action of pollen extract in nonbacterial
prostatitis in rats leading to decreased levels of
interleukin-1b, interleukin-6 and a tumour necrosis fac-
tor, decreases glandular inflammation [15] has been
demonstrated. The anti-inflammatory effect of pollen ex-
tract is approximately 10 times higher than that of as-
pirin [20] and did not lead to significant adverse events.
This aspect is very important to highlight, due to the
fact that the low prevalence of adverse effects correlates
with a high patient compliance rate to the treatment.
Moreover, several pre-clinical experiences demonstrated
that flower pollen extract is able to inhibit 5a-reductase
activity in the epithelium and stroma of the prostate in
vitro, inhibiting the formation of dihydrotestosterone
from testosterone [15]. This could be the reason for the
improvements in urinary symptoms reported by the pa-
tients. However, the inhibition of 5a-reductase activity
requires a long-term treatment as highlighted by several
authors [15]. Even if a placebo effect was generally re-
ported in patients treated with phytotherapeutic agents,
in the 4 RCTs, clinically significant improvements were
only observed in the pollen extract group and not in the
placebo group. Finally, while Wagenlehner and co-
workers found a decrease in leukocytes in post-prostate
massage urine samples in both patients and controls
[13], they did not find a significant difference between
the two groups in terms of leukocyte number and for
this reason leukocytes cannot be correlated with clinical
success [13]. This aspect supports the hypothesis that
the presence of inflammatory cells in the post-prostate
massage urine sample is not a laboratory characteristic
that is able to predict treatment response.
Strengths and limitations of the present study
In this review we excluded all studies on the effect of
pollen extract on patients affected by benign prostatic
hyperplasia or other urological diseases that can deter-
mine symptoms. Moreover, we excluded all studies in
which the dosage of the compound was indicated in the
publication. For this reason, despite the latest review by
Wagenlehner we have excluded the paper by Li [30]. On
the other hand, the most important limitation of this re-
view is the lack of a pharmacokinetic evaluation of
pollen extract. As highlighted by Wagenlehner, pharma-
cokinetic studies on the absorption, distribution, metab-
olism or excretion of the active components of flower
pollen extracts have not been performed [15]. This is
due to the fact that it is not known which compounds
are primarily responsible for clinical efficacy [15].
Clinical implications
It is well known that there is no standard treatment or
CP/CPPS to date. Amongst all the drugs and therapeutic
approaches suggested and used, phytotherapeutic agents
are those most widely prescribed in every day clinical
practice with variable success. However, their use has
only rarely been evaluated in suitable clinical trials. On
the other hand, pollen extract has been sufficiently eval-
uated in preclinical and clinical studies [10, 13, 15].
Herein, we report encouraging results in terms of varia-
tions in NIH-CPSI and QoL scores in patients treated
with pollen extracts indicating that the use of pollen ex-
tract appears to be safe and well tolerated by patients
and, for this reason, the compliance to the treatment is
high.
Conclusion
In conclusion, based upon our study analysis, pollen ex-
tracts appear to be clinically beneficial as indicated by
the significant improvements in terms of the NIH-CPSI
and QoL scores of patients diagnosed with CP/CPPS.
Moreover, this therapeutic approach has an excellent
safety profile with limited reported adverse effects. Fu-
ture publications containing robust evidence from add-
itional RCTs and longer-term follow-up would provide
doctors with more confidence regarding the use of
flower pollen extracts for their CP/CPPS patients.
Abbreviations
CP/CPPS: Chronic prostatitis/chronic pelvic pain syndrome; IPSS: International
prostatic symptoms score; NIH: National institutes of health; NIH-
CPSI: National institutes of health-chronic prostatitis symptom index;
NSAIDs: Non-steroidal anti-inflammatory drugs; QoL: Quality of life;
RCTs: Randomized clinical trials; SF-36: The short form (36) health survey
Acknowledgements
We are grateful to Juliet Ippolito for manuscript language revision.
Funding
None.
Availability of data and materials
Not applicable.
Cai et al. BMC Urology (2017) 17:32 Page 7 of 8
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Authorscontributions
Study conception and design: CT, MV. Acquisition, analysis and interpretation
of data: CT, AU, LRR, VP. Drafting of manuscript: Cai T. Critical revision and
supervisions: DNC, MV. All authors read and approved the final manuscript.
Competing interests
Tommaso Cai, Paolo Verze and Vincenzo Mirone are consultant for and have
received research support from IDIpharma.
Consent for publication
Not applicable.
Ethics approval and consent to participate
Not applicable.
PublishersNote
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Author details
1
Department of Urology, Santa Chiara Regional Hospital, Trento, Italy.
2
Department of Urology, University of Naples, Federico II, Naples, Italy.
3
Department of Urology, Ospedale SantAndrea, Sapienza University of Rome,
Rome, Italy.
Received: 25 February 2017 Accepted: 16 April 2017
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30. Li NC, Na YQ, Guo HQ. Clinical study with prostat (Poltit) for treatment for
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... ared the effects of this drug with the effects of Nonsteroidal anti-inflammatory drugs (NSAID)(Pirola et al., 2017). Another interesting study showed positive effects of cernitin pollen on sex-hormone-induced nonbacterial prostatitis in rats. Pollen extracts protected acinar epithelial cells and inhibited stromal proliferation(Kamijo et al., 2001).Cai, Verze, Rocca, Anceschi, et al. (2017) andCai, Verze, Rocca, Palmieri, et al. (2017) ...
... Group A (32 patients) receiving oral capsules of pollen extract and vitamins and Group B (33 patients) receiving bromelain for 3 months. After the set time, 24 patients in Group A showed reduction in the NIH-CPSI score as compared to 8 patients from Group B. Interleukin (IL8) level was also lower in Group A from the time of initiation of the study(Cai, Verze, Rocca, Anceschi, et al., 2017;Cai, Verze, Rocca, Palmieri, et al., 2017).Iwamura et al. (2015) carried out a comparative study between Eviprostat and pollen extract on patients with category III CP/CPPS. The outcome showed a significant reduction of symptoms of category III CP/CPPS by both Eviprostat and pollen extract, indicating that pollen extract has an identical effect as Eviprostat on category III CP/CPPS ...
Article
Full-text available
Chronic pelvic pain syndrome (CPPS) can be triggered by a various types of gynecological, gastrointestinal, urological, and musculoskeletal disorders. Recently, the role of the central nervous system has proven to be an integral part on the development of any chronic pain syndrome, including CPPS. However, owing to the complex and heterogeneous etiology and pathophysiology of CPPS, the establishment of effective therapeutic interventions remains challenging for both physicians and patients. Nonetheless, recent studies have pointed that medicinal plants and their secondary metabolites can be effectively used in CPPS therapy, besides contributing to restore the patients' quality of life and potentiate the conventional CPPS management. In this sense, this review aims to provide a careful overview on the biomedical data for the use of medicinal plants use and their secondary metabolites on CPPS management.
... The clinical efficacy of pollen extract in the treatment of prostatitis, also associated with pelvic pain [12], has been widely demonstrated in controlled clinical trials [13,14]. In an experimental study, Nagashima et al. [15] investigated the effects of pollen extract on inflammatory cytokines (IL-1 beta, IL-6 and TNF-alpha) in an animal model of prostatic disease treated with pollen extract (630 and 1260 mg/kg, p.o.) or testosterone (2.5 mg/kg, s.c.). ...
Article
Full-text available
Benign prostatic hyperplasia (BPH) is a common cause of male lower urinary tract symptoms (LUTS) that can reduce quality of life. Even if several drugs can be used in its treatment, the development of adverse drug reactions (ADRs) represents the most common cause of low adherence. In the present study, we evaluate both the efficacy and the safety of a new nutrient fixed combination of Pollen Extract plus Teupolioside, named Xipag®, in patients with LUTS. We conduct a pilot single center open label clinical study between 1 March 2020 and 30 June 2020 in patients with BPH referred to general practitioner’s ambulatories. Male patients > 45 years, sexually active, with clinical symptoms of LUTS and with a diagnosis of HPB were enrolled and received one tablet/day of Xipag® (T0), for three months (T1: end of treatment). The IPSS and IIEF-5 questionnaires were carried out at T0 and T1 and represent the first end point, whereas the primary safety end point was considered the absence of ADR or of drug–drug interactions related to Xipag® administration. During the study period, 25 subjects aged 43 to 76 years (mean 62.7 ± 9) were enrolled and completed the study. The clinical evaluation in T1 documented that Xipag® induced a statistically significant improvement (p < 0.01) in symptoms, as documented by the IPSS questionnaire (range 22.7–88.9; mean 55.2 ± 23.6), without the development of ADRs. In conclusion, this is the first real-world study that showed the efficacy and the safety of Xipag® in the BPH patients with LUTS.
... In the era of bacterial resistance, the use of antibiotics for CP remains controversial, since urogenital samples of CP/CPPS patients are usually negative [7]. Phytotherapeutics represent an adequate alternative due to their negligible side-effects, despite the lack of general consensus and deducible evidence from prospective controlled clinical trials [8][9][10]. In recent years, there has been an increased growing interest in several nutraceutical agents, such as glycine max [11], Boswellia [12], urtica dioica [13] and pinus pinaster [14], in the management of urinary tract infections (UTIs) and CP. ...
Article
Full-text available
The present study evaluates the efficacy of a combination of soyabean extracts associated with Curcuma Longa, Boswellia, Pinus pinaster and Urtica dioica (PROSTAFLOG®) in patients affected by CP/CPPS, through the evaluation of interleukin-8 (IL-8) plasma seminal levels. All patients diagnosed with CP/CPPS, attending the same urologic center, were enrolled in this randomized, controlled phase III study. Participants were randomized to receive oral capsules of PROSTAFLOG® (two capsules at bedtime every 24 h) or Ibuprofen 600 mg (1 tablet daily), lasting for a period of four weeks. NIH-CPSI and SF-36 questionnaires, as urological evaluations with a transrectal ultrasound (TRUS), the Meares–Stamey test, and IL-8 dosage in seminal plasma were performed at baseline and at 3 months follow-up. A total of 77 patients (mean age of 34.5 ± 6.1) were enrolled (PROSTAFLOG® (n = 39); ibuprofen (n = 38)) in the study. At 3 months, in the PROSTAFLOG® series, 69.2% of patients showed a significant reduction in the NIH-CPSI score, compared with 34.2% in the ibuprofen group (p < 0001). The mean IL-8 levels were significantly lower in the PROSTAFLOG® cohort compared with the ibuprofen series (p < 0.0001), while a significant reduction in the IL-8 level between the enrolment and last follow-up evaluation was also observed in this group (p < 0.0001). Additionally, a significant reduction in the volume of the seminal vesicles assessed by TRUS was also found in the PROSTAFLOG® series during the observational timeframe (18.3 ± 7.1 mL vs. 11.2 ± 2.4 mL (p < 0.0001). In conclusion, PROSTAFLOG® significantly improves the QoL in patients affected by CP/CPPS and it provides a significant reduction in IL-8 seminal levels as the overall seminal vesicles volume.
... In vivo studies have shown that flavonoid compounds can be used to treat prostatitis. Some clinical studies have shown that the flavonoids can significantly reduce the NIH-CPSI score in CP/CPPS patients [130][131][132]. Flavonoids can substantially decrease the TNF-α and IL-8 in the serum and prostate tissues of the CP/CPPS rats model [133]. ...
Article
Full-text available
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is the most frequent form of prostatitis, and has a serious impact on patients' quality of life, and causes severe symptoms. The pain in the pelvic, perineal and penile areas, lower abdominal pain, and pain during urination or ejaculation are the main complaints of CP/CPPS. The underlying complex and unknown pathophysiology of this syndrome have made the management of CP/CPPS and the availability of monotherapy challenging. To identify an effective monotherapy, a plethora of clinical trials failed due to its puzzling etiology. Antibiotics, anti-inflammatory, and a-blockers have been commonly used for the treatment of CP/CPPS, but the desired and complete effects have not been gotten yet. The patients and clinicians are attracted to alternative therapies because of their multi-targeted effects. Attention toward natural compounds effectiveness and safety, supporting the development of a new nutraceutical science. In the alternative remedies for the treatment of prostatic diseases, medicinal herbs, in the form of herb parts or extracts, are getting attention due to their positive effects on prostatic diseases. At present, there is no available detailed literature review about the efficacy of medicinal herbs in the treatment of CP/CPPS. This review aimed to explore the useful medicinal herbs in the treatment of CP/CPPS from different perspectives and their possible mechanism of action in managing CP/CPPS.
... The evidence-based treatments for CP/CPPS are not as adequate as other "prostate diseases" [4,5]. Previous publications have reported the successful application of phytotherapeutic agents, such as pollen extract, quercetin, or saw palmetto/Serenoa repens (SR), with pain-alleviating effects [6][7][8][9]. Moderate-quality evidence indicates that phytotherapy probably causes a small decrease in prostatitis symptoms with few adverse events [10], however, the present literatures provide few powerful evidence for the recommendations of Serenoa repens extract (SRE) for CP/CPPS [5]. In addition, there has been rare reports on large-scale, placebo-controlled, SRE single-use trials. ...
Article
Full-text available
Purpose To perform a placebo-controlled trial to evaluate the efficacy and safety of Serenoa repens extract (SRE) for the treatment of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Methods We conducted a double-blind, randomized, placebo-controlled, multicenter, clinical phase 4 study of 221 patients with CP/CPPS across 11 centers. Participants were randomly assigned in a 2:1 ratio to receive SRE or placebo for 12 weeks. The primary efficacy endpoint was the change in total score on the National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI). Secondary efficacy endpoints included improvements within each domain of NIH-CPSI, clinical response rate, and International Index of Erectile Function 5 items (IIEF-5). Results In total, 226 patients were enrolled and randomized between January 2017 and June 2018. Of these 221 patients were included in the intent-to-treat analysis: 148 in the SRE group and 73 patients in the placebo group. Compared to the placebo, SRE led to statistically significant improvements in the NIH-CPSI total score and sub-scores. The significant improvements of NIH-CPSI scores were established after 2 weeks from the first dose, and continued to the end of the treatment. Furthermore, a significantly higher rate of patients achieved a clinical response in the SRE group compared with that in the placebo group (73.0% vs 32.9%, P < 0.0001). Only minor adverse events were observed across the entire study population. Conclusions SRE was effective, safe, and clinically superior to placebo for the treatment of CP/CPPS. ChiCTR-IPR-16010196, December 21, 2016 retrospectively registered
... However, it is seemingly inconsistent with observed improvement following administration of therapeutic pollen extract preparations in randomized controlled trials of CP/CPPS patients. 20 Therefore, to address this discrepancy and evaluate whether pollen does in fact trigger UCPPS flares, we took advantage of data collected in our case-crossover study of flare triggers in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) one-year longitudinal study. ...
Article
Full-text available
Purpose: To determine whether pollen triggers urologic chronic pelvic pain syndrome (UCPPS) flares. Materials and methods: We assessed flare status every two weeks for one year as part of the Multidisciplinary Approach to the study of Chronic Pelvic Pain (MAPP) case-crossover study of flare triggers. Flare symptoms, flare start date, and exposures in the three days before a flare were queried for the first three flares and at three randomly selected non-flare times. These data were linked to daily pollen count by date and the first three digits of participants' zip codes. Pollen count in the 3 days before and day of a flare, as well as pollen rises past established thresholds, were compared to non-flare values by conditional logistic regression. Poisson regression was used to estimate flare rates in the three weeks following pollen rises past established thresholds in the full longitudinal study. Analyses were performed in all participants and separately in those who reported allergies or respiratory tract disorders. Results: Although no associations were observed for daily pollen count and flare onset, positive associations were observed for pollen count rises past medium or higher thresholds in participants with allergies or respiratory tract disorders in the case-crossover (odds ratio=1.31, 95% confidence interval [CI]: 1.04-1.66) and full longitudinal (relative rate=1.23, 95% CI: 1.03-1.46) samples. Conclusions: We found some evidence to suggest that rising pollen count may trigger UCPPS flares. If confirmed in future studies, these findings may help to inform flare pathophysiology, prevention, treatment, and control over the unpredictability of flares.
... Discussions Flower pollen extracts have provided evidence for efficacy and tolerability for the treatment of BPH and chronic prostatitis. Flower pollen extract is an effective anti-inflammatory nutraceutical product, thanks to inhibition of prostaglandin and leukotrienes synthesis as well as the inhibition of many cytokines as NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) [6]. Lowering of PSA levels it can be useful to discriminate patients with asymptomatic BPH from those who need further tests like mpMRI or prostate biopsy. ...
... Another pollen extract (DEPROX 500) has been shown to significantly improve total symptoms, pain and QoL compared to ibuprofen [371]. A SR and meta-analysis of pollen extract for the treatment of PPS showed significant improvement in overall QoL [372]. Quercetin, a polyphenolic bioflavonoid with documented antioxidant and anti-inflammatory properties, improved NIH-CPSI scores significantly in a small RCT [373]. ...
Article
Background No data are available regarding the impact of time between a previous transrectal prostate biopsy (PB) and holmium laser enucleation of the prostate (HoLEP) on perioperative outcomes. Objective To evaluate the impact of time from PB to HoLEP on perioperative outcomes. Design, setting, and participants A total of 172 consecutive patients treated with HoLEP within 12 mo of a single previous transrectal PB at two tertiary centers were included. Outcome measurements and statistical analysis Patients were stratified into two groups according to the median time from PB to HoLEP (namely, ≤6 and >6 mo). The primary outcome was intraoperative complications. Multivariate logistic regressions were used to identify the predictors of intraoperative complications. Linear regressions were used to test the association between the time from PB to HoLEP and intraoperative complications, enucleation efficiency, and enucleation time. Results and limitations In total, 93 (54%) and 79 (46%) patients had PB ≤ 6 and >6 mo before HoLEP, respectively. Patients in PB ≤ 6 mo group experienced higher rates of intraoperative complications than those in PB > 6 mo group (14% vs 2.6%, p = 0.04). At multivariable analysis, time between PB and HoLEP was an independent predictor of intraoperative complications (odds ratio: 0.74; 95% confidence interval: 0.6–0.9; p = 0.006). Finally, the risk of intraoperative complications reduced by 1.5%, efficiency of enucleation increased by 4.1%, and enucleation time reduced by 1.7 min for each month passed from PB to HoLEP (all p ≤ 0.006). Selection of patients with only one previous PB represents the main limitation. Conclusions The time from PB to HoLEP of ≤6 mo is associated with a higher risk of intraoperative complications, lower enucleation efficacy, and longer enucleation time. Patient summary Patients with a prostate biopsy (PB) ≤6 mo before holmium laser enucleation of the prostate (HoLEP) had significantly worse outcomes than those with a PB > 6 mo before HoLEP.
Article
Full-text available
Purpose To evaluate the functional outcomes as they relate to the preservation of urinary continence and sexual function after treatment with the temporarily implanted nitinol device (iTind; Medi-Tate Ltd, Israel); a novel minimally invasive treatment for lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). Methods Men with symptomatic BPH (IPSS ≥ 10, Qmax < 12 ml/s, and prostate volume (PV) < 120 ml) were invited to participate in this single-arm, prospective multicenter study (MT06). Patients were not washed out of BPH medications before the procedure. The iTind was implanted through a 22F rigid cystoscope under intravenous sedation and was removed 5–7 days later through a 22F Foley catheter under local anesthesia. Post-operative VAS and complications (Clavien Dindo-Grading System) were recorded. Preservation of urinary continence and erectile and ejaculatory function were assessed according to ISI, MSHQ-EjD and SHIM questionnaires. Post-operative IPSS, QoL, Qmax and PVR were also assessed at 1, 3, and 6 months post-operatively. Results This interim report includes data out to 6 months on the first 70 patients enrolled in the study. The median age was 62.31 years, and the mean prostate volume was 37.68 ml (15–80 ml). Baseline and follow-up data are reported in Table 1. No intraoperative complications were observed, the average post-operative VAS score was 3.24 ± 2.56. On average patients returned to daily life after 4.3 days following the retrieval procedure. Sexual function and urinary continence were preserved in all subjects according to the ISI, SHIM and MSHQ-EjD questionnaires and significant improvements (p < 0.0001) from baseline levels were recorded in IPSS, QoL and peak flow. Conclusion iTind is a well-tolerated, minimally invasive treatment for BPH-related LUTS which preserves sexual function and urinary continence, offers a rapid recovery and return to daily life, and a significant improvement of symptoms and urinary flow at 6-month follow-up.
Article
Full-text available
Background Previously reported results of a prospective, randomized placebo-controlled study showed that the pollen extract (Cernilton) significantly improved total symptoms, pain, and quality of life in patients with inflammatory prostatitis/chronic pelvic pain syndrome (CP/CPPS) without severe side effects. A phytotherapeutic agent, Eviprostat, is reportedly effective in a rat model of nonbacterial prostatitis. The aim of the present study was to compare the efficacy and safety of Eviprostat to that of the pollen extract in the management of CP/CPPS. Methods The patients with category III CP/CPPS were randomized to receive either oral capsules of Eviprostat (two capsules, q 8 h) or the pollen extract (two capsules, q 8 h) for 8 weeks. The primary endpoint of the study was symptomatic improvement in the NIH Chronic Prostatitis Symptom Index (NIH-CPSI). Participants were evaluated using the NIH-CPSI and the International Prostate Symptom Score (IPSS) at baseline and after 4 and 8 weeks. Results In the intention-to-treat analysis, 100 men were randomly allocated to Eviprostat (n = 50) or the pollen extract (n = 50). Response (defined as a decrease in the NIH-CPSI total score by at least 25 %) in the Eviprostat group and the pollen extract group was 88.2 and 78.1 %, respectively. There was no significant difference in the total, pain, urinary, and quality of life (QOL) scores of the NIH-CPSI between the two groups at 8 weeks. This was also the case with the total, voiding, and storage symptoms of the IPSS. There were no severe adverse events observed in any patients in this study. Conclusion Both the pollen extract and Eviprostat significantly reduced the symptoms of category III CP/CPPS without any adverse events. Eviprostat may have an identical effect on category III CP/CPPS compared the pollen extract. Trial registration The study was registered with the University Hospital Medical Information Network Clinical Trials Registry in Japan (UMIN000019618); registration date: 3 November 2015.
Article
Full-text available
Systematic reviews should build on a protocol that describes the rationale, hypothesis, and planned methods of the review; few reviews report whether a protocol exists. Detailed, well-described protocols can facilitate the understanding and appraisal of the review methods, as well as the detection of modifications to methods and selective reporting in completed reviews. We describe the development of a reporting guideline, the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015 (PRISMA-P 2015). PRISMA-P consists of a 17-item checklist intended to facilitate the preparation and reporting of a robust protocol for the systematic review. Funders and those commissioning reviews might consider mandating the use of the checklist to facilitate the submission of relevant protocol information in funding applications. Similarly, peer reviewers and editors can use the guidance to gauge the completeness and transparency of a systematic review protocol submitted for publication in a journal or other medium.
Article
Full-text available
The therapeutic efficacy for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is currently unsatisfactory. The aim of the present study was to assess the safety and efficacy of pollen extract in association with vitamins (DEPROX 500(®)) in males with CP/CPPS. All patients with a diagnosis of CP/CPPS attending the same urologic centre between March and October 2012 were enrolled in this randomised controlled phase III study. Participants were randomised to receive oral capsules of DEPROX 500(®) (two capsules every 24 h) or ibuprofen (600 mg, one tablet three times a day) for four weeks. The National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI), International Prostate Symptom Score and Quality of Well-Being (QoL) questionnaires were used. In the intention-to-treat analysis, 87 males (25 class IIIa and 62 class IIIb) with a mean age of 33.6±5.9 years were randomly allocated to the DEPROX 500(®) (n=41) or ibuprofen (n=46) treatment groups. At the follow-up examination (following one month of treatment), in the DEPROX 500(®) group, 31/41 patients (75.6%) reported an improvement in quality of life, defined as a reduction of the NIH-CPSI total score by ≥25%, compared with 19/46 (41.3%) in the control group (P=0.002). The greater improvement in the DEPROX 500(®) group compared with the ibuprofen group was statistically significant (treatment difference in the NIH-CPSI pain domain, -2.14±0.51, P<0.001; QoL scores, P=0.002). All patients were negative at the Meares-Stamey test evaluation. Adverse events were less frequent in the DEPROX 500(®) group than in the ibuprofen group. The DEPROX 500(®) treatment significantly improved total symptoms, pain and quality of life compared with ibuprofen in patients with CP/CPPS, without severe side-effects.
Article
We studied the effect of Cernitin pollen-extract (Cernilton®, CN-009), a preparation made from eight kinds of pollen such as timothy, rye, and maize etc., on the function of urinary bladder in conscious rats using the method that reported previously by Kontani et al. The surgical procedure was performed under ether anesthesia, and after the recovery, the rat was restricted in a Ballman cage during the experiment. The bladder contraction was induced by the constant infusion of physiological saline. The effect of CN-009 was evaluated by using the following parameters measured from the cystometrogram; number of micturition (NM, times/hr), micturition threshold pressure (MTP, cmH 2O) and peak pressure during bladder contraction (PP, cmH 2O). The single administration of CN-009 (630 and 1260mg/kg, i.d.) did not affect the three parameters mentioned above. On the other hand, administered CN-009 (630 or 1260mg/kg, p.o. for 6 or 13 days and i.d. on the very day of the experiment) for 7 or 14 successive days increased PP in the dose- and time-dependent manners, and the PP was increased significantly (p<0.05-0.01) on the group administered high dose for long period compared to that of control group. CN-009 did not affect NM and MTP much. These results suggested that CN-009 administered subacutely enhanced PP and promoted the function of urinary bladder.