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© 2016 Journal of Pharmacy & Pharmacognosy Research, 4 (5), 187-198
ISSN 0719-4250
http://jppres.com/jppres
Original Article | Artículo Original
_____________________________________
Clinical evaluation of patients with benign prostatic hyperplasia, treated
with the natural product Calprost®: a randomized, controlled study
[Evaluación clínica de pacientes con hiperplasia prostática benigna, tratados con el producto natural Calprost®:
estudio aleatorizado, controlado]
Magnelis Machado-Leiva1, Daise Jiménez-Rodríguez2, Tatiana Festary-Casanovas2, Deydree C. Silveira-Pacheco3, Emilio
S. Barroso-de la Cruz4, Mariela Suárez-Reyes1, Genma Salas-Cruz1, Haydee Wong-Arocha3, Roberto Fernández-Viera4,
Ángela D. Tuero-Iglesias5, René Delgado-Hernández2, Idrian García-García2*, for the Calprost Study Group
1Urology and Natural and Traditional Medicine Services, Clinical-Surgical Hospital “Dr. Luis Díaz Soto”, Havana, Cuba
2Clinical Trials Group, Research Direction, Center for Drug Research and Development, Ave. 26 and Puentes Grandes, No. 1605, Nuevo Vedado,Havana, Cuba
3Urology Service, Clinical-Surgical Hospital "Joaquín Albarrán", Havana, Cuba
4Urology Service, Clinical-Surgical Hospital “Iván Portuondo”, San Antonio de los Baños, Artemisa, Cuba
5Center for Genetic Engineering and Biotechnology, Havana, Cuba.
*E-mail: idrian.garcia@cidem.cu
Abstract
Resumen
Context: Benign Prostatic Hyperplasia (BPH) is a common disease that
course with Lower Urinary Tract Symptoms (LUTS), mainly in over 50
years-old men. Commonly indicated drugs such as alpha adrenergic-
blockers are life-treatment with some adverse reactions. Center for Drug
Research and Development produce a microencapsulated lipophilic
extract of pumpkin seed oil (Calprost®) with anti-androgenic, anti-
inflammatory, antioxidant, antiproliferative and diuretic properties.
Aims: To evaluate the effect and safety of Calprost® in patients with BPH
and LUTS.
Methods: A multicenter, randomized, controlled, open exploratory
clinical trial was conducted. Two experimental groups, study group
(Calprost®, 140 mg daily) (n=81), and control group (terazosin, 2 mg daily)
(n=50) were conformed. All the patients were treated during three
months. Efficacy was evaluated through International Prostate Symptoms
Score (IPSS), residual bladder volume and prostate volume.
Results: Most of the included patients (74.0%) were white skin color and
their mean age was 66 yrs. Fifteen patients, nine of them from terazosin
group, withdraw the trial voluntarily. A significant reduction in the
overall IPSS scale was obtained for both groups. Nevertheless, some
obstructive (intermittency, straining) and irritative (frequency, urgency)
urinary symptoms decreased more markedly in the Calprost® group being
milder. Median residual and prostatic volumes decreased significantly
(p=0.048 and p=0.002, respectively) only into the Calprost® group. Most of
the adverse events were recorded in the terazosin group (79.4%), where
postural hypotension prevailed.
Conclusions: The natural product Calprost® was probed as a successful
treatment of patients with BPH/LUTS, being also well-tolerated.
Contexto: La Hiperplasia Prostática Benigna (HPB) es una enfermedad
común en hombres mayores de 50 años de edad, que cursa con Síntomas
del Tracto Urinario Bajo (STUB). Los tratamientos de por vida con
medicamentos bloqueadores alfa-adrenérgicos producen algunas
reacciones adversas. El Centro de Investigación y Desarrollo de
Medicamentos produce un extracto lipofílico microencapsulado de aceite
de semillas de calabaza (Calprost®) con propiedades anti-androgénicas,
anti-inflamatorias, antioxidantes, antirproliferativas y diuréticas.
Objetivos: Evaluar el efecto y seguridad del Calprost® en pacientes con
BPH/STUB.
Métodos: Se realizó un estudio exploratorio, multicéntrico, aleatorizado,
controlado y abierto. Se conformaron dos grupos experimentales, estudio
(Calprost®, 140 mg diarios) (n=81), y control (terazosina, 2 mg diarios)
(n=50). Todos los pacientes fueron tratados durante tres meses. La
eficacia se evaluó mediante la sintomatología urinaria (escala IPSS),
volumen vesical residual y volumen prostático.
Resultados: La mayoría de los pacientes (74.0%) fueron blancos, con edad
promedio de 66 años. Quince pacientes, nueve de ellos del grupo
terazosina, abandonaron el estudio voluntariamente. Hubo disminución
significativa de la escala global de síntomas en ambos grupos, aunque
algunos de ellos se redujeron notablemente solo en el grupo Calprost®,
llegando a ser más ligeros. La mediana tanto del volumen residual
(p=0.048) como del prostático (p=0.002) disminuyó de manera
significativa solo en el grupo tratado con Calprost®. El porcentaje de
eventos adversos presentados fue mayor con la terazosina (79.4%),
prevaleciendo la hipotensión postural.
Conclusiones: El producto natural Calprost® fue efectivo en el tratamiento
de la HPB/STUB, siendo además bien tolerado.
Keywords: Benign prostatic hyperplasia; Calprost®; IPSS; lower urinary
tract symptoms, pumpkin seed oil, terazosin.
Palabras Clave: Aceite de semilla de calabaza; Calprost®; hiperplasia
prostática benigna; IPSS; síntomas del tracto urinario bajo; terazosina.
ARTICLE INFO
Received | Recibido: July 4, 2016.
Received in revised form | Recibido en forma corregida: September 1, 2016.
Accepted | Aceptado: September 8, 2016.
Available Online | Publicado en Línea: September 9, 2016.
Declaration of interests | Declaración de Intereses: Authors DJR, TFC, RDH and IGG are employees of the Center for Drug Research and
Development (CIDEM), Havana, Cuba, where Calprost® formulation is produced. The rest of the authors have no competing interests at all.
Funding | Financiación: The study was supported by the national project I13004 (Cuba).
Academic Editor | Editor Académico: Marisela Valdés.
Machado-Leiva et al.
BPH treatment with the natural product Calprost®
http://jppres.com/jppres
J Pharm Pharmacogn Res (2016) 4(5): 188
INTRODUCTION
Benign Prostatic Hyperplasia (BPH) is the be-
nign growth of the prostatic gland. BPH is one of
the adult man's more frequent pathologies. It is
characterized by the presence of obstructive and
irritative symptoms of the lower urinary tract that
can alter individual's quality of life and to limit
their daily activities. The histological prevalence
increases from 1/5 men with 50-60 yrs. to 4/5 men
with 80 yrs or more (Bushman, 2009; Roehrborn et al.,
2011; Roehrborn and McConnell, 2012).
Current pharmacological treatment includes al-
pha adrenergic-blockers (tamsulosin, doxazosin,
alfuzosin, terazosin) since the contractile properties
of the prostate are mediated by the activation of
alpha 1 adrenergic receptors. Their results are en-
couraging, although long-term benefits are ignored,
and they are not exempt of adverse effects as pos-
tural hypotension (Edwards, 2008). On the other hand,
5-alpha reductase inhibitors as finasteride are tar-
geted to decrease epithelial hyperplasia degree, re-
lated to the androgens level, but undesired effects
as decrease of the libido and impotence could oc-
cur. When these treatments are discontinued symp-
toms usually reappear (Helling, 2008). Finasteride was
effective reducing prostate size and its complica-
tions, although its impact on symptoms was modest
and relatively slow (Tarter and Vaughan, 2006).
Phytotherapy has been used thoroughly in the
treatment of BPH. Particularly extracts from herbal
medicines Pygeum africanum, Urtica dioica, Bixa
orellana, Curcubita pepo and Serenoa repens (saw
palmetto) report successful results in the relief of
the prostatic symptoms, and good tolerability
(Morán et al., 2013). In the medical practice urologists
and Natural and Traditional Medicine specialists
frequently indicate ingestion of pumpkin seeds for
this affection; most of the times lacking to consider
an exact dosage. A Cuban microencapsulated lipo-
philic extract of pumpkin seed oil (Calprost®) was
obtained in the Center for Drug Research and De-
velopment (CIDEM, in Spanish) (López-Hernández et
al., 2009) and its biological effects were well-proven
in experimentation animals (Bellma-Menéndez et al.,
2006; Tillán-Capó et al., 2009). The present investigation
aims to evaluate the effect and safety of Calprost® in
patients with HPB, using as control group patients
treated with terazosin.
MATERIAL AND METHODS
A multicenter, randomized, controlled, open-
label exploratory study was carried out at the Urol-
ogy Services of the Clinical-Surgical Hospitals “Dr.
Luis Díaz Soto”, Havana, Cuba and ”Iván
Portuondo”, Artemisa, Cuba. Another participant
institution was the “Joaquín Albarrán” Hospital,
Havana, Cuba, where the trial was conducted under
uncontrolled conditions since only patients treated
with Calprost® were included.
The clinical protocol was approved by the Ethics
Committees from each clinical site and by the Cu-
ban Regulatory Authority for this type of products,
Institute of Nutrition and Hygiene of Foods (INHA,
in Spanish), Havana, Cuba. The study complied
with the ethical standards included in the 1964 Hel-
sinki declaration and its later amendments. All pa-
tients prior to study enrollment provided their writ-
ten informed consent to participate.
Patients
Patients to be included in the trial must have
been Cuban citizens, between 50 and 80 years-old,
with clinical diagnosis of mild or moderate BPH.
The diagnosis comprised the presence of Lower
Urinary Tract Symptoms (LUTS), either obstructive
or irritative, using the International Prostate Symp-
toms Score (IPSS), physical examination including
rectal tact, and ultrasound. Exclusion criteria were:
history of allergy, idiosyncrasy or hypersensibility to
drugs, acute or uncompensated chronic diseases at
entry and history or clinical evidence of some of the
following pathologies: urethral stenosis, bladder
litiasis, prostate cancer, bladder cancer, bladder
diverticulis, neurogenic bladder, neurological dis-
ease, diabetes mellitus and medullar lesion. Pa-
tients could withdraw the trial voluntarily, due to
occurrence of severe adverse reactions, lack of
treatment adhesion (>30 doses), by appearance of
any exclusion criteria or if they received some dis-
ease-modifier drugs concomitantly with Calprost®.
Machado-Leiva et al.
BPH treatment with the natural product Calprost®
http://jppres.com/jppres
J Pharm Pharmacogn Res (2016) 4(5): 189
Study design and treatment
Patients where corresponded were distributed
according to a computer-generated random num-
ber list, stratified by center, to receive, orally, 140
mg of Calprost® (70.0 mg Cucurbita pepo L. cap-
sules, excipient, CIDEM, Havana, Cuba) (study
group) or daily 2 mg (one tablet) of terazosin
(Novatec Laboratories, Medsol Group, Havana, Cu-
ba) (control group). Calprost® dose was chosen
based on the whole pharmacological data (see Dis-
cussion section) from which the minimum effective
dose extrapolated to humans was calculated in a
range between 100-150 mg per 70 kg.
Both treatments were given ambulatorily during
three months. Patients included in the study group
should receive daily, one capsule of Calprost® at
8:00 am and the other at 8:00 pm. Those patients
included under uncontrolled conditions received
the tested medication with the same schedule.
Terazosin was taken at night before bedtime.
The study was open-label since Calprost® and
terazosin presentations were not similar. Other
treatments could be administered to mitigate ad-
verse events, after medical consent. None of them
could affect the results because interactions neither
direct effects on the tested variables.
Evaluation
The main efficacy outcome was the presence and
severity of urinary symptoms using the IPSS ques-
tionnaire (Cam et al., 2003). It is based on the answers
to seven questions concerning urinary symptoms;
obstructive (incomplete emptying, Intermittency,
weak stream, straining) and irritative (frequency,
urgency, nocturia). The doctor completed the ques-
tionnaire by each question with the patient answer
at each visit. Each question allowed the patient to
choose one out of six answers (¿how often?) indi-
cating increasing severity of the particular symp-
tom. Answers for the six first symptoms were: not
at all, less than 1 in 5 times, less than half the time,
about half the time, more than half the time and
almost always. Regarding nocturia, possible an-
swers were: none, 1 time, 2 times, 3 times, 4 times
and 5 times. The answers were assigned points from
0 to 5. Total score could therefore range from 0 to
35 as follows: mild (symptom score less than or
equal to 7), moderate (symptom score range 8-19)
and severe (symptom score range 20-35). See Fig. 1
for English version of the Spanish questionnaire
applied.
Secondary variables included residual bladder
volume, prostate volume and patients’ quality of
life. Residual urine volume (post-void residual
urine) was determined by means of bladder ultra-
sonography (Aloka ProSound Alpha 5, Tokyo, Ja-
pan) after voiding. Residual urine volume reflects
bladder and outlet activity during the emptying
phase of micturition. The volume of 50 mL consti-
tutes the lower threshold defining abnormal resid-
ual urine volume. Meanwhile, prostatic volume was
estimated by abdominal ultrasound (Aloka
ProSound Alpha 5, Tokyo, Japan). The common
procedure one-dimensional measurement was used
to calculate the prostatic volume. The prolate ellip-
soid formula, multiplying the largest
anterioposterior (Height), transverse (Width) and
cephalocaudal (Length) prostate diameters by 0.524
(H x W x L x /6) was used (Eri, 2002).
Patient’s perceived quality of life was classified
according to IPSS guideline as: delighted, pleased,
mostly satisfied, mixed, mostly dissatisfied, unhap-
py or terribly wrong (Fig. 1). All these evaluations
were done in both groups at entry and at the end of
treatment (month 3). Rectal tact was only done for
diagnosis purposes.
Additionally patients were classified as respond-
ers (therapeutic success) or non-responders (thera-
peutic failure). Responders were who achieved a
decrease in prostate symptoms score and decreased
prostate volume and residual urine volume at the
end of the study. Patients who experienced an in-
crease in prostate symptoms score, prostate volume
and residual urine volume were non-responders.
Those patients that voluntarily discontinued treat-
ment, had disease worsening or severe adverse
events were also considered as failures.
Safety and tolerability were monitored during
the study by means of adverse events control.
Events were severe if produce patient's death,
threatens patient's life, requires or prolongs hospi-
talization or produce a significant or persistent dis-
ability. The medical terminology for adverse events
and their intensity classification (in 5 grades) was
applied according to the Common Terminology Cri-
Machado-Leiva et al.
BPH treatment with the natural product Calprost®
http://jppres.com/jppres
J Pharm Pharmacogn Res (2016) 4(5): 190
teria for Adverse Events (CTCAE, 2010). The causal
relationship was classified as very probable (defini-
tive), probable, possible or remote (doubtful)
(Naranjo et al., 1998).
International Prostate Symptom Score (I-PSS)
Patient Name: ______________________ Date of birth: ____________ Date completed _________
In the past month:
Not at
All
Less
than 1 in
5 Times
Less than
Half the
Time
About
Half the
Time
More than
Half the
Time
Almost
Always
Your
score
1. Incomplete Emptying
How often have you had
the sensation of not emp-
tying your bladders?
0
1
2
3
4
5
2. Frequency
How often have you had to
urinary less than every two
hours?
0
1
2
3
4
5
3. Intermittency
How often have you found
you stopped and started
again several times when
you urinated?
0
1
2
3
4
5
4. Urgency
How often have you found
it difficult to postpone
urination?
0
1
2
3
4
5
5. Weak Stream
How often have you had a
weak urinary stream?
0
1
2
3
4
5
6. Straining
How often have you had to
strain to start urination?
0
1
2
3
4
5
None
1 Time
2 Times
3 Times
4 Times
5 Times
7. Nocturia
How many times did you
typically get up at night to
urinate?
0
1
2
3
4
5
Total I-PSS Score
Score: 1-7: Mild 8-19: Moderate 20-35: Severe
Quality of Life Due to
Urinary Symptoms
Delighted
Pleased
Mostly
Satisfied
Mixed
Mostly
Dissatisfied
Unhappy
Terrible
If you were to spend the
rest of your life with your
urinary condition just the
way it is now, how would
you feel about that?
0
1
2
3
4
5
6
Figure 1. International Prostate Symptoms Score (IPSS) questionnaire, based on American Urological Association (AUA)
Symptom Index.
Machado-Leiva et al.
BPH treatment with the natural product Calprost®
http://jppres.com/jppres
J Pharm Pharmacogn Res (2016) 4(5): 191
Additionally, blood samples were taken for rou-
tine hematological and biochemical determinations
before and after treatment. Hematological counts
(hemoglobin, hematocrit, leukocytes) and blood
chemistry (glycemia, cholesterol, triglycerides,
creatinine, urea, liver enzymes, serum albumin, and
total protein) were done according to usual clinical
laboratory procedures, using advanced automated
analyzers (Elimat, Hitachi, Tokyo, Japan; Inlab 158,
CPM, Milan, Italy). Imagenological and laboratory
evaluations were done blindly regarding the pa-
tients’ group allocation.
Statistical analysis
Sample size was calculated using the equation n
= [(Zα + Zβ)σ/δ]2 assuming 0.05 and 0.85 for type I
and II errors. The “2N” Program for Design of Clini-
cal Trials was used (Hauer-Jensen, 1990). A 15% excess
was considered to compensate withdrawals. This
yielded a range of 130-150 patients for this trial.
Data were double entered and validated and then
imported into SPSS for Windows (version 15.0, IBM
Analytics 2006, Armonk, North Castle, NY, USA) and
Epidat (version 3.1, Directorate General of Public
Health (Xunta de Galicia) 2006, Santiago de
Compostela, Spain) for further analysis. Continuous
variables were expressed as mean ± standard deviation
(SD) or median ± interquartile range (QR) and mini-
mum and maximum values (range). With these varia-
bles a normality analysis (Kolmogorov-Smirnov’s test
or Shapiro Wilk’s test) and homogeneity of variance
(Levene’s test) were carried out. Groups were compared
at the beginning and at the end of treatment using the
Student's t-test (parametrical) or the Mann-Whitney’s U
test (non-parametrical), depending on the normality as-
sumption. These variables were also analyzed using
paired analysis (Student’s t test or Wilcoxon’s test). The
chi-squared test was used to analyze the dependence or
independence between demographic and baseline char-
acteristics and evaluation parameters. Significance level
chosen was 0.05. Stratified analyses according to inves-
tigation site were also done. Categorical variables were
given as frequencies and percentages.
RESULTS
One-hundred thirty-one patients were enrolled
from November 2012 to October 2014; then follow-
up continued up to January 2015. Eighty-one pa-
tients received Calprost® and 50 terazosin. Fifty pa-
tients (25 per treatment group) were included both
"Luis Díaz Soto" and "Iván Portuondo" hospitals. In
the "Joaquín Albarrán" Hospital 31 patients received
Calprost® formulation. A total of 15 patients (11.5%)
withdrew voluntarily the trial; nine of them were
receiving treatment with terazosin. These with-
drawals occurred mostly during the second month
of treatment.
Characteristics at entry of the included patients
are shown in Table 1. Groups were homogeneous
regarding each demographic characteristic. Mean
age was around 65 years for both groups and white
skin color prevailed (70%). The prostate size in the
Calprost® group was mostly grade I, being predom-
inantly grade II in terazosin group.
Global IPSS median values at the end of the
study were significantly reduced in both treatment
groups. However, differences between groups were
no detected in both evaluation times (Table 2). Ac-
cording to IPSS data, before treatment most of the
patients in both groups showed moderate symp-
toms, which changed to mild at the end, which was
74% in Calprost® group and 54% in the terazosin
group, as observed in Fig. 2. Only one patient, this
case from the control group, remained with severe
symptoms at the end of the study.
In order to obtain a better clinical comparison
between groups, IPSS initial and final mean values
for each urinary symptom were plotting (Fig. 3). In
the case of obstructive symptoms, although all
scores decreased, final values reached around or
below value 1 (less than 1 in 5 times) only in the
Calprost® group. Similar behavior was obtained
with the irritative symptoms (except nocturia) in
the same group. In contrast, in the control group,
the reduction in the intermittency was almost neg-
ligible and a slight increase in the urgency was ob-
served.
The residual bladder volume was significantly
lower at the end of the study in those patients
treated with Calprost® in comparison with
terazosin-treated patients. The magnitude of this
reduction (10 mL) was also significant into the
study group. However, in the terazosin group a not
significant increment of 3 mL occurred. Meanwhile,
both initial and final median prostate volumes were
significantly lower in the Calprost® group, where
Machado-Leiva et al.
BPH treatment with the natural product Calprost®
http://jppres.com/jppres
J Pharm Pharmacogn Res (2016) 4(5): 192
initial-final reduction was significant. For this vari-
able, once more an increment was evidenced in the
control group, but this change was not significant
(Table 2).
Table 1. Demographic and baseline characteristics of the patients involved in the clinical trial with Calprost® (140 mg/d) and
terazosin (2 mg/d) during three months.
Characteristic
Calprost® group
n=81
Terazosin group
n=50
Skin color
White
63 (77.8%)
34 (68.0%)
Non-white
18 (22.2%)
16 (32.0%)
Age (years)
67 ± 8 (50 – 80)
66 ± 8 (50 – 80)
Weight (kg)
72.6 ± 10.0 (53.0 – 94.0)
74.1 ± 11.2 (52.5 – 93.0)
Height (cm)
168 ± 7 (150 – 190)
166 ± 6 (155 – 178)
BMI (kg/m2)
25.6 ± 3.4 (18.3 – 32.5)
26.8 ± 3.7 (20.3 – 34.4)
Prostate size
Grade I
45 (55.6%)
13 (26.0%)
Grade II
32 (39.5%)
26 (52.0%)
Grade IIII
4 (4.9%)
11 (22.0%)
Data are reported as number of patients (%) or mean standard deviation (range).
Prostate size was determined by rectal tact examination; <5mm: Grade I; >5mm to 10mm: Grade II; >10mm: Grade III.
BMI: Body Mass Index
Table 2. Overall symptomatology and imagenological results before and after treatment with Calprost® (140 mg/d) and terazosin
(2 mg/d) during three months.
Variable
Calprost® group
Terazosin group
p
(Mann-Whitney’s U test)
IPSS
Initial
11 12 (2 – 33)
14 11 (2 – 31)
0.056
Final
4 5 (0 – 16)
4 6 (0 – 22)
0.828
p (Wilcoxon’s test)
0.0001
0.0001
–
Residual urine vol-
ume (mL)
Initial
55 72 (0 – 400)
59 45 (4 – 227)
0.675
Final
45 53 (0 – 240)
62 50 (0 – 275)
0.029
p (Wilcoxon’s test)
0.048
0.163
–
Prostate volume
(cm3)
Initial
38 27 (8 – 143)
57 40 (20 – 142)
0.0001
Final
36 26 (3 – 206)
61 41 (14 – 142)
0.0001
p (Wilcoxon’s test)
0.002
0.438
–
Data are reported as median ± interquartile range (range).
IPSS: International Prostate Symptoms Score
Machado-Leiva et al.
BPH treatment with the natural product Calprost®
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J Pharm Pharmacogn Res (2016) 4(5): 193
Figure 2. Severity of lower urinary tract symptoms during three months of treatment with Calprost® (140 mg/d) or terazosin (2
mg/d).
Data correspond to the percentage distribution of patients with BPH according total IPSS before (gray bars, n=131) and after treatment (black bars,
n=116) in each group. Withdrawals were not included in post-treatment data.
Figure 3. Specific urinary symptoms before and after treatment with Calprost® (140 mg/d) and terazosin (2 mg/d) during three
months.
Legend: Each point corresponds to the median score value for each symptom, using IPSS scale, in each group of treated patients. Deviations are not
shown for the sake of simplicity of the illustration. IPSS: International Prostate Symptoms Score.
All variations initial vs. final were significant (p0.05, Wilcoxon’s test) except for Intermittency, frequency and urgency in the terazosin group.
Machado-Leiva et al.
BPH treatment with the natural product Calprost®
http://jppres.com/jppres
J Pharm Pharmacogn Res (2016) 4(5): 194
Quality of life improved in both groups (Table
3). After treatment, approximately half of the pa-
tients included in the study group felt as “pleased”.
At the same time most of the patients in control
group were “mostly satisfied”. The five patients who
felt terribly wrong at entry improved after Calprost®
treatment, one of them to “pleased” status. No in-
fluence of prostate size or other baseline character-
istic on outcome variables was detected (data not
shown).
The percentage of patients with overall satisfac-
tory response was markedly superior in those pa-
tients treated with Calprost® (69% vs. 31%). This
evaluation was done under the intention-to-treat
principle, where all withdrawals are considered as
failures (Table 4). The largest number of responders
treated with Calprost® (22 patients) was obtained in
the "Iván Portuondo" Hospital.
Fourteen adverse events were presented during
the treatment (Table 5). At least one event occurred
in 6% of the patients in the Calprost® group and
24% in the terazosin group. Postural hypotension
was the most relevant event, only recorded in the
control group. Other constitutional symptoms
(headache, blurry vision, dizziness) prevailed in the
same group. On the other hand, soft stools oc-
curred only in three patients treated with Calprost®.
Table 3. Quality of life of the patients involved in the clinical trial with Calprost® (140 mg/d) and terazosin (2 mg/d) during three
months.
Category
Calprost® group
n=81
Terazosin group
n=50
Before treatment
Delighted
3 (3.7%)
--
Pleased
4 (4.9%)
--
Mostly satisfied
23 (28.4%)
12 (24.0%)
Mixed
22 (27.2%)
16 (32.0%)
Mostly dissatisfied
23 (28.4%)
22 (44.0%)
Unhappy
1 (1.2%)
--
Terribly wrong
5 (6.2%)
--
After treatment
Delighted
6 (7.4%)
3 (6.0%)
Pleased
39 (48.1%)
19 (38.0%)
Mostly satisfied
24 (29.6%)
28 (56.0%)
Mixed
7 (6.4%)
--
Mostly dissatisfied
4 (4.9%)
--
Unhappy
1 (1.2%)
--
Terribly wrong
--
--
Data are reported as number of patients (%).
Machado-Leiva et al.
BPH treatment with the natural product Calprost®
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J Pharm Pharmacogn Res (2016) 4(5): 195
Table 4. Overall response in patients involved in the clinical trial with Calprost® (140 mg/d) and
terazosin (2 mg/d) during three months.
Response
Calprost® group
n=81
Terazosin group
n=50
Successful
56 (69.1%)
10 (20.0%)
Failures
25 (30.9%)
40 (80.0%)
Data are reported as number of patients (%).
Table 5. Adverse events during treatment with Calprost® (140 mg/d) and terazosin (2 mg/d) during three months.
Adverse event
Calprost® group
n=81
Terazosin group
n=50
Any adverse event
5 (6.2%)
12 (24.0%)
Postural hypotension
–
7 (14.0%)
Headache
1 (1.2%)
3 (6.0%)
Asthenia
1 (1.2%)
2 (4.0%)
Sickness
1 (1.2%)
2 (4.0%)
Blurry vision
–
3 (6.0%)
Soft stools
3 (3.7%)
–
Dizziness
–
3 (6.0%)
Dry mouth
–
2 (4.0%)
Abdominal pain
–
1 (2.0%)
Anorexia
–
1 (2.0%)
Arterial hypotension
–
1 (2.0%)
Fatigue
–
1 (2.0%)
Insomnia
–
1 (2.0%)
Itching scalp
1 (1.2%)
–
Data are reported as number of patients (%).
Most of the events were classified as mild in
both groups, percentage slightly higher in the
Calprost® group (71.4% vs. 59.3%). None event was
classified as severe. Regarding intensity, four grade
3 adverse events, two of them postural hypotension,
were reported in patients treated with terazosin,
being well controlled with or without pharmacolog-
ical intervention (e.g. fludrocortisone). Headache
events were resolved with dipyrone treatment. Five
events in the control group were definitively caused
by the treatment whereas probable or possible
events prevailed in the study group. Urinary symp-
toms, closely related to the disease, were not ac-
counted as adverse reactions. Significant differences
or variations in clinical laboratory tests were not
detected and mean values kept within normal rang-
es.
DISCUSSION
The efficacy of the natural product Calprost® in
patients with HPB could be considered at least at
the same level of a well-established therapy as
terazosin. In this study, urinary symptoms de-
creased with both treatments according with global
Machado-Leiva et al.
BPH treatment with the natural product Calprost®
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J Pharm Pharmacogn Res (2016) 4(5): 196
IPSS scale but some obstructive and irritative symp-
toms were reduced more notably in the Calprost®
group. These observations were confirmed by
imagenological studies, since patients treated with
this natural product reduced significantly residual
bladder volume (below 50 mL) in comparison with
those treated with terazosin. Additionally, reduc-
tion in prostate volume was only evidenced in the
study group.
The above-commented results together with the
adherence to treatment influenced the clear differ-
ences in the overall comparative assessment of re-
sponse to treatment, where the percentage of re-
sponders was clearly superior in the Calprost®
group. This could be explained that terazosin only
acts reducing smooth muscle tone and reducing
hypertonia or dynamic obstruction of the urinary
tract produced by the prostate gland. In contrast,
Calprost® action involves several mechanism of ac-
tion that could potentiate their efficacy (Pérez-Guerra
et al., 2011).
Cucurbita pepo L. seed oil has a demonstrated
biological activity as 5-alpha reductase inhibitor
and antiandrogenic. Additionally, anti-
inflammatory, antioxidant, antiproliferative and
diuretic activities have been observed with this
product (Calabaza, 2014; Gossell-Williams et al., 2006). The-
se effects could be produced by the action of the
main components of pumpkin seed, polyunsaturat-
ed fatty acids, mostly linoleic, oleic, palmitic and
stearic acids (Menéndez-Castillo et al., 2006). The poten-
tial alpha adrenergic antagonist effect of microen-
capsulated seed oil of Cucurbita pepo was proven in
animal models. In this study the urinary output
flow in rats was improved, given by the relaxation
of smooth muscle and the reduction of the symp-
tomatology caused by urinary retention (Tillán-Capó
et al., 2009). A dose higher than 200 mg/kg of the ex-
tract inhibited testosterone-induced prostatic
growth in an experimental murine model of BPH
(Bellma-Menéndez et al., 2006). Experimental pharma-
cology studies conducted in different biomodels of
inflammation demonstrated anti-inflammatory ef-
fect of the extract inhibiting induction of cyclooxy-
genase. Different in vitro tests performed in mouse
peritoneal macrophages justified from the molecu-
lar point of view this anti-inflammatory effect
(Núñez-Figueredo, unpublished observations).
This extract did not show acute toxicity after oral
administration of 2000 mg/kg in rats. The admin-
istration of 1000 mg/kg/day for 90 days did not
cause toxic symptoms and mortality in the treated
animals. Only slight variations in hemoglobin, leu-
kocytes, glucose and transaminases that not exceed
normal values were reported after treatment. No
histopathological changes in any of the organs test-
ed (liver, kidneys, adrenals, testes, epididymides,
ovaries, thymus, spleen, brain, heart) were ob-
served. The micronucleus induction test in mouse
bone marrow showed that the extract, administered
orally at different dose levels is not cytotoxic nor
genotoxic (Piloto J, unpublished observations).
In the clinics, the administration of 90 mg of a
mixture containing delta7 sterols isolated from
Cucurbita pepo to patients suffering BPH, four and
three days before prostatectomy, decreased signifi-
cantly dihydrotestosterone levels in prostatic tissue
as well as serum acid phosphatase (Colectivo de
Autores, 2009).
Our results are consistent with findings in a
double-blind trial where Curcurbita pepo L. was
better than placebo after three months of treat-
ment, since symptoms improved significantly; par-
ticularly nocturia, without the presence of adverse
reactions (Carbin et al., 1990). In other double-blind,
placebo-controlled study, significant effects pre-
venting and reducing nocturia and other urinary
symptoms were achieved (Nishimura et al., 2014). This
natural product seems to be especially effective in
the early stages of the disease (Pagano et al., 2014).
Regarding the use of other natural products, no
differences in IPSS scale improvement were ob-
tained between Serenoa repens 320 mg/day and
tamsulosin 0.4 mg/day in 811 patients with moder-
ate to severe BPH, followed during 12 months
(Debruyne et al., 2002). In contrast, saw palmetto
treatment (160 mg twice a day) showed no signifi-
cant differences regarding placebo in the symptoms
score, changes in prostate size, residual urine vol-
ume, quality of life and development of adverse re-
actions (Bent et al., 2006). The concomitant use of
Cucurbita pepo and saw palmetto (each 320
mg/day) by other authors (Hong et al., 2009) produced
a serum prostate specific antigen reduction after
three months of treatment, but no changes were
Machado-Leiva et al.
BPH treatment with the natural product Calprost®
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J Pharm Pharmacogn Res (2016) 4(5): 197
observed in prostate volume and quality of life
score was improved only after six months.
Patients treated with Calprost® had fewer ad-
verse events and consequently less voluntary aban-
donments than terazosin group. Several authors
report a high incidence of orthostatic hypotension,
dizziness, malaise, low blood pressure, weakness,
headache, nausea, sexual affectations, among oth-
ers, in patients treated with terazosin (Roehrborn et
al., 1996; Millán-Rodríguez, 2005). As a result, many pa-
tients are not satisfied with this medication and
they not conclude the treatment period. In the cur-
rent study, more intense events were very probably
caused by terazosin treatment. In the literature,
adverse reactions to natural products derived from
pumpkin seed oil are nausea, insomnia, dizziness
and abdominal pain (Calabaza, 2014). Some of them
were no registered in the Calprost® group.
Currently, there are several drugs used in the
treatment of BPH/LUTS, which differ in efficacy
and safety. However, the search for new, increasing-
ly effective and safe agents remains in force until
the present; hence a boom in the use of
phytotherapeutic alternatives to treat BPH is per-
ceived in recent years. The combination of these
drugs with established treatments could be a feasi-
ble strategy to reduce urinary symptoms and im-
prove quality of life of the affected patients.
CONCLUSIONS
The results obtained may justify the rationality
to use Calprost®, an effective and safe natural prod-
uct for the treatment of BPH patients, non-
responder or intolerant to conventional treatments.
Further, more extensive, controlled clinical trials
are encouraged to confirm this assessment.
APPENDIX
The other members of the Calprost Study Group are: Pável
E García-Valido, Joaquina Gómez-Peire, Yasmel Tarafa-Rosales,
Lázaro Capote-Pereira, Midalis Gracial-Serrano, Teresa Pujols
Limonta (Hospital “Dr. Luis Díaz Soto”), Alberto L Elejalde-
Hernández, Rosaura Ruiz-Fernández (Hospital "Joaquín
Albarrán"), Marina Álvarez (Hospital “Iván Portuondo”), Beat-
riz Elizagaray (Center for Drug Research and Development).
CONFLICT OF INTEREST
Authors DJR, TFC, RDH and IGG are employees of the Cen-
ter for Drug Research and Development (CIDEM), Havana,
Cuba, where Calprost® formulation is produced. The rest of the
authors have no competing interests at all. The Ministry of
Public Health of Cuba supported the clinical trial (hospital
facilities and general medical care of the patients).
ACKNOWLEDGEMENT
The authors wish to thank Nereyda Peñalver, Darlene
Guédez, Damaris Herrera and Luz María Abreu for their assis-
tance in the clinical work. The study was supported by the na-
tional project I13004: Development of a formulation from a
lipophilic extract of Cucurbita pepo seeds for the treatment of
benign prostatic hyperplasia. The authors received Calprost®
formulation free from CIDEM, Havana, Cuba.
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_________________________________________________________________________________________________________________
Author contributions:
Contribution
Machado
-Leiva M
Jiménez-
Rodríguez D
Festary-
Casanovas T
Silveira-
Pacheco DC
Barroso-de
la Cruz ES
Suárez-
Reyes M
Salas-
Cruz G
Wong-
Arocha H
Fernández-
Viera R
Tuero-
Iglesias AD
Delgado-
Hernández R
García-
García I
Calprost
Study Group
Concepts or Ideas
X
X
X
X
Design
X
X
Definition of
intellectual content
X
X
X
X
X
X
X
Literature search
X
X
X
X
Clinical studies
X
X
X
X
X
X
X
X
X
X
X
X
Data acquisition
X
X
X
X
X
X
X
X
X
X
Data analysis
X
X
X
X
X
Statistical analysis
X
Manuscript
preparation
X
X
Manuscript editing
X
X
Manuscript review
X
X
X
Citation Format: Machado-Leiva M, Jiménez-Rodríguez D, Festary-Casanovas T, Silveira-Pacheco DC, Barroso-de la Cruz ES, Suárez-Reyes M, Salas-Cruz G, Wong-Arocha H,
Fernández-Viera R, Tuero-Iglesias ÁD, Delgado-Hernández R, García-García Idrian, for the Calprost Study Group (2016) Clinical evaluation of patients with benign prostatic hyper-
plasia, treated with the natural product Calprost®: a randomized, controlled study.J Pharm Pharmacogn Res 4(5): 187-198.
