Evaluating the efficacy and safety of Himplasia (PC-27) in the... management of benign hyperplasia

[Indian Journal of Clinical Practice (2004): (14), 11, 31-36]
Evaluating the efficacy and safety of Himplasia (PC-27) in the medical
management of benign hyperplasia
Ketan Shukla, M.S., M.Ch (Urology), Consultant Urologist & Transplant Surgeon
Sterling Hospital, Behind Drive-in Cinema, Ahmedabad, India,
and
Kolhapure, S.A.*, MD, Senior Medical Advisor,
R&D Center, The Himalaya Drug Company, Bangalore, India.
[*Corresponding author]
INTRODUCTION
Benign Prostatic Hyperplasia (BPH) also referred to as benign prostatic hypertrophy, is a
common disease in aging males. According to WHO, more than 50% males in the 50 plus age
groups have BPH and the incidence might be as high as 90% at 85 years.
BPH is characterized by enlargement of prostatic nodules due to a proliferative process
involving both the stromal and epithelial elements of the prostate1,2. As the prostate enlarges,
the surrounding tissue offers resistance, causing the prostate to press against the urethra. Over
a period of time, the urinary bladder wall becomes thicker, sensitive irritation and the bladder
begins to contract even with a small quantity of urine, causing more frequent urination. The
other clinical manifestations of BPH include obstructive and irritative urinary tract symptoms
and infection, urinary retention and hematuria3.
The etiology of BPH is not well understood and it is known that BPH doesn't occur in men
whose testes were removed before puberty. According to one hypothesis with advancing age,
the levels of active testosterone in the blood decrease, leaving higher levels of estrogen; and
experimental studies have suggested that BPH may occur because of higher levels of estrogen
within the prostate, leading to the cellular hyperplasia. Another hypothesis focuses on
dihydrotestosterone (DHT), a potent derivative of testosterone in the prostate, which may
promote cellular hyperplasia. Malignant transformation has been found in 9.51% of patients
with BPH and often these changes are predicted by the presence of a rise in marker the levels
of prostate specific antigen (PSA) and acid phosphatase4.
The goal of BPH treatment is to reduce excessive cell growth by inhibiting conversion of
testosterone into DHT and preventing attachment of estrogen to its receptors in prostate
tissue. Depending on the severity of symptoms, “watchful waiting”, drug therapy and surgery
are the treatment options for BPH5.
Recent clinical trials have suggested that 5α-reductase enzyme inhibitors and long acting
α-adrenoreceptor antagonistic drugs are effective in the treatment of BPH. 5α-reductase
inhibitors prevent the conversion of testosterone to DHT; while α-blockers relax smooth
muscle tissue in the bladder neck and prostate, which increases urinary flow and reduces
bladder outlet obstruction. But, these drugs have adverse effects like headache, dizziness,
hypotension, fatigue, reduced libido, impotence, breast tenderness and breast enlargement,
and reduced sperm count4,6. Due to these limitations, phytotherapy has been extensively
researched and some phytochemicals have been shown beneficial in the management of
BPH7-9.
This study was planned to evaluate Himplasia (PC-27), a polyherbal formulation, in BPH.
Each tablet of Himplasia (PC-27) contains powders of Gokshura (Tribulus terrestris),
Putikaranja (Caesalpinia bonducella), Puga (Areca catechu), Shatavari (Asparagus
racemosus), Varuna (Crataeva nurvala) and Akika pishti.
MATERIALS AND METODS
Study design
The study was an open, non-comparative clinical trial, approved by the Institutional Ethics
Committee, conducted between April 2002 and July 2003.
Inclusion criteria
Fifty patients suffering from BPH were included in the study, and categorized by the
American Urological Association (AUA) symptom score index as mild (0-7 points),
moderate (8-19 points) and severe (20-35 points)10.
Exclusion criteria
Patients with diabetes mellitus, prostate and bladder carcinoma, prostatitis, neurogenic
bladder, stricture urethra, vesical calculus, and those on drugs likely to affect bladder
function, were excluded from the study. Patients with severe cardiovascular, kidney or liver
disorder an indicated for surgery with refractory retention and recurrent or persistent gross
hematuria were also excluded from the study.
Study procedures
At the first visit, a detailed medical history, with special emphasis on urinary symptoms
(urgency, frequency, nocturia, hesitancy, straining, intermittency, terminal dribbling and
sensation of incomplete voiding) was obtained from all patients. In all patients, a thorough
systemic examination was done, followed by a digital rectal examination for determining
prostate size, presence of nodule, asymmetry and tenderness. Routine biochemical blood and
specific tests (LFTs, RFTs, serum PSA) were done for all patients. All patients were
investigated by uroflowmetry, and, voided volume, voiding and flow times, time to maximum
flow, maximum flow rate (MFR) and average flow rate (AFR) were recorded. The prostate
size was determined by abdominal ultrasound and/or transrectal ultrasonography. All patients
were advised to consume a capsule of Himplasia (PC-27), once daily, for six months.
Follow-up and assessment
The patients were followed up for 6 months and AUA symptom score evaluation was
recorded after completion of each month. A complete clinical, biochemical, ultrasonography
and uroflowmetry examination was carried out at the end of the sixth month.
Primary and secondary outcome measures
The predefined primary outcome measure for efficacy was a decrease in AUA score at the
end of 6 months. Secondary outcome measures were short-term and long-term safety
assessed by incidence of adverse events, patient compliance to therapy and improvement in
hematological and biochemical parameters.
Adverse events
All adverse events reported or observed by patients were recorded with information about
severity, date of onset, duration and action taken regarding the study drug. Relation of
adverse events to study medication was predefined as “Unrelated” (a reaction that does not
follow a reasonable temporal sequence from the administration of the drug), “Possible”
(follows a known response pattern to the suspected drug, but could have been produced by
the patient’s clinical state or other modes of therapy administered to the patient), and
“Probable” (follows a known response pattern to the suspected drug that could not be
reasonably explained by the known characteristics of the patient’s clinical state).
Patients were allowed to voluntarily withdraw from the study, if they had experienced serious
discomfort during the study or sustained serious clinical events requiring specific treatment.
For patients withdrawing from the study, efforts were made to ascertain the reason for
dropout. Non-compliance (defined as failure to take less than 80% of the medication) was not
regarded as treatment failure, and reasons for non-compliance were noted.
Statistical analysis
Statistical analysis was done according to intention-to-treat principles. Changes in various
parameters from baseline values and values after the 6th month were evaluated by a paired ‘t’
test. The minimum level of significance was fixed at 95% confidence limit and a 2-sided p
value of <0.05 was considered significant.
RESULTS
In the 50 patients, 3 opted for
surgery and 2 developed acute
retention of urine and were
excluded from the study. The mean
age of the remaining patients was
63.77 years (range 50 - 89) (Figure
1).
Figure 1: Age distribution of patients
Almost all patients began to show
symptomatic relief by the second
month of treatment with Himplasia
(PC-27) and further improvement
in all parameters was evident by the end of 6 months along with a noticeable alleviation in
symptoms. The average AUA symptom score reduced significantly from baseline 22.15
(range: 10-32) to 12.69 (range: 0-35) (p<0.0001) at the end of 6 months, and the difference
between the means was statistically significant (t=7.619, p<0.05, the mean of
differences=10.92, and 95% confidence interval: 8.006-13.83) (Figure 2a).
The MFR showed an improvement from the baseline of 9.67 (range: 2-20) to 12.69 (range :
0-35) at the end of study. There was significant reduction in the prostate size from 38.24
(range: 16-80) to 35.304 (range: 16-80) (t=2.893, p=0.0067) and the difference in the means
statistically significant (mean of differences=1.958, 95% confidence interval: 0.5801-3.336)
(Figure 2b).
There was significant reduction in postvoid residual urine volume from 83.77 ml (range: 0300) to 58.67 ml (range: 0-350) (p=0.0031, t=3.262) and the difference in means was
statistically significant (mean of differences=24.30, 95% confidence interval=8.980-39.61)
(Figure 2c).
The peak flow values (mean, standard deviation, standard error of means, lower, and upper
95% confidence interval) for both groups at baseline and at the end of study were 10.41 and
14.12, 4.349 and 6.414, 0.7459 and 1.100, 8.894 and 11.88 and 11.93 and 16.36) respectively
and the difference in the means was statistically significant (p=0.0036, t=3.138) (Figure 2d).
The average flow rate (mean, standard deviation, standard error of means, lower, and upper
95% confidence interval), for both groups, at baseline and at the end of study were 5.485 &
7.121, 2.502 & 3.189, 0.4355 & 0.5552, 4.598 & 5.990 and 6.372 & 8.252) respectively and
the difference in the means was statistically significant (p=0.0024, t=3.300) (Figure 2e).
Figure 2: Uroflowmetry parameters of all parameters, at baseline and at the end of 6 months
There was no statistically significant difference in the values of the voided volume
(p=0.3027, t=1.070), for both groups at baseline and at the end of study. The change in the
serum PSA values for both groups at baseline and at the end of study was also nonsignificant
(p=0.2875, NS, t=1.081).
There were no clinically significant drug related adverse events reported or observed during
the entire study period.
DISCUSSION
BPH is a common condition in older men, leading to morbidity primarily through lower
urinary tract symptoms and obstructive urinary symptoms are common, occurring in the
majority of males in the 50+ age groups, 20-30% of who undergo prostatectomy11. The
treatment of BPH has changed substantially in recent years, with an increased emphasis on
non-surgical approaches. Improvement in urinary symptoms and the quality of life are
important issues for decision making in treating BPH patients.
Uroflowmetry measures the pressure generated in the bladder during voiding. Patients with
stress or urge incontinence usually have a normal or increased urinary flow rate and a
reduced flow rate may indicate BPH. The post-void residual urine (PVR) test measures the
amount of urine that remains in the bladder after urination and a PVR less than 50ml
generally indicates adequate bladder emptying; while measurements of 100 - 200ml or more
often indicate blockage.
Advances in medical therapy for the management of BPH have lead to development of a
formulation that overcomes the symptoms of BPH12. Currently used drugs such as
5α-reductase enzyme inhibitors cause a decrease in libido and sexual potency13, while
α-adrenoreceptor antagonistic drugs can lead to various untoward ailments such as vertigo,
fatigue, palpitation, headache, tachycardia, asthenia, nausea, diarrhea, nasal congestion and
impotence on prolonged use14. Throughout the world, research seeks a remedy for BPH safe
and free from side effects on prolonged use15,16. Amino acids (a combination of glycine,
alanine and glutamic acid), beta sitosterol, flaxseed oil, and some herbs (Serenoa repens,
Pygeum africanum and Urtica dioica) have been found beneficial in management of
BPH16,17.
In this study, the significant reduction in the average AUA symptom score at the end of 6
months indicates that Himplasia (PC-27) provides significant symptomatic relief in BPH,
which may be due to a significant reduction in the prostate size as confirmed by ultrasound
examination. The favourable significant changes in the uroflowmetry parameters
(improvement in MFR, reduction in post void residual urine volume and improvement in
peak flow values) also suggest that Himplasia (PC-27) had improved the clinical picture of
the study patients.
In this study, there were no significant changes in PSA levels from the baseline to the end of
the study period. PSA is a specific antigen produced by the cells of the prostate capsule and
periurethral glands. Patients with BPH or prostatitis produce large amounts of PSA, and PSA
level is also determined in part by size and weight of the prostate. Most men with slightly
elevated PSA levels do not have prostate cancer, and many men with prostate cancer have
normal PSA levels, but highly elevated levels may indicate the presence of cancer. Agespecific PSA evidence suggests that the PSA level increases with age.
The beneficial effects of Himplasia (PC-27) might be due to the synergistic action of its
ingredients. The main constituents of Himplasia (PC-27) are Tribulus terrestris, Caesalpinia
bonducella, Asparagus racemosus, Areca catechu, Crataeva nurvala and Akika pishti.
Tribulus terrestris has analgesic, antibacterial, diuretic and smooth muscle relaxant properties
and found beneficial in treating symptoms of BPH18,19. Caesalpinia bonducella has antiinflammatory, urinary antiseptic and diuretic properties. Asparagus racemosus is a potent
diuretic and antispasmodic, has immunomodulatory effects on the prostate, and antiinflammatory, lithotriptic, demulcent and tonic properties useful in disorders of urinary
tract20. Areca catechu has antimicrobial properties useful in the treatment of urinary disorders
and Crateva nurvala is useful in the treatment of urinary disorders caused by BPH21.
In this study, it was observed that on account of its antispasmodic, diuretic and antibacterial
property, Himplasia (PC-27) displayed a multi-dimensional favourable effect in patients with
BPH. It was also observed that Himplasia (PC-27) alleviated the other symptoms of BPH and
displayed a significant improvement in uroflow dynamics. This study also indicated a
dependable safety profile for Himplasia (PC-27), for long-term use in the management of
BPH.
CONCLUSION
With increasing life expectancy, BPH is emerging as an important disease responsible for
major chunk of morbidity amongst the geriatric population. The available drug therapy
options in the management of BPH are linked with various adverse effects, which limit their
long-term usage. In this study, Himplasia (PC-27) was found to be beneficial for
symptomatic control and also in reducing prostate size, with significant improvement in uro
flow dynamics. From the above results, it can be stated that Himplasia (PC-27) is effective
and safe for long-term clinical usage in the management of BPH.
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