Benign the feeling of well being. The overgrowth


Benign prostatic
hyperplasia: An Introduction

Benign prostatic
hyperplasia (BPH) is the non-malignant enlargement of the prostate gland and is
one of the most common conditions affecting the elderly males.1,2 Prostrate
enlargement can produce voiding symptoms that can lead to pathological changes
in the urinary bladder and the kidney.2

refers to stromal and glandular epithelial hyperplasia that occurs in the
periurethral transition zone of the prostate that surrounds the urethra. BPH
clinically manifest as lower urinary tract symptoms (LUTS) that consist of
irritative symptoms (urgency, frequency, nocturia) and obstructive symptoms (hesitancy,
a weak and interrupted urinary stream, straining to initiate urination, a
sensation of incomplete bladder emptying). Prolonged obstructions may
eventually lead to acute urinary retention (AUR), recurrent urinary tract
infection (UTI), haematuria, bladder calculi, and renal insufficiency.1


BPH is a quality
of life disorder, and affects man’s ability to initiate or terminate urine flow
stream and reduces the feeling of well being.  The overgrowth of smooth muscle tissue and
glandular epithelial tissue in BPH is attributed to a number of different
causes such as aging, late activation of cell growth, genetic factors, and
hormonal changes.1


Half of the men by the
age of 60 exhibit histological evidence of BPH and by 90 years 90% of men
develop histology of BPH. 1Age and normal androgenic factors are
postulated to be the two well established factors that cause BPH.  The prevalence of LUTS increases steadily
with increasing age. A community-based survey in UK reported 41% overall
prevalence of LUTS.3

The high prevalence of
histologic BPH, bothersome LUTS, benign prostatic enlargement (BPE), and bladder
outlet obstruction (BOO) has been emphasised. Over the next few decades the
number of patients presenting with these symptoms to health care providers will
probably increase significantly.3

from the United Nations demonstrate that the percentage of the population aged
65 years or older increased significantly between 2000 and 2005, both in
underdeveloped and more developed regions, and from 7% to 11% worldwide. In
addition, life expectancy has changed from 56 years for the observation period
1965 to 1970 to 65 years for 2000 to 2005. Although developed regions have a
longer life expectancy, but the incremental increase is greater in Africa,
Asia, and Latin America and the Caribbean regions.3

Diagnosis and evaluation

Men commonly fail to
seek help for LUTS associated with BPH. Therefore, it is imperative that
primary care physicians routinely inquire about urinary function with men over
the age of 50.4

All patients presenting
with LUTS should undergo physical examination including a careful digital
rectal examination (DRE).5

Diagnostic tests

Prostatic Symptom Score

This is a questionnaire
that was developed by a committee of American Urological Association. An
indexing tool called the International Prostate Symptoms Score (IPSS) can help
to evaluate the key lower urinary tract symptoms. Unlike laboratory tests or
other objective tests, this scoring system measures the patient’s own
experience. The higher the score, the more severe is the condition. Patients
score on this test gives a highly accurate assessment of the effect of lower
urinary tract symptoms on the quality of a man’s life.

Other Indexing

addition to IPSS, other indexing systems that are being used to help assess the
patient are Madsen-Iversen point system, the Boyarsky guidelines, Maine Medical
Assessment Score, Symptom Problem Index (SPI) and the BPH Impact Index (BII),
which gauge different quality-of-life and disease issues.


Physical examination

Digital Rectal

The DRE is used to
detect an enlarged prostate.  The doctor
inserts a gloved and lubricated finger into the patient’s rectum and feels the
prostate to estimate its size and to detect nodules or tenderness. Although the
examination is quick and painless, it is embarrassing for some. The test helps
to rule out prostate cancer, but it is generally underestimates the prostate
size. The examination is not considered accurate for diagnosing prostatic
hyperplasia, and is never the primary diagnostic tool for either BPH or cancer.2


Uroflowmetry is used to
measure the speed of urine flow in order to determine obstruction in bladder.
To perform this test, the patient is asked to urinate into a special toilet
equipped with an uroflowmeter. It is important that the patient remains still
while urinating to help ensure accuracy, and that he urinates normally and does
not exert strain to empty his bladder or attempt to retard his urine flow. Many
factors like straining or holding back because of self-consciousness can affect
urine flow. Hence, experts recommend that the test be repeated at least twice.
The values more than 15 mL per second and voiding volume of 150 mL or more is
considered to be the normal range.2

Urine Analysis

A urinalysis involves a
physical and chemical examination of urine and is performed to detect signs of
bleeding or infection. Urine is examined under a microscope. Although urinary
infection is uncommon in younger men, it occurs more frequently in older men,
particularly those with BPH. A urinalysis also helps rule out bladder cancer.2

Prostate Specific
Antigen (PSA)

A PSA test measures the
level of PSA in the patient’s blood and is the standard screening test for
prostate cancer. A PSA is recommended annually for all men over 50-years-old
and for men over 40 who are at high risk for prostate cancer. BPH itself can
also raise PSA levels, but the test has generally been optional for men with
suspected BPH. The decrease in the prostate size corresponds to the decrease in
the PSA levels. Every 19% decrease in the PSA levels there is a decrease of
prostate volume by 10%.2

Postvoid Residual

Postvoid residual urine
(PVR) volume is one of the important tests for urinary incontinence, the amount
of urine left after urination. Normally, about 50 mL or less of urine is left.
Urine more than 200 mL is a definite sign of abnormalities. The most common
method for measuring PVR is by transabdominal ultrasonography. PVR can also be
measured using a catheter, a soft tube that is inserted into the urethra within
a few minutes of urination.2


The Canadian Urological
Association (CUA) has established treatment algorithm for BPH and is based
primarily on a combination of the degree of symptoms, the amount of bother, and
the size of the prostate.4

BPH rarely causes
serious complications and men usually have a choice between treating it than
opting for watchful waiting treatment options: The primary goals of treatment
for BPH are to improve urinary flow and to reduce symptoms.2

Options are available





For patients
with a low IPSS symptom score (zero to seven) watchful waiting is an
appropriate treatment. However, follow-up monitoring is important. Patients
with higher IPSS symptom scores should be given information on appropriate
treatment options.2 Despite a high American Urological Association
Symptom Index (AUA-SI) or IPSS score, watchful waiting remains to be a
patient’s choice as the level of symptom distress that a patient can tolerate
varies greatly. A variety of lifestyle changes like restricting fluid intake, avoiding
foods or beverages that cause irritation (e.g., caffeine or alcohol), monitoring
some medications (e.g., diuretics, decongestants, antihistamines, and
antidepressants), timed voiding (bladder retraining), pelvic floor exercises,
and treatment for constipation.4

Medical treatment

Common symptoms
of BPH are due to increased resistance to the flow of urine through the bladder
neck and compressed prostatic urethra. Medical treatments have been devised to
decrease the size of the prostate, and thereby decrease the resistance to
urinary flow.1
of medical therapies may not match the efficacy of surgical therapies, but they
can provide adequate symptom relief.4

Non-selective alpha-1

Doxazosin and
terazosin, second-generation alpha blockers, are recommended as treatment
options for patients with LUTS secondary to BPH. They act by reducing prostatic
smooth muscle tone and thus, have an immediate effect on urinary flow.  First-generation alpha-blockers and prazosin are not
recommended. The side effects reported with alpha blockers are dizziness,
postural hypotension, fatigue, asthenia and retrograde ejaculation. These side
effects can be reduced by bedtime administration and slow titration of the
dosage. Alpha blockers can be used with other therapies as needed.2,4

Selective alpha-1 blocker

Alfuzosin and
tamsulosin, third-generation alpha blockers, are more selective in relaxing
prostatic smooth muscle and therefore does not affect blood pressure.  Tamsulosin, a highly selective alpha-1
adrenergic antagonist, was developed to avoid the side effects of non-selective
agents. Patients who do not respond to non-selective alpha blockers may respond
to tamsulosin and it may also have fewer side effects because of the
selectivity, including hypotension. Compared to second-generation agents the
risk of dizziness is lower with tamsulosin and alfuzosin. Initial dosage of
tamsulosin is 0.4 mg once-daily, with a maximum dosage of 0.8 mg/day.
Tamsulosin shows no antihypertensive effect and is more expensive than non- selective
alpha blockers.2,4

5-Alpha reductase inhibitors

Dutasteride and
finasteride, 5-ARIs, act by blocking the conversion of testosterone to
dihydrotestosterone (DHT). DHT is an androgen that is believed to be
responsible for prostate enlargement. The 5-ARI class is the sole hormonal
therapy to date that demonstrates both efficacy and acceptable safety for the
treatment of BPH. Finasteride, which inhibits type 2 5-AR, suppresses serum DHT
by 70.8% ± 18.3% at 24 weeks but not to castrate levels. Finasteride treatment
led to significant improvements in urinary symptoms and flow rates. According
to the Prospect study, the improvements with finasteride are significantly less
than those with any alpha blocker or surgery. Adverse effects of finasteride
include decreased libido, ejaculatory disorder, and impotence. Dutasteride has
sexual side effects similar to finasteride.2,4


The CUA and AUA
guidelines recommend dutasteride and finasteride as appropriate treatment for
patients with LUTS associated with demonstrable prostatic enlargement, but
should not be used to treat men with LUTS without prostatic enlargement.  Finasteride and dutasteride both reduces PSA
levels by approximately 50% after 6 months and this PSA suppression is
maintained over time. If PSA rises while on a 5-ARI, drug compliance should be

Combination therapy

therapy of 5-ARI and an alpha-blocker is helpful in managing static and dynamic
component in patients with an enlarged prostate gland having symptoms of BOO.  The underlying principle for this
recommendation is that alpha blocker provides rapid relief of symptoms without
targeting the underlying disease process and 5-ARI provides mid or more
sustained relief of symptoms. Also, ARI reduces the risk of serious complications
like acute urinary retention (AUR) and/or the need for BPH-related surgery. According
to the Medical Therapy of Prostatic Symptoms (MTOPS) trial combination therapy
(finasteride and doxazosin) reduced the risk of progression by 66% compared to
placebo and with either drug by itself (34% for finasteride and 39% for


Surgical treatment

If medical treatment
fails, surgery should be considered as treatment. Surgery should be performed
if patients who have refractory urinary retention, fail catheter removal, or
have recurrent urinary tract infections, persistent haematuria, bladder stones,
or renal insufficiency. For patients with high IPSS symptom scores who want
surgical treatment and are good candidates for it, surgery can be the initial
treatment. Surgical procedures that can be performed are described below.2

Open Prostatectomy

In this method the
inner portion of the prostate is surgically removed using a suprapubic or
retropubic approach. It is the oldest and most effective treatment for
relieving the symptoms of BPH and increasing maximum urinary flow. In patients
who undergo this procedure symptomatic improvement rate is 98%, while the
treatment rate is only 2%. However, this procedure is the most invasive
treatment for BPH and is associated with the most morbidity. Hence, this
procedure is typically used in patients with a very large prostate gland or
structural problems such as a large median lobe that protrudes into the bladder
or a large bladder calculus or urethral diverticulum.2

Resection of the Prostate (TURP)

TURP is the most
commonly employed surgical procedure for BPH, and it reduces symptoms in 88% of
patients. Approximately 10% of patients require retreatment within five years.
The procedure results in complications, the most frequent complications being
inability to void, clot retention, and secondary infection. Bleeding, the most
morbid complication occurs in only 1% of patients. Long-term complications include
retrograde ejaculation, impotence, partial incontinence, and total

electrovaporization (TUVP)

A modification
of TURP, TUVP utilises high electrical current to vaporise and coagulate the
obstructing prostate tissue. Although long-term efficiency of TUVP is
comparable with TURP, many patients experience irritative side effects.1             


microwave thermotherapy (TUMT)

TUMT  destruct 
malignant cells without affecting normal cells by raising the
temperature of the cells using low-level radiofrequency (microwave) in the
prostate up to 40°-45° C (hyperthermia), 46°-60° C (thermotherapy), and 61° to
75° C (transrectal thermal ablation). TUMT is safe and cost effective
treatment, with reasonable improvement in urine flow rate and minimal
impairment on sexual function.1


focused ultrasound (HIFU)

protein denaturation and coagulative necrosis of prostatic tissue have been
achieved by using HIFU frequencies of 4 MHZ. Although significant increase in uroflow
and a decrease in postvoid residual volume have been observed, the cost is
three times higher than that of TURP.1

Tamsulosin in BPH

Tamsulosin, a
sulfamoylphenthylamine is a new uroselective alpha-1A adrenoreceptor subtype
antagonist. It is approximately 99% protein bound and undergoes hepatic
metabolism. Most of the parent drug and metabolites are excreted in urine; up
to 14% is excreted as unchanged drug.6 Role of tamsulosin in the
treatment of BPH has been demonstrated in many clinical studies.

Clinical studies

Milicevic S and Bijelic R conducted a study to establish
the efficacy and safety of a daily dose of tamsulosin 0.4 mg in patients with
functional symptoms of BPH through an evaluation of reduction of subjective
symptoms, quantified through the IPSS.7


The study reported reduction in symptoms after 4 weeks
(35.51%) and 12 weeks (55.11%) of treatment (Table 1). The Quality of Life
Index showed marked improvement of 44.54% after 4 weeks and 68.82% after 12 weeks.7



Table 1: The efficacy of tamsulosin – total





In a randomised placebo-controlled
trial conducted by Mohanty NK et al., efficacy,
safety and advantages of tamsulosin in the management of BPH was evaluated. The
study results showed tamsulosin to be very effective in the management of BPH
cases, not requiring surgery, with few side effects and good patient compliance.
A significant change in IPSS was
seen in the tamsulosin group as compared to the placebo group at the end of the
study. The improvement with tamsulosin was significantly greater as compared to
the placebo group at all time intervals and for all the three parameters (Table






2: Total, obstructive and initiative International Prostate Symptoms Scores




Rahardjo D et al., conducted an open-label,
randomised, multicenter study, to compare the efficacy and safety of tamsulosin
hydrochloride and doxazosin in patients with LUTS due to BPH. The study
reported that tamsulosin is more effective than doxazosin in the treatment of
LUTS due to BPH. Tamsulosin group had a significant improvement in Qmax and
Qave compared to the doxazosin group (Table 3).8

compared to baseline, while in the doxazosin group

was no significant difference. In addition, tamsulosin

less of an adverse impact on blood pressure than dox-

and was well tolerated.











3: Mean and percentage change from baseline of efficacy parameters




Tamsulosin with ADS
technology: Advantages

 After its introduction in 1990’s, tamsulosin
has been most commonly used  in the
treatment of BPH; but the available tamsulosin modified release (MR) capsule
formulation has been associated with some drawbacks.  The current capsule is food dependent and if
it is taken in the fasting state, maximum plasma concentration (Cmax) and the
area under the curve (AUC) increases by about 70% and 30%, respectively,
compared to when it is taken after breakfast. Hence, the labelling information
recommends that tamsulosin MR should be dosed after breakfast or the first meal
of the day. Non-compliance with this recommendation will lead to increased
exposure to tamsulosin, which can lead to a higher risk for
vasodilatation-related adverse events like dizziness, headache, etc.9


It is important
to develop new pharmaceutical formulations to improve the convenience and/or
risk/benefit ratio of well established medicinal products. By controlling the
release and absorption of drugs in the gastrointestinal (GI) tract and
specifically in the colon, improved safety and/or efficacy can be achieved.
This will enable once-daily administration resulting in a continuous 24-hour
pharmacological effect. Technologies like multi-unit membrane-coated pellets,
osmotic pump technology (OROS) and GeoMatrix have been developed and used for
tamsulosin MR. However, these technologies are water-dependant and require
water in GI to release the active ingredient.9


Hence, a novel
technology, advanced delivery system (ADS) has been developed.10 This technology is a
controlled release system of a gel matrix type that is composed of a
gel-forming agent and a gel-enhancing agent as its major components. This
technology has been shown to provide pH-independent drug release and
GI-agitation resistant gel formation.9



ADS technology
was developed to overcome the drawbacks of existing tamsulosin MR formulation.
The ADS technology has following benefits10:


hours consistent release in colon where water is poorly available

Improved control of nocturia and IPSS

It shows a steady plasma level after dosing with a improved Cmax/C24h

quality of sleep

can be taken with or without food

Independent of food intake

Reduced Cmax related side

Reduced incidence of postural hypotension


Tamsulosin with ADS technology is a
unique formulation. This technology ensures 24 hour consistent drug release
throughout the entire GI tract. The drug gets sufficiently hydrated during its
transit through the upper GI tract so that it is able to release sufficient
amount of the drug even in the colon where water is poorly available. With
conventional MR formulations of tamsulosin release of the drug occurs only in
stomach and small intestine, thus providing suboptimal serum drug levels over
24 hour dosing interval, hence leading to poor control of symptoms, especially
nocturia (Figure 1).10







ADS technology






1:  Hydration and drug release in small
intestine and colon by ADS technology and conventional matrix hydration



ADS technology provides a continuous
release of the drug in the GI tract even in colon, thus maintaining a constant
24 hour plasma drug levels and hence offers a better symptom control of the
most bothersome symptom i.e., nocturia that affect the quality of life. There is
slower release of tamsulosin which leads to a reduction in Cmax and
hence there is lower risk of treatment-emergent adverse events, such as
orthostatic hypotension.10 


In conventional MR formulations,
release of drug occurs in stomach and small intestine rather than the colon.
Due to this, there is suboptimal serum drug level over 24 hour dosing interval
and hence poor symptom control. Moreover, the conventional MR when taken on
empty stomach increases the risk of unwanted cardiovascular effects (CVS)
effects such as orthostatic hypotension, dizziness and syncope (fainting) (Figure





2:  Tamsulosin with ADS technology is
superior to conventional tamsulosin formulations





BPH is the most common disorder amongst the geriatric population.
Patient evaluation and careful differential diagnosis are important steps in
making an accurate clinical diagnosis. Tamsulosin have been found to be safe
and effective in the treatment of BPH. Delivery of tamsulosin with ADS
technology has improved the efficacy and safety of the drug and has surpassed
the drawbacks of previous technologies.



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D Benign prostatic hyperplasia: An overview of existing treatment. Indian J Pharmacol. 2011 Feb; 43(1):

2.      Praveen
R. Benign prostatic hyperplasia: Updated review. Res J Pharm. 2013;4 (8):45-50.

3.      Roehrborn
CG. Benign Prostatic Hyperplasia: An Overview. Rev Urol. 2005; 7(Suppl 9): S3–S14.

4.      Tanguay
S, Awde M, Brock G, et al. Diagnosis
and management of benign prostatic hyperplasia in primary care. Can Urol Assoc J. 2009 Jun; 3(3 Suppl
2): S92–S100.

5.      Shrivastava
A, Gupta VB. Various treatment options for benign prostatic hyperplasia: A
current update.  J Midlife Health. 2012 Jan;3(1):10-9.

6.      Mohanty
NK, Arora RP, Nayak RL, Malhotra V. A randomized comparative study of
tamsulosin vs placebo in the treatment of benign prostatic hyperplasia. Indian J Urol. 2003; 20(1):40-45.

7.      Milicevic
S, Bijelic R. Efficacy and safety of tamsulosin in the treatment of benign
prostatic hyperplasia. Med Arch.

8.      Rahardjo
D, Soebadi DM, Sugandi S, et al.
and safety of tamsulosin hydrochloride compared to doxazosin in the treatment
of Indonesian patients with lower urinary tract symptoms due to benign
prostatic hyperplasia. Int J Urol.
2006 Nov;13(11):1405-9.

9.      Michel
MC, Korstanje C, Krauwinkel W, Kuipers M. The
Pharmacokinetic Profile of Tamsulosin Oral Controlled Absorption System
(OCAS1). European Urology Supplements. 2005;4:15–24.

10.  Data
on file.