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 Benign prostatichyperplasia: An IntroductionBenign prostatichyperplasia (BPH) is the non-malignant enlargement of the prostate gland and isone of the most common conditions affecting the elderly males.

1,2 Prostrateenlargement can produce voiding symptoms that can lead to pathological changesin the urinary bladder and the kidney.2 BPHrefers to stromal and glandular epithelial hyperplasia that occurs in theperiurethral transition zone of the prostate that surrounds the urethra. BPHclinically manifest as lower urinary tract symptoms (LUTS) that consist ofirritative symptoms (urgency, frequency, nocturia) and obstructive symptoms (hesitancy,a weak and interrupted urinary stream, straining to initiate urination, asensation of incomplete bladder emptying). Prolonged obstructions mayeventually lead to acute urinary retention (AUR), recurrent urinary tractinfection (UTI), haematuria, bladder calculi, and renal insufficiency.1 BPH is a qualityof life disorder, and affects man’s ability to initiate or terminate urine flowstream and reduces the feeling of well being.  The overgrowth of smooth muscle tissue andglandular epithelial tissue in BPH is attributed to a number of differentcauses such as aging, late activation of cell growth, genetic factors, andhormonal changes.1EpidemiologyHalf of the men by theage of 60 exhibit histological evidence of BPH and by 90 years 90% of mendevelop histology of BPH.

1Age and normal androgenic factors arepostulated to be the two well established factors that cause BPH.  The prevalence of LUTS increases steadilywith increasing age. A community-based survey in UK reported 41% overallprevalence of LUTS.3 The high prevalence ofhistologic BPH, bothersome LUTS, benign prostatic enlargement (BPE), and bladderoutlet obstruction (BOO) has been emphasised. Over the next few decades thenumber of patients presenting with these symptoms to health care providers willprobably increase significantly.

3 Estimatesfrom the United Nations demonstrate that the percentage of the population aged65 years or older increased significantly between 2000 and 2005, both inunderdeveloped and more developed regions, and from 7% to 11% worldwide. Inaddition, life expectancy has changed from 56 years for the observation period1965 to 1970 to 65 years for 2000 to 2005. Although developed regions have alonger life expectancy, but the incremental increase is greater in Africa,Asia, and Latin America and the Caribbean regions.3Diagnosis and evaluationMen commonly fail toseek help for LUTS associated with BPH. Therefore, it is imperative thatprimary care physicians routinely inquire about urinary function with men overthe age of 50.4All patients presentingwith LUTS should undergo physical examination including a careful digitalrectal examination (DRE).5Diagnostic tests InternationalProstatic Symptom ScoreThis is a questionnairethat was developed by a committee of American Urological Association.

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Anindexing tool called the International Prostate Symptoms Score (IPSS) can helpto evaluate the key lower urinary tract symptoms. Unlike laboratory tests orother objective tests, this scoring system measures the patient’s ownexperience. The higher the score, the more severe is the condition.

Patientsscore on this test gives a highly accurate assessment of the effect of lowerurinary tract symptoms on the quality of a man’s life.Other IndexingSystemsInaddition to IPSS, other indexing systems that are being used to help assess thepatient are Madsen-Iversen point system, the Boyarsky guidelines, Maine MedicalAssessment Score, Symptom Problem Index (SPI) and the BPH Impact Index (BII),which gauge different quality-of-life and disease issues. Physical examinationDigital RectalExaminationThe DRE is used todetect an enlarged prostate.  The doctorinserts a gloved and lubricated finger into the patient’s rectum and feels theprostate to estimate its size and to detect nodules or tenderness.

Although theexamination is quick and painless, it is embarrassing for some. The test helpsto rule out prostate cancer, but it is generally underestimates the prostatesize. The examination is not considered accurate for diagnosing prostatichyperplasia, and is never the primary diagnostic tool for either BPH or cancer.2UroflowmetryUroflowmetry is used tomeasure 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 toiletequipped with an uroflowmeter. It is important that the patient remains stillwhile urinating to help ensure accuracy, and that he urinates normally and doesnot exert strain to empty his bladder or attempt to retard his urine flow. Manyfactors like straining or holding back because of self-consciousness can affecturine 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 isconsidered to be the normal range.2 Urine AnalysisA urinalysis involves aphysical and chemical examination of urine and is performed to detect signs ofbleeding or infection. Urine is examined under a microscope. Although urinaryinfection 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 SpecificAntigen (PSA)A PSA test measures thelevel of PSA in the patient’s blood and is the standard screening test forprostate cancer. A PSA is recommended annually for all men over 50-years-oldand for men over 40 who are at high risk for prostate cancer. BPH itself canalso raise PSA levels, but the test has generally been optional for men withsuspected BPH. The decrease in the prostate size corresponds to the decrease inthe PSA levels.

Every 19% decrease in the PSA levels there is a decrease ofprostate volume by 10%.2Postvoid ResidualUrinePostvoid residual urine(PVR) volume is one of the important tests for urinary incontinence, the amountof 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 commonmethod for measuring PVR is by transabdominal ultrasonography. PVR can also bemeasured using a catheter, a soft tube that is inserted into the urethra withina few minutes of urination.2 ManagementThe Canadian UrologicalAssociation (CUA) has established treatment algorithm for BPH and is basedprimarily on a combination of the degree of symptoms, the amount of bother, andthe size of the prostate.4BPH rarely causesserious complications and men usually have a choice between treating it thanopting for watchful waiting treatment options: The primary goals of treatmentfor BPH are to improve urinary flow and to reduce symptoms.

2 Options are availableare1: ·        Watchfulwaiting·        Medicaltreatment ·        SurgicaltreatmentWatchfulwaitingFor patientswith a low IPSS symptom score (zero to seven) watchful waiting is anappropriate treatment. However, follow-up monitoring is important. Patientswith higher IPSS symptom scores should be given information on appropriatetreatment options.2 Despite a high American Urological AssociationSymptom Index (AUA-SI) or IPSS score, watchful waiting remains to be apatient’s choice as the level of symptom distress that a patient can toleratevaries greatly. A variety of lifestyle changes like restricting fluid intake, avoidingfoods or beverages that cause irritation (e.g., caffeine or alcohol), monitoringsome medications (e.g.

, diuretics, decongestants, antihistamines, andantidepressants), timed voiding (bladder retraining), pelvic floor exercises,and treatment for constipation.4 Medical treatmentCommon symptomsof BPH are due to increased resistance to the flow of urine through the bladderneck and compressed prostatic urethra. Medical treatments have been devised todecrease the size of the prostate, and thereby decrease the resistance tourinary flow.1Efficacyof medical therapies may not match the efficacy of surgical therapies, but theycan provide adequate symptom relief.4 Non-selective alpha-1blockersDoxazosin andterazosin, second-generation alpha blockers, are recommended as treatmentoptions for patients with LUTS secondary to BPH.

They act by reducing prostaticsmooth muscle tone and thus, have an immediate effect on urinary flow.  First-generation alpha-blockers and prazosin are notrecommended. The side effects reported with alpha blockers are dizziness,postural hypotension, fatigue, asthenia and retrograde ejaculation. These sideeffects can be reduced by bedtime administration and slow titration of thedosage. Alpha blockers can be used with other therapies as needed.2,4 Selective alpha-1 blockerAlfuzosin andtamsulosin, third-generation alpha blockers, are more selective in relaxingprostatic smooth muscle and therefore does not affect blood pressure.

  Tamsulosin, a highly selective alpha-1adrenergic antagonist, was developed to avoid the side effects of non-selectiveagents. Patients who do not respond to non-selective alpha blockers may respondto tamsulosin and it may also have fewer side effects because of theselectivity, including hypotension. Compared to second-generation agents therisk of dizziness is lower with tamsulosin and alfuzosin. Initial dosage oftamsulosin 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- selectivealpha blockers.2,4 5-Alpha reductase inhibitors(ARIs)Dutasteride andfinasteride, 5-ARIs, act by blocking the conversion of testosterone todihydrotestosterone (DHT). DHT is an androgen that is believed to beresponsible for prostate enlargement.

The 5-ARI class is the sole hormonaltherapy to date that demonstrates both efficacy and acceptable safety for thetreatment of BPH. Finasteride, which inhibits type 2 5-AR, suppresses serum DHTby 70.8% ± 18.3% at 24 weeks but not to castrate levels. Finasteride treatmentled to significant improvements in urinary symptoms and flow rates. Accordingto the Prospect study, the improvements with finasteride are significantly lessthan those with any alpha blocker or surgery. Adverse effects of finasterideinclude decreased libido, ejaculatory disorder, and impotence.

Dutasteride hassexual side effects similar to finasteride.2,4  The CUA and AUAguidelines recommend dutasteride and finasteride as appropriate treatment forpatients with LUTS associated with demonstrable prostatic enlargement, butshould not be used to treat men with LUTS without prostatic enlargement.  Finasteride and dutasteride both reduces PSAlevels by approximately 50% after 6 months and this PSA suppression ismaintained over time. If PSA rises while on a 5-ARI, drug compliance should bechecked.2,4 Combination therapyCombinationtherapy of 5-ARI and an alpha-blocker is helpful in managing static and dynamiccomponent in patients with an enlarged prostate gland having symptoms of BOO.

  The underlying principle for thisrecommendation is that alpha blocker provides rapid relief of symptoms withouttargeting the underlying disease process and 5-ARI provides mid or moresustained relief of symptoms. Also, ARI reduces the risk of serious complicationslike acute urinary retention (AUR) and/or the need for BPH-related surgery. Accordingto the Medical Therapy of Prostatic Symptoms (MTOPS) trial combination therapy(finasteride and doxazosin) reduced the risk of progression by 66% compared toplacebo and with either drug by itself (34% for finasteride and 39% fordoxazosin).1,4 Surgical treatmentIf medical treatmentfails, surgery should be considered as treatment. Surgery should be performedif patients who have refractory urinary retention, fail catheter removal, orhave recurrent urinary tract infections, persistent haematuria, bladder stones,or renal insufficiency.

For patients with high IPSS symptom scores who wantsurgical treatment and are good candidates for it, surgery can be the initialtreatment. Surgical procedures that can be performed are described below.2Open ProstatectomyIn this method theinner portion of the prostate is surgically removed using a suprapubic orretropubic approach. It is the oldest and most effective treatment forrelieving the symptoms of BPH and increasing maximum urinary flow. In patientswho undergo this procedure symptomatic improvement rate is 98%, while thetreatment rate is only 2%. However, this procedure is the most invasivetreatment for BPH and is associated with the most morbidity. Hence, thisprocedure is typically used in patients with a very large prostate gland orstructural problems such as a large median lobe that protrudes into the bladderor a large bladder calculus or urethral diverticulum.2 TransurethralResection of the Prostate (TURP)TURP is the mostcommonly employed surgical procedure for BPH, and it reduces symptoms in 88% ofpatients.

Approximately 10% of patients require retreatment within five years.The procedure results in complications, the most frequent complications beinginability to void, clot retention, and secondary infection. Bleeding, the mostmorbid complication occurs in only 1% of patients. Long-term complications includeretrograde ejaculation, impotence, partial incontinence, and totalincontinence.2 Transurethralelectrovaporization (TUVP)A modificationof TURP, TUVP utilises high electrical current to vaporise and coagulate theobstructing prostate tissue. Although long-term efficiency of TUVP iscomparable with TURP, many patients experience irritative side effects.

1               Transurethralmicrowave thermotherapy (TUMT)TUMT  destruct malignant cells without affecting normal cells by raising thetemperature of the cells using low-level radiofrequency (microwave) in theprostate up to 40°-45° C (hyperthermia), 46°-60° C (thermotherapy), and 61° to75° C (transrectal thermal ablation). TUMT is safe and cost effectivetreatment, with reasonable improvement in urine flow rate and minimalimpairment on sexual function.1 High-intensityfocused ultrasound (HIFU)Effectiveprotein denaturation and coagulative necrosis of prostatic tissue have beenachieved by using HIFU frequencies of 4 MHZ. Although significant increase in uroflowand a decrease in postvoid residual volume have been observed, the cost isthree times higher than that of TURP.1 Tamsulosin in BPHTamsulosin, asulfamoylphenthylamine is a new uroselective alpha-1A adrenoreceptor subtypeantagonist. It is approximately 99% protein bound and undergoes hepaticmetabolism. Most of the parent drug and metabolites are excreted in urine; upto 14% is excreted as unchanged drug.6 Role of tamsulosin in thetreatment of BPH has been demonstrated in many clinical studies.

Clinical studiesMilicevic S and Bijelic R conducted a study to establishthe efficacy and safety of a daily dose of tamsulosin 0.4 mg in patients withfunctional symptoms of BPH through an evaluation of reduction of subjectivesymptoms, 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 LifeIndex showed marked improvement of 44.54% after 4 weeks and 68.82% after 12 weeks.7  Table 1: The efficacy of tamsulosin – totalIPSS    In a randomised placebo-controlledtrial conducted by Mohanty NK et al., efficacy,safety and advantages of tamsulosin in the management of BPH was evaluated. Thestudy results showed tamsulosin to be very effective in the management of BPHcases, not requiring surgery, with few side effects and good patient compliance.

A significant change in IPSS wasseen in the tamsulosin group as compared to the placebo group at the end of thestudy. The improvement with tamsulosin was significantly greater as compared tothe placebo group at all time intervals and for all the three parameters (Table2).6      Table2: 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 tamsulosinhydrochloride and doxazosin in patients with LUTS due to BPH. The studyreported that tamsulosin is more effective than doxazosin in the treatment ofLUTS due to BPH. Tamsulosin group had a significant improvement in Qmax andQave compared to the doxazosin group (Table 3).8groupcompared to baseline, while in the doxazosin grouptherewas no significant difference.

In addition, tamsulosinhadless of an adverse impact on blood pressure than dox-azosinand was well tolerated.          Table3: Mean and percentage change from baseline of efficacy parameters   Tamsulosin with ADStechnology: Advantages After its introduction in 1990’s, tamsulosinhas been most commonly used  in thetreatment of BPH; but the available tamsulosin modified release (MR) capsuleformulation has been associated with some drawbacks.  The current capsule is food dependent and ifit is taken in the fasting state, maximum plasma concentration (Cmax) and thearea under the curve (AUC) increases by about 70% and 30%, respectively,compared to when it is taken after breakfast. Hence, the labelling informationrecommends that tamsulosin MR should be dosed after breakfast or the first mealof the day. Non-compliance with this recommendation will lead to increasedexposure to tamsulosin, which can lead to a higher risk forvasodilatation-related adverse events like dizziness, headache, etc.9 It is importantto develop new pharmaceutical formulations to improve the convenience and/orrisk/benefit ratio of well established medicinal products.

By controlling therelease and absorption of drugs in the gastrointestinal (GI) tract andspecifically in the colon, improved safety and/or efficacy can be achieved.This will enable once-daily administration resulting in a continuous 24-hourpharmacological effect. Technologies like multi-unit membrane-coated pellets,osmotic pump technology (OROS) and GeoMatrix have been developed and used fortamsulosin MR. However, these technologies are water-dependant and requirewater in GI to release the active ingredient.9  Hence, a noveltechnology, advanced delivery system (ADS) has been developed.10 This technology is acontrolled release system of a gel matrix type that is composed of agel-forming agent and a gel-enhancing agent as its major components.

Thistechnology has been shown to provide pH-independent drug release andGI-agitation resistant gel formation.9  ADS technologywas developed to overcome the drawbacks of existing tamsulosin MR formulation.The ADS technology has following benefits10: ·        24hours 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/C24hratio·        Betterquality of sleep·        Itcan be taken with or without food·        Independent of food intake·        Reduced Cmax related sideeffects·        Reduced incidence of postural hypotension Tamsulosin with ADS technology is aunique formulation. This technology ensures 24 hour consistent drug releasethroughout the entire GI tract. The drug gets sufficiently hydrated during itstransit through the upper GI tract so that it is able to release sufficientamount of the drug even in the colon where water is poorly available. Withconventional MR formulations of tamsulosin release of the drug occurs only instomach and small intestine, thus providing suboptimal serum drug levels over24 hour dosing interval, hence leading to poor control of symptoms, especiallynocturia (Figure 1).

10      Conventional matrix   ADS technology       Figure1:  Hydration and drug release in smallintestine and colon by ADS technology and conventional matrix hydration  ADS technology provides a continuousrelease of the drug in the GI tract even in colon, thus maintaining a constant24 hour plasma drug levels and hence offers a better symptom control of themost bothersome symptom i.e., nocturia that affect the quality of life. There isslower release of tamsulosin which leads to a reduction in Cmax andhence there is lower risk of treatment-emergent adverse events, such asorthostatic 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 intervaland hence poor symptom control. Moreover, the conventional MR when taken onempty stomach increases the risk of unwanted cardiovascular effects (CVS)effects such as orthostatic hypotension, dizziness and syncope (fainting) (Figure2).10    Figure2:  Tamsulosin with ADS technology issuperior to conventional tamsulosin formulations   ConclusionBPH is the most common disorder amongst the geriatric population.

Patient evaluation and careful differential diagnosis are important steps inmaking an accurate clinical diagnosis. Tamsulosin have been found to be safeand effective in the treatment of BPH. Delivery of tamsulosin with ADStechnology has improved the efficacy and safety of the drug and has surpassedthe drawbacks of previous technologies.

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      MilicevicS, Bijelic R. Efficacy and safety of tamsulosin in the treatment of benignprostatic hyperplasia. Med Arch.2012;66(3):173-6.8.      RahardjoD, Soebadi DM, Sugandi S, et al.

Efficacyand safety of tamsulosin hydrochloride compared to doxazosin in the treatmentof Indonesian patients with lower urinary tract symptoms due to benignprostatic hyperplasia. Int J Urol.2006 Nov;13(11):1405-9.9.      MichelMC, Korstanje C, Krauwinkel W, Kuipers M. ThePharmacokinetic Profile of Tamsulosin Oral Controlled Absorption System(OCAS1).

European Urology Supplements. 2005;4:15–24.10.  Dataon file.