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RESEARCH ARTICLE
Year : 2003  |  Volume : 20  |  Issue : 1  |  Page : 40-45
 

A randomized comparative study of tamsulosin vs placebo in the treatment of benign prostatic hyperplasia


Department of Urology, V.M. Medical College and Safdarjang Hospital, New Delhi, India

Correspondence Address:
N K Mohanty
C-II/124, Moti Bagh-1, New Delhi - 110 021
India
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Source of Support: None, Conflict of Interest: None


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   Abstract 

Objective: The rationale of using α1, blockers in the man­agement of benign prostatic hyperplasia (BPH) is based upon blocking the adrenergic receptors which regulate urinary outflow The prostate adenoma is predominantly stromal, having 40% of smooth muscle innervated by sym­pathetic adrenergic nerves stimulation of which accounts for 50% of outflow obstruction. Tamsulosin is an uroselective α1a/d blocker, controls both the lower urinary irritative and obstructive symptoms. The present study is a placebo controlled study evaluating the efficacy, safety and advantages of tamsulosin in the management of BPH.
Methods: A total number of 72 patients between 40-80 years of age were randomized to two groups. One group (38 patients) received tamsulosin (0.4 mg) daily and the other group (34 patients) received placebo for a period of two months with periodic follow up at 2nd , 4 th and 8 th week with IPSS (International Prostate Symptom Score) and uroflowmetry and ultrasonography at 8 th week.
Results: Our results show tamsulosin to be very effec­tive in the management of BPH cases, not requiring sur­gery, with few side effects and good patient compliance. The improvement was seen both in IPSS (total, obstruc­tive and irritative) and in urodynamic parameters. The differences were consistently superior with tamsulosin as compared to placebo in both the IPSS as well as uroflow­metry measurements.
Conclusion: Tamsulosin was found to be a very safe, well tolerated drug showing significant improvement in urinary outflow symptoms, reducing post void urine volume and decreasing IPSS with minimal tolerable adverse events.


Keywords: Medical management, tamsulosin, benign prostate.


How to cite this article:
Mohanty N K, Arora R P, Nayak RL, Malhotra V. A randomized comparative study of tamsulosin vs placebo in the treatment of benign prostatic hyperplasia. Indian J Urol 2003;20:40-5

How to cite this URL:
Mohanty N K, Arora R P, Nayak RL, Malhotra V. A randomized comparative study of tamsulosin vs placebo in the treatment of benign prostatic hyperplasia. Indian J Urol [serial online] 2003 [cited 2019 Aug 22];20:40-5. Available from: http://www.indianjurol.com/text.asp?2003/20/1/40/37123



   Introduction Top


Benign prostatic hyperplasia (BPH), a common disor­der among ageing males affects 1 out of 4 men over 50 years of age with an increasing prevalence worldwide due to more geriatric population. 70% of men at 60 years of age have prostatism but only 50% of them require surgi­cal intervention while the rest can be relieved of their symp­tomatology with medical therapy:

The bladder outlet obstruction caused by BPH has two components, static and dynamic. The static element is secondary to anatomical obstruction while the dynamic refers to the regulation of smooth muscle of prostatic ad­enoma and bladder neck mediated via alpha adreno­receptors.

Human prostate predominately expresses α1a (70%) and to less extent α1d adrenoreceptors. Recent studies show that α1a adrenoreceptors have 4 splice variants α1a1-4 of which α1a-1 (wild type-75%) and α1a-4 (20%) predominates in hu­man prostate. [1],[2] According to Schwinn α1d (66%) is present in human detrusor. While α1a is mainly responsible for blad­der outlet obstruction (BOO) symptoms like weak stream, hesitancy, intermittency and terminal dribbling, α1d is re­sponsible for bladder instability symptoms and is related to irritative symptoms such as nocturia, frequency and urgency.

Several studies suggest that the relationship between bladder instability and outlet obstruction is not so straight­forward as thought to be . [3],[4],[5],[6] There is a lack of correlation between relief of obstruction and filling symptoms. Re­sidual filling symptoms after TURP and improvement in filling symptoms with nonselective α1 adrenoreceptor an­tagonists indicate that detrusor instability is due to α1 adrenoreceptor Tamsulosin is an uroselective adreno­receptor antagonist (α1a and α1d) hence improves both void­ing and filling symptoms. [7],[8],[9],[10],[11]

Though both α1a and α1b are present on blood vessels (coronary, mammary, splanchnic) but with ageing the a l. adrenoreceptors density doubles than α1b hence highly uroselective drug like tamsulosin which have more affin­ity for α1a receptors, have fewer side effects on blood pres­sure in elder than young men. In BPH, α1a predominates 70%. [12],[13],[14] and out of which α1a-1 isoform are most abundant. [15]

Tamsulosin, a sulfamoylphenthylamine is a new uro­selective α1a/d adrenoreceptor subtype antagonist. [16],[17] Tamsulosin is approximately 99% protein bound and un­dergoes hepatic metabolism with most of the parent drug and metabolites, excreted in urine; up to 14% is excreted as unchanged drug.

The present study was aimed to study the safety and efficacy of tamsulosin (0.4mg) once daily dose as com­pared to placebo for two months in Indian patients with symptomatic BPH to justify the role of α1a/d blockers in medical management of BPH. Tamsulosin being the first α1a/d adrenoreceptor antagonist was selected in our study to give a comprehensive management in BPH taking care of both obstructive and irritative symptoms with minimum side effects.


   Patients and Methods Top


This was a placebo controlled randomized trial con­ducted in the Dept. of Urology of VM. Medical College and Safdarjang Hospital, New Delhi. Male patients in age group of 40-80 years with lower urinary tract obstruc­tive symptoms due to BPH were included for the study. Inclusion criteria were IPSS of 10 or more, maximum flow rate less than 12-13m1/sec and average flow rate less than 6ml/sec, a voided urinary volume = 150m1 and PSA < 4ng/ml. Patients with PSA between 4-10ng/ml or more had a 6 quadrant prostate biopsy negative for prostate ma­lignancy, supported with TRUS (Trans Rectal Ultrasound). Patient having neurogenic bladder, stricture urethra, blad­der neck stenosis, previous surgery on prostate, chronic renal failure and hepatic derangement were excluded from the study.

  • Patients qualifying for the study gave a written con­sent prior to their enrolment.
  • A detailed history, clinical examination of the study group patient was done followed by digital rectal ex­amination (DRE), ultrasound examination of abdo­men, total serum PSA, Uroflowrate, base line values of blood urea and creatinine, hemogram, hepatic func­tion parameters, urine for routine and culture sensi­tivity (c/s) was done. Blood pressure in sitting and standing position was recorded. Electrocardiogram was done at the beginning of the study.
  • Patients were then randomized to receive either pla­cebo or tamsulosin by computer generated randomiza­tion code. Patients received sustained release capsules of tamsulosin (0.4mg) or identical placebo capsules approximately 30 minutes before breakfast once daily for a period of 8 weeks.


Follow-up

  • Patients were then regularly followed up at the end of 2 nd 4 th 8 th , week to record the efficacy and safety variables based on IPSS score, uroflowrate (UFR), ultrasound with post void residual urine volume and any side effects, if observed. Blood pressure was regularly checked up in each follow up. A repeat blood profile of hemogram, liver function test (LFT), kidney function test (KFT), urine C/S was done at the end of the study.


Statistical Analysis

Students paired t-test was used to measure the changes in the uroflowmetry measures within each group. The non parametric Wilcoxons test was used to measure the changes in the IPSS symptom scores. Fishers test was used to measure the changes in the adverse events as com­pared to the baseline. The difference in these changes between the two groups was assessed by using the stu­dent's unpaired test.


   Results Top


A total number of 76 patients were initially enrolled, 38 in each group were randomized for this study but 4 from the placebo group after enrolment did not come for therapy. Only 72 patients started the therapy, 38 in tamsulosin group and 34 in placebo group, 2 patients from Tamsulosin group and 1 patient from placebo group were again lost to follow up midway during the study. Thus a total of 69 patients, 36 in tamsulosin group and 33 in placebo group completed the study and were evaluated.

The baseline demographic details showed no signifi­cant difference between the two groups. Average age was 61.3±8.5 years in tamsulosin group and 62.7±13.8 years in placebo group. Nineteen patients were hypertensive in tamsulosin group while 18 patients were hypertensive in placebo group. The mean residual urine volume was 107±44.3m1 in tamsulosin group and 102±42.8m1 in pla­cebo group. The duration of prostatism was 18±4 months in tamsulosin group and 16±5 months in placebo group.

IPSS (International Prostate Symptoms Scores) The baseline IPSS, both obstructive and irritative symp­toms, were not significantly different but there was a significant change 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 - 1] (p<0.001). The total IPSS from baseline 19.53 dropped to 6.9 in Tamsulosin group as compared to 18.52 and 12.7 in placebo group with mean change being 12.6 in former and 5.8 in the latter which was statistically significant (p<0.001). In the tamsulosin group there was significant improvement in both obstructive and irritative score as compared to the placebo group.

UFR (Urine Flow Rate)

There was again an appreciable improvement in all the measurement found with tamsulosin group with no im­provement in the placebo group [Table - 2]. The maximum flow rate improved from average 10.5m1/sec to 15.7m1/ sec with 53.6% change in the tamsulosin group but in the placebo group the change was found minimal i.e. from average 11.6m1/sec to 12.5ml/sec with 9.9% change only with a p-value of <0.001 which was significant. The per­centage of improvement in the flow rate was observed to be very significant in tamsulosin group (88.1%) as com­pared to placebo group (5.8%).

Ultrasound

Though the maximum voided volume did not show any significant change in either group, but a significant reduc­tion in volume of the post voided residual urine was ob­served in the tamsulosin group (-38.8m1) as compared to placebo group (-4.4ml).

BP (Blood Pressure)

There was no significant difference in the vital parameters between the two groups excepting diastolic/systolic blood pressure [Table - 3] which showed a fall in tamsulosin group, as compared to placebo group. The fall from aver­age 138mmHg to 128mmHg (Systolic) and 86mmHg to 81 mmHg (diastolic) was observed in the tamsulosin group while in the control group the fall in systolic BP was from 137mmHg to 132mmHg and diastolic pressure remaining unchanged. Though a 10mmHg fall in systolic and 5mmHg fall in diastolic pressure was observed in the tamsulosin group, this fall had no clinical significance on the patients.

Adverse events

The total number of adverse events which were reported during the study are listed in [Table - 4]. The common events reported during the study were dizziness, headache, fa­tigue but there was no difference in the number of events reported initially in both the groups. During follow up period the incidence of adverse events showed increase in both the groups. None of the patients in either of the group had to be withdrawn from the study due to any adverse event.

Quality of Life

Quality of life improved among tamsulosin group due to improved flow rate and decreased symptom score. Many of the patients from the placebo group after the study were given tamsulosin for management of their features of prostatism.

About 85% of patients taking Tamsulosin showed sig­nificant over all improvements as compared to 28% among placebo group.


   Discussion Top


For a comprehensive medical management of BPH, both BOO (Bladder Outlet Obstruction) and bladder filling/ir­ritative symptoms have to be taken care by drugs which will have both antagonist property on α1a, and α1d adreno­receptors. Of the many currently used a adrenoreceptor antagonists like prazocin, terazocin, doxazocin and alfuzo­cin, none have selectivity for α1a/d subtype excepting tamsulosin which is moderately uroselective for both α1a, and α1d[11],[16] .

Tamsulosin is a new prostate specific post-synaptic α1a, adrenoreceptor antagonist with greater affinity for α1a subtype which predominates in the prostate, bladder neck and urethra. In vitro the prostate selectivity ratio i.e. ratio of the binding affinity for α1a receptors to α1b receptors is 29 for tamsulosin but less than I for prazocin, terazocin or doxazocin thus making tamsulosin a much safer drug for having lower potential to cause hypotension.

Critical analysis of our result data very clearly illus­trates the beneficial effect of tamsulosin in medical man­agement of BPH. Being an uroselective antagonist it controls both irritative and obstructive symptoms of pros­tatism thereby giving a total therapeutic effect in reliev­ing symptoms in BPH.

The result of our study in comparable to many interna­tional studies conducted. Abrams et al [8] in their randomized placebo control clinical trial on 296 patients found tamsulosin to be well tolerated drug showing significant improvement in UFR and symptoms score. Lee et al [18] from Korea found tamsulosin to be a safe drug showing statistically significant improvement in urine flow and symptom score as compared to placebo. The Japanese study conducted by Kawabe et al [19] and the Chinese study conducted by Yan Jun et al [20] showed results similar to our result.

Our study showed a fast onset of action as early as 2 nd week and improvement was maintained through out the treatment period. The improvement was seen both in IPSS and urodynamic parameters. The differences were con­sistently superior with tamsulosin as compared to placebo. Tamsulosin was found to be very effective, safe and well tolerated drug with no significant differences with placebo as far as the vital signs and adverse events were concerned.


   Conclusions Top


Our study confirms that tamsulosin being an uroselective adrenoreceptor antagonist is a very effective, safe and well tolerated drug for medical management of symptomatic benign prostate hyperplasia.


   Acknowledgement Top


We are grateful to Mr. Mahendra Joshi for his help in preparing and typing manuscript.

 
   References Top

1.Schwinn DA, Michelotti GA. α1, adrenoreceptors in the lower uri­nary tract and vascular bed : potential role for the α1d subtype in filling symptoms and effects of ageing on vascular expression. BJU Int 2000, 85 suppl (2): 6-11.  Back to cited text no. 1    
2.Fitzpatrick JM. Facts and future lines of research in lower urinary tract symptoms in men and women : an overview of the role of α1 adrenoreceptors antagonist. BJU Int 2000: 85 suppl (2): 1-5.  Back to cited text no. 2    
3.Caine M. Alpha adrenergic blockers for the treatment of benign prostatic hyperplasia. Urol Clin North Am 1990: 17: 641-9.  Back to cited text no. 3    
4.Chapple CR. Smith D. The pathophysiological changes in the blad­der obstructed by BPH. Br J Urol 1994: 73: 117-23.  Back to cited text no. 4    
5.Steers WD. De GW. Effect of bladder outlet obstruction on mictu­rition reflex pathways in the rat. J Urol 1988; 140: 864-71.  Back to cited text no. 5    
6.Steers WD, Albo M. Tuttle JB. Calcium channel antagonists pre­vent urinary bladder growth and neuroplasticity following mechani­cal stress. Am J Physiol 1994; 266:R20.  Back to cited text no. 6    
7.Richardson C, Donatucci C, Page S, Wilson K. Schwinn D. Phar­macology of tamsulosin : saturation binding isotherms and compe­tition analysis using cloned α1 -adrenergic receptor subtypes. Comparison with alfuzosin, doxazosin, prazosin, terazosin and (+) YM617. Prostate 1997; 33: 55-9.  Back to cited text no. 7    
8.Abrams P, Schulman CC. Vaage S and the European Tamsulosin Study Group. Tamsulosin, a selective α1c, -adrenoreceptor antago­nist: a randomized, controlled trail in patients with benign prostatic `obstruction' (symptomatic BPH). Br J Urol 1995; 76; 325-36.  Back to cited text no. 8    
9.Chapple CR, Wyndaele JJ, Nordling J, Boeminghaus F, Ypma AFGVM, Abrams P on behalf of the European Tamsulosin Study Group. Tamsulosin, the first prostate selective α1a - adrenoreceptor antagonist : a meta-analysis of two randomized. placebo-control­led multi centre studies in patients with benign prostatic obstruc­tion (symptomatic BPH). Fur Urol 1996: 29: 155-67.  Back to cited text no. 9    
10.Lepor H. Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Urology 1998; 51: 892-­900.  Back to cited text no. 10    
11.Chapple CR. Pharmacotherapy for benign prostatic hyperplasia - the potential for - adrenoceptor subtype-specific blockade. Br J Urol 1998; 81: 34-47.  Back to cited text no. 11    
12.Lepor H, Tang R, Shapiro E. The alpha-adrenoreceptor subtype mediating tension of human prostatic smooth muscle. Prostate 1993: 22: 301-7.  Back to cited text no. 12    
13.Price DT, Schwinn DA, Lomasney JW, Allen LF, Caron MG, Lefkowitz RJ. Identification, quantification and localization of mRNA for three distinct α1-adrenergic receptor subtypes in human prostate. J Urol 1993; 150: 446-51.  Back to cited text no. 13    
14.Goetz AS, Lutz MW. Rimele TJ, Saussy Dl Jr. Characterization of α1 adrenoreceptor subtypes in human and canine prostate mem­branes. J Pharmacol Exp Ther 1994; 271: 1228-33.  Back to cited text no. 14    
15.Walden PD. Gerardi C. Lepor H. Localization and expression of the α1A-1 , α1B and α1D adrenoreceptor in hyperplastic and non­hyperploastic human prostate. J Urol 1999: 161: 635-40.  Back to cited text no. 15    
16.Andersson KE, Lepor H. Wyllie MG. Prostatic α1-adrenoreceptors and uroselectivity. Prostate 1997: 30: 202-15.  Back to cited text no. 16    
17.Noble AJ. Chess-Williams R, Couldwell C et al. The effects of tamsulosin. a high affinity antagonist at functional α1A, and α1D - adrenoreceptor subtypes. Br J Pharmacol 1997: 120: 23 1-8.  Back to cited text no. 17    
18.Lee E, Lee C. Clinical comparison of selective and non-selective α1A adrenoreceptor antagonists in benign prostatic hypetplasia. Stud­ies on tamsulosin in a fixed dose and terazocin in an escalating doses in Korean patients. Br J Urol 1997: 32; 210-213.  Back to cited text no. 18    
19.Kawabe K, Nijima T, Ueno T, Takimoto Y, Aso Y, Kato H. Use of an α1 blocker, YN617 in the treatment of benign prostatic hyper­trophy. J Urol 1990; 144: 908-911.  Back to cited text no. 19    
20.Yan-Jun N, Ying Lu G, Fang Liu G et al. Clinical comparison of selective and non selective α1A adrenoreceptor antagonists for blad­der outlet obstruction associated with benign prostatic hyperplasia. 3dr Asian Congress Urology (Seoul) 1996.  Back to cited text no. 20    



 
 
    Tables

  [Table - 1], [Table - 2], [Table - 3], [Table - 4]



 

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    Abstract
    Introduction
    Patients and Methods
    Results
    Discussion
    Conclusions
    Acknowledgement
    References
    Article Tables

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