Bph patients with cardiovascular comorbidities:Choice of alpha-blockers

Introduction

Benign prostate hyperplasia (BPH) occurs in over 50% of men over 60 years of age, most of whom have lower urinary tract symptoms (LUTS), and the incidence appears to be increasing thanks to the increased longevity of men; naturally, urology as a specialty is concerned with important geriatric issues.²Kojima Y, Kubota Y, Sasaki S, et al. Translational pharmacology in aging men with benign prostatic hyperplasia: molecular and clinical approaches to alpha1- adrenoceptors. Curr Aging Sci. 2009;2(3):223-39.   In effect, clinical BPH, hallmarked by the occurrence of moderate-to-severe LUTS, occurs in about one quarter of men in their 50s, one third of men in their 60s, and about half of all men 80 years or older.³McVary KT. BPH: epidemiology and comorbidities. Am J Manag Care. 2006;12(5 Suppl):S122-8.  

LUTS associated with BPH (LUTS/BPH) greatly affects the patient’s quality of life, and with rising age implications physicians should also be aware of other issues associated with advancing age, such as cardiovascular diseases (CVD), which may complicate the treatment of aging men with LUTS/BPH . Indeed, the presentation of one condition may correlate with the development of another, and men with bothersome LUTS/BPH often present with various other agerelated conditions, including heart disease, hypertension, diabetes, and the metabolic syndrome, which can complicate management decisions.⁴Zakaria L, Anastasiadis AG, Shabsigh R. Common conditions of the aging male: erectile dysfunction, benign prostatic hyperplasia, cardiovascular disease and depression. Int Urol Nephrol. 2001;33(2):283-92.  ^,5Roehrborn CG, Rosen RC. Medical therapy options for aging men with benign prostatic hyperplasia: focus on alfuzosin 10 mg once daily. Clin Interv Aging. 2008;3(3):511-24.   Therefore, management of LUTS/BPH requires careful selection of the most appropriate treatment for each patient, and individualization may be necessary in discrete instances.

BPH – an insidious risk factor for CVD

While the presence of CVD conditions are among the general risk factors for the development of BPH, cardiovascular morbidity is found to be two times more prevalent in patients starting drug treatment for BPH when compared to age-matched population controls.⁶Ghafar MA, Puchner PJ, Anastasiadis AG, et al. Does the prostatic vascular system contribute to the development of benign prostatic hyperplasia? Curr Urol Rep. 2002;3(4):292-6.  ^,7Souverein PC, Herings RM, De la Rosette JJ, et al. Evaluating adverse cardiovascular effects of drug treatment for benign prostatic hyperplasia (BPH): methodological considerations. J Clin Epidemiol. 2001;54(5):518-24.   In sequence, many hypotheses have been created to explain traditional clinical risk factors of CVD, including age, male gender, cigarette smoking, inheritance, high blood pressure (BP), obesity, elevated fasting plasma glucose, diabetes mellitus, dyslipidemia, decreased physical activity and metabolic syndrome, or non-traditional risk factors such as oxidative stress, inflammation, vascular calcification, malnutrition, homocysteine and genetic variation. In fact, the results of studies on urological aspects of the metabolic syndrome seem to indicate that BPH could be regarded as a new aspect of the metabolic syndrome, and that an increased insulin level is a common underlying aberration promoting BPH.⁸H ammarsten J, Peeker R. Urological aspects of the metabolic syndrome. Nat Rev Urol. 2011;8(9):483-94.   Together, the prostate synthesizes and stores large amounts of cholesterol, and prostate tissues may be particularly sensitive to perturbations in cholesterol metabolism – hypercholesterolemia, a major risk factor for CVD, is also a risk factor for BPH.⁹Freeman MR, Solomon KR. Cholesterol and benign prostate disease. Differentiation. 2011;82(4-5):244-52.  

Karatas et al speculated that by causing nocturia-induced sleep disturbances, BP variability, increased sympathetic activity, non-dipping BP variations; BPH may be an insidious risk factor for CVD.¹⁰Karatas OF, Bayrak O, Cimentepe E, et al. An insidious risk factor for cardiovascular disease: benign prostatic hyperplasia. Int J Cardiol. 2010;144(3):452.   Thus, BPH may be related to increase BP, coronary ischemic heart disease or other cardiovascular pathologic conditions. Essentially, this attention on BPH may produce a new approach to the diagnosis and treatment of CVD and BPH in aged.

Cardiovascular risk factors correlate with prostate size in men with bladder outlet obstruction

Sandfeldt and Hohn conducted a study to investigate whether the risk profile for CVD correlates with prostate size in elderly men seeking medical attention for LUTS, by assessing physiological, biochemical and personality traits.¹¹Sandfeldt L, Hahn RG. Cardiovascular risk factors correlate with prostate size in men with bladder outlet obstruction. BJU International 2003;92(1): 64-68.   A total of 52 men (mean age 68 years, range 52-85) with bladder outlet obstruction, as verified by urodynamic testing, had their prostate size measured by transrectal ultrasonography. Their blood and urine was also examined, and their personality and heart rate variability tested. The measured variables were assessed statistically with regard to whether the prostate volume was smaller (22 men) or larger (30 men) than 50 mL.

Results showed that patients with a large prostate (mean 104 mL) had a higher mean arterial pressure (105 vs. 95 mmHg, P < 0.01), and serum glucose (5.3 vs. 4.8 mmol/L, P < 0.01) and serum cortisol (423 vs. 362 nmol/L, P = 0.06) concentrations as compared to those with a small gland (mean 31 mL) (Figure 1).

The components of the heart rate variability indicated that men with a large prostate had increased sympathetic activity. Thus, the study showed that men with LUTS caused by a very large prostate have more risk factors for CVD than those with a smaller gland.

Medical management of BPH relating to CVD

Treatment options for BPH include watchful waiting, pharmacologic therapy, and surgery (BPH as the main cause of LUTS may lead to acute urinary retention and need for BPH-related surgery). For individual patients, treatment choice depends on disease severity, co-morbidity, patient preferences, and the comparative efficacy and adverse effects of the available therapies.¹²Montorsi F Moncada I. Safety and Tolerability of Treatment for BPH. European Urology Supplements 2006; 5(20): 1004-1012.  

Lifestyle management

It has been long appreciated that a healthy lifestyle plays a critical role in cardiovascular health, and it is now apparent that the same is true in the development of BPH and LUTS. Indeed, most of the literature supports a clinically significant, independent, and strong inverse relationship between exercise and the development of BPH/LUTS. Numerous mechanisms for this relationship have been proposed, including decreased sympathetic tone, avoidance of metabolic syndrome, and reduced oxidative damage to the prostate.¹³Sea J, Poon KS, McVary KT. Review of exercise and the risk of benign prostatic hyperplasia. Phys Sportsmed. 2009;37(4):75-83.   Therefore, body weight should be managed well as it can lead to both cardiovascular as well as prostatic diseases, and patients need to know that a heart-healthy lifestyle is also a prostate-healthy lifestyle.¹⁴Naz Z, Anjum S. Effect of anthropometric measurements and personal data parameters on benign prostatic hyperplasia and carcinoma prostate. J Ayub Med Coll Abbottabad. 2010;22(3):54-7.  

Pharmacotherapy: Choice of α-blockers

The trend in the management of symptomatic BPH favours pharmacotherapy as a first line option.¹⁵Forray C, Noble SA. Subtype selective alpha1-adrenoceptor antagonists for the treatment of benign prostatic hyperplasia. Expert Opin Investig Drugs. 1999;8(12):2073-2094.  

In sequence, pharmacological management is the most common therapeutic approach for patients with BPH, and α-adrenoceptor antagonists are the most commonly prescribed initial treatment of LUTS suggestive of BPH. Alpha1-blockers have a rapid onset of action, and, with their use, maximum flow rate is improved after first administration, and optimal symptom relief is usually reached within 2-3 months. Additionally, alpha1-blockers are effective regardless of prostate size, and provide a similar degree of symptom relief in patients with or without bladder outlet obstruction.¹⁶H öfner K. alpha(1)-Blocker therapy in the nineties: focus on the disease. Prostate Cancer Prostatic Dis. 1999;2(S4):S9-S15.  

Effectively, alpha 1-blocker treatment works irrespective of the severity of symptoms, degree of subvesical obstruction, or prostate size.¹⁷Oelke M, Höfner K, Berges RR, et al. [Drug therapy of benign prostatic hyperplasia syndrome with alpha 1-receptor blockers. Basic principles and clinical results]. Urologe A. 2002;41(5):425-41.   Indeed, placebo-controlled and actively controlled randomized controlled trials (RCTs) evidenced the efficacy of alpha1-blockers in augmenting urine flow, relieving symptoms, reducing bother, and improving quality of life in patients with LUTS. This improvement involves both filling (irritative) and voiding (obstructive) symptoms, occurs promptly, and is well-maintained over time. Also, the treatment benefit is independent of prostate size and baseline PSA.¹⁸De Mey C. Alpha1-blocker therapy for lower urinary tract symptoms suggestive of benign prostatic obstruction: what are the relevant differences in randomized controlled trials? Eur Urol. 2000;38 Suppl 1:25-39.   Nonetheless, these α-adrenoceptor antagonists have different adverse effect profiles, and there are several indications that alpha1-blockers differ qualitatively with regard to their cardiovascular safety and tolerability.

BPH/hypertension, or BPH and hypertension: Treatment protocol over time

Primarily, in treatment of patients with BPH and hypertension, urologists could choose either to use alpha blockers to treat both hypertension and BPH, or to treat BPH using alpha blockers that do not interact with antihypertensive therapy, thus following both treatments in a row.¹⁹Tewari A, Narayan P. Alpha-adrenergic blocking drugs in the management of benign prostatic hyperplasia: interactions with antihypertensive therapy. Urology. 1999;53(3 Suppl 3a):14-20; discussion 41-2.   The former approach was in fact adopted by some clinicians previously by recommending α1 blocker monotherapy for patients with both BPH and hypertension.²⁰White WB, Moon T. Treatment of benign prostatic hyperplasia in hypertensive men. J Clin Hypertens. 2005;7:212-217.  

Indeed, the practice was consistent with reports that α1- adrenergic blocker therapy targets the pathophysiology of clinical BPH and improves LUTS through reductions in α1- adrenoceptor-associated contractions of prostatic smooth muscle.²⁰White WB, Moon T. Treatment of benign prostatic hyperplasia in hypertensive men. J Clin Hypertens. 2005;7:212-217.   However, there were rising concerns over the safety profile of these agents in relation to co-morbid BPH and hypertension – often, anti-hypertensive α1 blocker doses that are initially efficacious lose their BP-reducing effect, and this requires doses to be increased to maintain efficacy [for e.g. doxazosin must be titrated to relatively high doses (≥8 mg daily) to achieve symptomatic relief of LUTS], an outlook that may be poorly tolerated besides the intrinsic adverse effect profile of the drugs (doxazosin produces hypotension in patients with LUTS).²⁰White WB, Moon T. Treatment of benign prostatic hyperplasia in hypertensive men. J Clin Hypertens. 2005;7:212-217.  

Further, the results of ALLHAT (Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial) have challenged the appropriateness of using α1 blockers as first- or even second-line treatment for hypertension.²⁰White WB, Moon T. Treatment of benign prostatic hyperplasia in hypertensive men. J Clin Hypertens. 2005;7:212-217.   In sequence, later the American Urologic Association and Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High BP guidelines recommended independent treatment with the most appropriate pharmacologic agents for each condition; and, accordingly, when treating patients with BPH, clinicians should be aware of the potential impacts that α1 blockers may have on BP, and potential adverse events in patients who are normotensive as well as in patients with treated hypertension.2²⁰White WB, Moon T. Treatment of benign prostatic hyperplasia in hypertensive men. J Clin Hypertens. 2005;7:212-217.  

The rise of Tamsulosin – a safer alternative in BPH with CVD/hypertension

Essentially, the older α-adrenoceptor antagonists, terazosin and doxazosin, were initially approved for the treatment of hypertension and are associated with higher rates of dizziness, syncope and hypotension; and, additionally, the association of numerous adverse effects with said non-selective and short acting alpha-1 blockers (like phenoxybenzamine, prazosin and alfuzosin) has led to the development of long acting alpha-1 adrenoceptor blockers, e.g . Tamulosin, that being uro-selective significantly reduce the incidence of cardiovascular side effects, and increase patient compliance.²¹Kumar VL, Dewan S. Alpha adrenergic blockers in the treatment of benign hyperplasia of the prostate. Int Urol Nephrol. 2000;32(1):67-71.   Also, the older α-adrenoceptor antagonists are involved in more interactions, and have a greater number of precautions concerning their usage with other cardiovascular medications; for instance, combination of terazosin and other antihypertensive agents has been shown to cause clinically significant hypotension.²⁰White WB, Moon T. Treatment of benign prostatic hyperplasia in hypertensive men. J Clin Hypertens. 2005;7:212-217.  

Indeed, the approval by the Food and Drug Administration of Tamsulosin, an alpha1a-specific antagonist, offers physicians the opportunity to prescribe a selective alpha1-blocker for the treatment of BPH. Tamsulosin possesses potent and selective alpha a-antagonism, and was shown to selectively reduce the intra-urethral pressure in the prostatic segment of the urethra in-vivo.²²Takenaka T, Fujikura T, Honda K, et al. [Discovery and development of Tamsulosin hydrochloride, a new alpha 1-adrenoceptor antagonist]. Yakugaku Zasshi. 1995;115(10):773-89.  

Of note, amongst the newer α-adrenoceptor antagonists, Tamsulosin has a lower rate of dizziness than alfuzosin, does not reduce elevated BP in comparison with placebo, and has little effect on orthostatic BP control.²³Santillo VM, Lowe FC. Treatment of Benign Prostatic Hyperplasia in Patients with Cardiovascular Disease. Drugs & Aging 2006;23(10):795- 805(11).   Moreover, the drug, with its high affinity for alpha1a adrenergic receptor and alpha1d adrenergic receptor subtypes but not for alpha1b adrenergic receptor, shows efficacy similar to the non-subtype selective agents terazosin and doxazosin, and is associated with fewer cardiovascular side effects; note: terazosin and doxazosin have been shown to have significant cardiovascular side effects, such as asthenia/fatigue, postural hypotension, and dizziness when used to treat BPH patients.²⁴Roehrborn CG, Schwinn DA. Alpha1-adrenergic receptors and their inhibitors in lower urinary tract symptoms and benign prostatic hyperplasia. J Urol. 2004;171(3):1029-35.  

Effectively, Tamsulosin offers a pharmacologic means to better target alpha-blockade specifically to the prostatic smooth muscle and spare the vascular smooth muscle. In sequence, use of this agent has resulted in a lower incidence of clinically relevant effects on BP or heart rate and minimal cardiovascular adverse effects.²⁵Kaplan SA. alpha-Blocker Therapy: Current Update. Rev Urol. 2005;7 Suppl 8:S34-42.  

Tamsulosin with ADS technology – an innovative advantage

Although Tamsulosin was identified as a relatively safer drug in patients with BPH and hypertension, it could still lead to instances of orthostatic hypotension in individual cases. In a phase 3a study, Chapple et al noted significant mean change in supine systolic (SBP) and diastolic BP (DBP) from baseline to week 12 of treatment with Tamsulosin modified release (MR) 0.4 mg (Figure 2).²⁶Chapple CR, Al-Shukri SH, Gattegn B, et al. Tamsulosin Oral Controlled Absorption System (OCAS) in Patientswith Lower UrinaryTract Symptoms Suggestive of Benign Prostatic Hyperplasia (LUTS/BPH): Efficacy and Tolerability in a Placebo and Active Comparator Controlled Phase 3a Study. European Urology Supplements 2005;4:33-44.  

The concern paved way for continued progress and innovation in drug pharmacology, if found feasible, and drug delivery systems to have the best drug system aimed for improved outcomes; in fact, the mode of drug delivery presented a target for refinement. One such technique is the Advanced Delivery System (ADS technology) — Tamsulosin with ADS technology is a new improved formulation/delivery system of Tamsulosin. Tamsulosin ADS shows improved pharmacokinetics compared with the standard MR capsules that may translate in an improvement of the efficacy/safety ratio during the treatment of LUTS/BPH.

Unlike conventional Tamsulosin formulations that depend on the presence of water in the gastrointestinal tract (GIT) to release the active ingredient, the innovative ADS technology ensures continuous and consistent Tamsulosin release throughout the entire length of the GIT including the colon where water is poorly available. This results in a more constant exposure to Tamsulosin over 24 hours with a smaller peak-to-trough fluctuation (PTF) than the conventional formulations; and, also reduces/eliminates the dependency on food. In fact, the innovation appears superior to conventional MR formulation of tamsulosin that has a variable absorption profile dependent on when it is taken in relation to food and gastrointestinal transit time. Furthermore, as not all patients comply with the dosing recommendations in the patient leaflet, the independence of food intake might considerably improve the tolerability of Tamsulosin.²⁷Speakman M. Efficacy and safety of tamsulosin OCAS. BJU international 2006;98(Suppl 2): 13-17.   Consequently, the ADS advantage equates with less adverse effects on physiologic parameters.

Indeed, Tamsulosin ADS may be of greatest benefit to men with cardiovascular co-morbidities taking antihypertensive medications that might predispose them to symptomatic hypotensive episodes. Tamsulosin with ADS advantage provides a safe once daily treatment of LUTS/BPH with reduced risk of orthostatic hypotension.

Furthermore, in real life practice where also the very elderly and patients with cardiovascular co-morbidity and/or co-medication who are more vulnerable for orthostatic hypotension in particular during situations which further stress the cardiovascular system are treated, the difference may even be larger.²⁸Michel MC, Korstanje C, Krauwinkel W, et al. Cardiovascular Safety of the Oral Controlled Absorption System(OCAS) Formulation ofTamsulosin Compared to theModified Release (MR) Formulation. European Urology Supplements 2005;4:53-60.   Together, the constant 24-hour plasma concentrations might also provide better control of bothersome night-time symptoms of LUTS/BPH, such as nocturia (one of the most bothersome storage symptoms of BPH), thus, providing better sleep and enhanced quality of life.²⁷peakman M. Efficacy and safety of tamsulosin OCAS. BJU international 2006;98(Suppl 2): 13-17.  ^,29Djavana B, Milania S, Davies J. The Impact ofTamsulosin Oral Controlled Absorption System(OCAS) on Nocturia and the Quality of Sleep:Preliminary Results of a Pilot Study. European Urology Supplements 2005;4:61-68.  

Combination therapy

Alpha1-selective adrenergic receptor antagonists (e.g., Tamsulosin) remain the cornerstone of therapy for LUTS/BPH; and, additionally, 5-alpha-reductase inhibitors (e.g., Dutasteride) have been associated with improvements in LUTS/BPH in men with larger prostates, especially when used in combination with alpha1- adrenergic receptor antagonists. Yet, when selecting an appropriate course of therapy, side effects and any impact they may have on existing co-morbid conditions must be considered.³McVary KT. BPH: epidemiology and comorbidities. Am J Manag Care. 2006;12(5 Suppl):S122-8.  

It has been observed that combination therapy of α-blocker and 5α-reductase inhibitor results in great benefit for symptom improvement as well as risk reduction of disease progression and complications; and, in fact, most patients benefit from combination therapy of α-blocker and 5α-reductase inhibitor.³⁰Djavan B, Margreiter M, Dianat SS. An algorithm for medical management in male lower urinary tract symptoms. Curr Opin Urol. 2011;21(1):5-12.   While alpha-blockers relieve the dynamic component of obstruction, the 5-alpha-reductase inhibitors relieve the mechanical component of obstruction. More uroselective alpha-blockers may reduce the risk of cardiovascular side effects.³¹Narayan P, Tewari A. Overview of alpha-blocker therapy for benign prostatic hyperplasia. Urology. 1998;51(4A Suppl):38-45.  

The Tamsulosin/Dutasteride combination provides an ideal choice for treating LUTS associated with BPH. In keeping with these positive outcomes, in 2010 USFDA approved the fixed dose combination of Tamsulosin 0.4 mg and Dutasteride 0.5 mg. With its unique ADS advantage, the combination drug results in simultaneous release of both drugs, thus, providing better efficacy and compliance, and quality of life.

Conclusion

BPH, with accompanying LUTS, is a common age-related condition associated with a variety of co-morbidities.³²Colon I, Payne RE. Benign prostatic hyperplasia and lower urinary tract symptoms in African Americans and Latinos: treatment in the context of common comorbidities. Am J Med. 2008;121(8 Suppl 2):S18-26.   Drug treatment is the mainstay of treatment for symptomatic BPH, and is directed at relaxing prostatic smooth muscle, reducing prostate volume, or a combination of these effects. Herein, the most commonly used drugs for this indication are alpha1-adrenergic receptor antagonists, which relax prostatic smooth muscle, and 5-alpha-reductase inhibitors, which reduce prostatic androgen levels and consequently prostate size.³³O’Leary MP. Treatment and pharmacologic management of BPH in the context of common comorbidities. Am J Manag Care. 2006;12(5 Suppl):S129-40.   In effect, as alpha 1-blockers can effectively relieve symptoms and improve urinary flow, they are the treatment of first choice in patients with symptomatic BPH without or with a minor degree of subvesical obstruction.

Together, treatment for BPH must take patients’ comorbid conditions into consideration so that LUTS may be effectively relieved, with the smallest risk of exacerbating any concomitant conditions. Antihypertensive alpha1- blockers (terazosin and doxazosin in particular) are more likely to cause dizziness and other cardiovascular untoward effects, eventually leading to premature treatment discontinuation. In contrast, Tamsulosin is better tolerated, and may be a useful drug for the treatment of micturition disorders, with few cardiovascular side effects.¹⁸De Mey C. Alpha1-blocker therapy for lower urinary tract symptoms suggestive of benign prostatic obstruction: what are the relevant differences in randomized controlled trials? Eur Urol. 2000;38 Suppl 1:25-39.  ^,34Sudoh K, Tanaka H, Inagaki O, Asano M, Takenaka T. Effect of Tamsulosin, a novel alpha 1-adrenoceptor antagonist, on urethral pressure profile in anaesthetized dogs. J Auton Pharmacol. 1996;16(3):147-54.   Further, in practice, Tamsulosin with ADS advantage would offer a favorable option in treatment of patients with BPH with cardiovascular risk owing to its favourable efficacy/tolerability ratio and said superiority over Tamsulosin MR. Finally, the management of BPH should be individualized to patients’ circumstances and personal choices.³⁵Speakman MJ. Who should be treated and how? Evidence-based medicine in symptomatic BPH. Eur Urol. 1999;36 Suppl 3:40-51.  

References

1. Lunenfeld B. The ageing male: demographics and challenges. World J Urol. 2002;20(1):11-6.
2. Kojima Y, Kubota Y, Sasaki S, et al. Translational pharmacology in aging men with benign prostatic hyperplasia: molecular and clinical approaches to alpha1- adrenoceptors. Curr Aging Sci. 2009;2(3):223-39.
3. McVary KT. BPH: epidemiology and comorbidities. Am J Manag Care. 2006;12(5 Suppl):S122-8.
4. Zakaria L, Anastasiadis AG, Shabsigh R. Common conditions of the aging male: erectile dysfunction, benign prostatic hyperplasia, cardiovascular disease and depression. Int Urol Nephrol. 2001;33(2):283-92.
5. Roehrborn CG, Rosen RC. Medical therapy options for aging men with benign prostatic hyperplasia: focus on alfuzosin 10 mg once daily. Clin Interv Aging. 2008;3(3):511-24.
6. Ghafar MA, Puchner PJ, Anastasiadis AG, et al. Does the prostatic vascular system contribute to the development of benign prostatic hyperplasia? Curr Urol Rep. 2002;3(4):292-6.
7. Souverein PC, Herings RM, De la Rosette JJ, et al. Evaluating adverse cardiovascular effects of drug treatment for benign prostatic hyperplasia (BPH): methodological considerations. J Clin Epidemiol. 2001;54(5):518-24.
8. H ammarsten J, Peeker R. Urological aspects of the metabolic syndrome. Nat Rev Urol. 2011;8(9):483-94.
9. Freeman MR, Solomon KR. Cholesterol and benign prostate disease. Differentiation. 2011;82(4-5):244-52.
10. Karatas OF, Bayrak O, Cimentepe E, et al. An insidious risk factor for cardiovascular disease: benign prostatic hyperplasia. Int J Cardiol. 2010;144(3):452.
11. Sandfeldt L, Hahn RG. Cardiovascular risk factors correlate with prostate size in men with bladder outlet obstruction. BJU International 2003;92(1): 64-68.
12. Montorsi F Moncada I. Safety and Tolerability of Treatment for BPH. European Urology Supplements 2006; 5(20): 1004-1012.
13. Sea J, Poon KS, McVary KT. Review of exercise and the risk of benign prostatic hyperplasia. Phys Sportsmed. 2009;37(4):75-83.
14. Naz Z, Anjum S. Effect of anthropometric measurements and personal data parameters on benign prostatic hyperplasia and carcinoma prostate. J Ayub Med Coll Abbottabad. 2010;22(3):54-7.
15. Forray C, Noble SA. Subtype selective alpha1-adrenoceptor antagonists for the treatment of benign prostatic hyperplasia. Expert Opin Investig Drugs. 1999;8(12):2073-2094.
16. H öfner K. alpha(1)-Blocker therapy in the nineties: focus on the disease. Prostate Cancer Prostatic Dis. 1999;2(S4):S9-S15.
17. Oelke M, Höfner K, Berges RR, et al. [Drug therapy of benign prostatic hyperplasia syndrome with alpha 1-receptor blockers. Basic principles and clinical results]. Urologe A. 2002;41(5):425-41.
18. De Mey C. Alpha1-blocker therapy for lower urinary tract symptoms suggestive of benign prostatic obstruction: what are the relevant differences in randomized controlled trials? Eur Urol. 2000;38 Suppl 1:25-39.
19. Tewari A, Narayan P. Alpha-adrenergic blocking drugs in the management of benign prostatic hyperplasia: interactions with antihypertensive therapy. Urology. 1999;53(3 Suppl 3a):14-20; discussion 41-2.
20. White WB, Moon T. Treatment of benign prostatic hyperplasia in hypertensive men. J Clin Hypertens. 2005;7:212-217.
21. Kumar VL, Dewan S. Alpha adrenergic blockers in the treatment of benign hyperplasia of the prostate. Int Urol Nephrol. 2000;32(1):67-71.
22. Takenaka T, Fujikura T, Honda K, et al. [Discovery and development of Tamsulosin hydrochloride, a new alpha 1-adrenoceptor antagonist]. Yakugaku Zasshi. 1995;115(10):773-89.
23. Santillo VM, Lowe FC. Treatment of Benign Prostatic Hyperplasia in Patients with Cardiovascular Disease. Drugs & Aging 2006;23(10):795- 805(11).
24. Roehrborn CG, Schwinn DA. Alpha1-adrenergic receptors and their inhibitors in lower urinary tract symptoms and benign prostatic hyperplasia. J Urol. 2004;171(3):1029-35.
25. Kaplan SA. alpha-Blocker Therapy: Current Update. Rev Urol. 2005;7 Suppl 8:S34-42.
26. Chapple CR, Al-Shukri SH, Gattegn B, et al. Tamsulosin Oral Controlled Absorption System (OCAS) in Patientswith Lower UrinaryTract Symptoms Suggestive of Benign Prostatic Hyperplasia (LUTS/BPH): Efficacy and Tolerability in a Placebo and Active Comparator Controlled Phase 3a Study. European Urology Supplements 2005;4:33-44.
27. Speakman M. Efficacy and safety of tamsulosin OCAS. BJU international 2006;98(Suppl 2): 13-17.
28. Michel MC, Korstanje C, Krauwinkel W, et al. Cardiovascular Safety of the Oral Controlled Absorption System(OCAS) Formulation ofTamsulosin Compared to theModified Release (MR) Formulation. European Urology Supplements 2005;4:53-60.
29. Djavana B, Milania S, Davies J. The Impact ofTamsulosin Oral Controlled Absorption System(OCAS) on Nocturia and the Quality of Sleep:Preliminary Results of a Pilot Study. European Urology Supplements 2005;4:61-68.
30. Djavan B, Margreiter M, Dianat SS. An algorithm for medical management in male lower urinary tract symptoms. Curr Opin Urol. 2011;21(1):5-12.
31. Narayan P, Tewari A. Overview of alpha-blocker therapy for benign prostatic hyperplasia. Urology. 1998;51(4A Suppl):38-45.
32. Colon I, Payne RE. Benign prostatic hyperplasia and lower urinary tract symptoms in African Americans and Latinos: treatment in the context of common comorbidities. Am J Med. 2008;121(8 Suppl 2):S18-26.
33. O’Leary MP. Treatment and pharmacologic management of BPH in the context of common comorbidities. Am J Manag Care. 2006;12(5 Suppl):S129-40.
34. Sudoh K, Tanaka H, Inagaki O, Asano M, Takenaka T. Effect of Tamsulosin, a novel alpha 1-adrenoceptor antagonist, on urethral pressure profile in anaesthetized dogs. J Auton Pharmacol. 1996;16(3):147-54.
35. Speakman MJ. Who should be treated and how? Evidence-based medicine in symptomatic BPH. Eur Urol. 1999;36 Suppl 3:40-51.