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 Table of Contents  
REVIEW ARTICLE
Year : 2012  |  Volume : 1  |  Issue : 2  |  Page : 53-60

Various treatment options for benign prostatic hyperplasia: A current update


Department of Pharmaceutical Analysis, B. R. Nahata College of Pharmacy, Mandsaur, India

Date of Web Publication13-Sep-2012

Correspondence Address:
Alankar Shrivastava
Department of Pharmaceutical Analysis, B. R. Nahata College of Pharmacy, Mhow-Neemuch Road, Mandsaur - 458 001
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2278-0521.100940

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  Abstract 

In benign prostatic hyperplasia (BPH), there will be a sudden impact on overall quality of life of the patient. This disease occurs normally at the age of 40 and above and is also associated with sexual dysfunction. Thus, there is a need to update our knowledge on the current medications for this disease. The presented review provides information on medications available for BPH. Phytotherapies with some improvements in BPH are also included. Relevant articles were identified through a search of the English language literature indexed on MEDLINE, PUBMED, ScienceDirect, and the proceedings of scientific meetings. The search terms were benign prostatic hyperplasia, BPH, medications for BPH, drugs for BPH, combination therapies for BPH, and phytotherapies for BPH. Medications including watchful waitings, β1 -adrenoreceptor blockers, 5β-reductase inhibitors, and combination therapies including tamsulosin-dutasteride, doxazosin-finasteride, terazosin-finasteride, tolterodine-tamsulosin, and rofecoxib-finasteride were found. Herbal remedies such as Cernilton, Saxifraga stolonifera, Zi-Shen Pill (ZSPE), Orbignya speciosa, Phellodendron amurense, Ganoderma lucidum, Serenoa repens, pumpkin extract, and Lepidium meyenii (Red Maca) showing some improvement on BPH are included. Other than these, discussions on transurethral resection of prostate (TURP) and minimally invasive therapies (MITs) are also included. Recent advancements in terms of newly synthesized molecules are also discussed. Specific β1 -adrenoreceptor blockers such as tamsulosin and alfuzosin will remain the preferred choice of urologists for symptom relief. Medications with combination therapies still need more investigation to establish their preference in the initial stage for fast symptom relief, reduced prostate growth, and obviously for reducing the need for BPH-related surgery. Due to lack of proper evidence, phytotherapies are not gaining much advantage. MITs and TURP are expensive and are rarely supported by healthcare systems.

Keywords: Alpha one adrenoreceptor blockers, Benign prostatic hyperplasia, 5 alpha one reductase inhibitters, therapies for BPH, treatment for BPH


How to cite this article:
Shrivastava A, Gupta VB. Various treatment options for benign prostatic hyperplasia: A current update. Saudi J Health Sci 2012;1:53-60

How to cite this URL:
Shrivastava A, Gupta VB. Various treatment options for benign prostatic hyperplasia: A current update. Saudi J Health Sci [serial online] 2012 [cited 2019 Apr 25];1:53-60. Available from: http://www.saudijhealthsci.org/text.asp?2012/1/2/53/100940


  Introduction Top


At the start of a new millennium, prostatic diseases continue to affect and account for a substantial number of lives lost in the USA. An estimated 1 in 11 men develop a malignant neoplasm of the prostate and approximately 37,000 men die each year from prostate cancer. [1],[2] In European Community countries, more than 35,000 annual deaths are forecast due to prostate cancer. [1],[3] Prostate cancer mortality results from metastases to the bone and lymph nodes, together with progression from androgen-dependent to androgen-independent disease. [1],[4] The high mortality associated with these tumors is due to the fact that more than 50% of newly diagnosed patients present with advanced, metastatic disease. [5],[6] Radical prostatectomy, androgen-ablation monotherapy, and radiotherapy are considered to be curative for localized disease, [7],[8],[9] but there is no effective treatment for metastatic prostate cancer, which increases patient survival.

In humans, the prostate lies immediately below the base of the bladder, surrounding the proximal portion of the urethra, and consists of canals and follicles lined with columnar epithelial cells and surrounded by a fibromuscular stroma consisting of connective tissue and smooth muscle. The prostate contributes to seminal fluid, where its secretions are important in optimizing conditions for fertilization by enhancing the viability of sperm in both male and female reproductive tracts. In all mammals, the prostatic secretions are stored in the acini and released into the urethra at ejaculation by contraction of the prostatic (stromal) smooth muscle. [10]

Benign prostatic hyperplasia (BPH) is a progressive disease that is commonly associated with bothersome lower urinary tract symptoms (LUTS) such as frequent urination, urgency, nocturia, decreased and intermittent force of stream, and the sensation of incomplete bladder emptying. The term BPH actually refers to a histologic condition, namely, the presence of stromal glandular hyperplasia within the prostate gland. [11]

BPH is a common and progressive clinical disease of aging men, which may be associated with enlargement of the prostate, bothersome LUTS, and bladder outlet obstruction (BOO). In the large-scale Multinational Survey of the Aging Male, 34% of men in the USA and 29% of European men aged 50-80 years reported moderate to severe LUTS. Sexual dysfunction is another common condition in aging men; the results of the Multinational Survey of the Aging Male also showed that LUTS is an independent risk factor for sexual dysfunction in aging men. Both of these age-dependent conditions have a measurable effect on the overall quality of life (QOL). Thus, LUTS and sexual dysfunction are common and important health concerns of men aged ≥50 years. [12]

At least 300,000 patients with LUTS are treated annually by physicians in Japan, and this figure is expected to increase in the coming years. [13]

BPH is defined as a disease that manifests as a lower urinary tract dysfunction due to benign hyperplasia of the prostate, usually associated with enlargement of the prostate and LUTS suggestive of lower urinary tract obstruction. [14] Although BPH is generally not a life-threatening condition, it can have a marked effect on a patient's QOL. [15] The cost of managing BPH is >$4 billion per year. [16]


  Diagnosis Top


When assessing men presenting with LUTS, all patients should undergo a physical examination including a careful digital rectal examination (DRE). DRE is unreliable in assessing the size of the prostate and has been found to underestimate; the larger the prostate, the more its size is underestimated. However, it is important to assess the prostate because some men are still found to have prostate cancer on the basis of DRE. In addition, urine analysis and serum prostate-specific antigen (PSA) assay are recommended as part of the diagnosis and as a marker to help differentiate men with BPH from those with prostate cancer, when in the opinion of the physician, the PSA is abnormal. PSA levels rise with age; so during assessment, to achieve a specificity of 70% and maintain a sensitivity between 65% and 70%, approximate age-specific figures for detecting men with prostate glands of >40 mL are: PSA levels of >1.6 ng/mL, >2.0 ng/mL, and >2.3 ng/mL for men with BPH aged 50-59 years, 60-69 years, and 70-79 years, respectively. [17]


  Treatment Options for BPH Top


The predominant treatment of BPH over the last 60 years has been based on an ablative surgical approach. Recently acquired knowledge on epidemiology and pathophysiology (of the prostate and bladder) as well as information acquired from endocrinologic and urodynamic investigations have made the urologists to reevaluate the conventional guidelines on which both diagnosis and treatment have been based. [18]

The increasing elderly population within society has caused healthcare givers and the pharmaceutical industry to spend more effort on age-related diseases such as BPH. The prostate is a male sex auxiliary gland situated just below the bladder and surrounding the urethra. Excessive growth of the prostate with age results in BPH, which causes obstruction of the bladder outlet and eventually leads to LUTS. [19] LUTS and BPH are progressive conditions in many men, and such progression is characterized by increased prostate size, worsening of symptoms, worry, QOL, deterioration of flow rate and urodynamics, and finally development of outcomes such as acute urinary retention (AUR) and surgical interventions. [20]

Over the last decade, multiple new treatment modalities for symptomatic BPH have arisen. New minimally invasive surgical therapies (MIST), new medications, and novel combinations of medical therapies have expanded the number of treatment options - still ranging from watchful waiting (WW) to open surgery. The range of treatment options is as broad as the BPH spectrum of symptoms. BPH is rarely lethal; most agree that management should safely improve the QOL. [21] The aim of therapy for BPH is to improve the QOL by providing symptom relief and increasing maximum flow rate, as well as reducing disease progression and the development of new morbidities. [22] Pharmacologic therapies recommended by the various guidelines for male LUTS are presented in [Table 1].
Table 1: Pharmacologic therapies recommended by the analyzed guidelines for male lower urinary tract symptoms[23]

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Watchful waiting

WW is a management strategy in which the patient is monitored by his physician without receiving any active intervention for LUTS. [23] WW refers to active monitoring of patients with BPH symptoms. Deciding on absolute indications for surgery is more straightforward than deciding on which men are the best candidates for WW. [21] In men in whom surgery is not indicated, WW has been shown to be safe over a 5-year period. In a study by Ball et al., 107 men with LUTS not requiring surgery were followed for 5 years. [21],[24] Only 10 patients underwent surgery during that time: 2 for acute retention and 8 for worsening symptoms. Of the 97 untreated patients, 31 reported subjective improvement, 50 were unchanged, and 16 felt worse.

Drug monotherapy

α1-Adrenoreceptor blockers

α1 -Adrenergic receptors (AR) mediate many of the physiological functions of the endogenous catecholamines, noradrenaline and adrenaline, such as smooth muscle contraction or cellular hypertrophy. Moreover, they are the molecular target for clinically used drugs for the treatment of, e.g. arterial hypertension or BPH. [25] The predominance of α1 -AR in the bladder neck or prostate (40 times the bladder concentration) helped focus the interest on α1 -adrenergic blocking agents in the treatment of symptomatic BPH. Presently, α1 -adrenoreceptor antagonists (α1 -blockers that include doxazosin, terazosin, tamsulosin, and alfuzosin) are common for treating BPH-related LUTS. They treat the dynamic component of BPH by blocking α1 -receptor-mediated sympathetic stimulation to relax the smooth muscle in the prostate. All these agents produce their effects on voiding within hours of administration, regardless of prostate size, without altering serum PSA or volume. [26]

The α1 -blockers reduce smooth muscle tone in the prostate and result in rapid improvements in urinary symptoms and flow. Currently available α1 -blockers include the nonselective α1 -blockers, terazosin, doxazosin, and alfuzosin, and the highly selective α1A -blocker, tamsulosin. These agents have comparable efficacy; the main difference among these agents relates to their tolerability profiles. [27]

Silodosin is a new agent with high selectivity for α1A -receptors, which predominate in the male bladder outflow tract relative to α1B -receptors. It has been demonstrated in vitro that silodosin's α1A -to-α1B binding ratio is extremely high (162:1), suggesting the potential to markedly reduce dynamic neurally mediated smooth muscle relaxation in the lower urinary tract while minimizing undesirable effects on blood pressure regulation. Both preclinical and clinical studies support the contention that silodosin has high uroselectivity and a positive cardiovascular safety profile, likely related to its selectivity for the α1A -AR subtype. Silodosin has a rapid onset of action and a sustained efficacy on LUTS due to BPH. [28]

Naftopidil is a α1D -selective blocker which has been recently reported to less likely induce ejaculatory disorders. Efficacies on LUTS of the two α-1 blockers, silodosin and naftopidil, are almost equivalent, with a small advantage of silodosin on voiding symptoms. The α1D -selective blocker, naftopidil, may possess superior property of preserving sexual function (especially for ejaculation), compared with the α1A -selective blocker, silodosin. [29]

The greatest safety concern associated with the use of these agents is the occurrence of vasodilatory symptoms such as dizziness and orthostatic hypotension resulting from inhibition of α1 -ARs in the systemic vasculature; this effect is minimized by use of agents that selectively antagonize the α1A -AR. [30]

α1 -AR antagonists are a reasonably well-tolerated drug class, but cardiovascular side effects can occur and these can lead to serious morbidity such as falls and fractures. Although the available data are not conclusive, it appears that patients with cardiovascular comorbidities and those concomitantly using antihypertensives and/or phosphodiesterase (PDE)-5 inhibitors might be particularly at risk. The safety of tamsulosin in such risk groups is better documented than that of other α1 -AR antagonists, and this should affect drug choice in patients with LUTS/BPH belonging to any of these risk groups. [31]

5α-reductase inhibitors

5α-reductase inhibitors (5ARIs) inhibit the conversion of testosterone to dihydrotestosterone (DHT), the primary androgen involved in both normal and abnormal prostate growth. There are currently two 5ARIs licensed for the management of BPH, finasteride and dutasteride. Dutasteride, the only 5ARI to inhibit both type 1 and type 2 5α-reductase, induces a more profound reduction of serum DHT in the range of 90-95% compared with 70-75% for finasteride. [32]

Finasteride was the first steroidal 5α-reductase inhibitor approved by US Food and Drug Administration (USFDA). In human, it decreases the prostatic DHT level by 70-90% and reduces the prostatic size. Dutasteride, another related analog, has been approved in 2002. Unlike finasteride, dutasteride is a competitive inhibitor of both 5α-reductase type I and type II isozymes, and reduces DHT levels >90% following 1 year of oral administration. Finasteride and dutasteride are the only two steroidal clinically used drugs that have evolved from nearly 40 years of research on steroids as 5α-reductase inhibitors, but many compounds have shown promising results, such as epristeride which is under clinical trial. [33]

Epristeride, a novel 5α-reductase inhibitor, is an interesting drug in the treatment of BPH. It belongs to the class of carboxysteroids. It has been shown to be an uncompetitive inhibitor against both testosterone and nicotinamide adenine dinucleotide phosphate-oxidase (NADPH). Its inhibitory action results from a preferential association to an enzyme binary complex containing NADP, and hence increases in testosterone concentration do not overcome its inhibition. It is a specific inhibitor of type 2 5α-reductase isoenzyme. It also attenuates the growth rate of some androgen-responsive prostate cancers. [34]

Both finasteride and dutasteride have also shown promise in preventing prostate cancer in men at risk for developing the disease. [35]

Side effects of 5ARI treatment mainly relate to sexual function, with a decreased libido in 6%, erectile dysfunction in 8%, and decreased ejaculation in 4% (compared with 3%, 4%, and 1%, respectively, for placebo). Current guidelines recommend that patients initiated on a 5ARI are reviewed [International Prostate Symptom Score (IPSS), uroflowmetry, and post-void residual volume assessment] after 12 weeks and at 6 months to determine response and then annually, provided there is no deterioration of symptoms. [32]

FK-143, 4-[3-[3-[bis (4-isobutylphenyl) methyl amino] benzoyl]-lH-indol-l-yl] butyric acid is a potent dual inhibitor of both human 5α-reductase isozymes. In vitro it inhibited human and rat prostatic 5α-reductase in a dose-dependent manner with an half maximal inhibitory concentration (IC 50 ) of 1.9 and 4.2 nM, respectively, in a non-competitive fashion, while in vivo it showed potent inhibitory activity against castrated young rat model. This compound can be a potential drug for the treatment of BPH. [36-38]

Combination therapies

In the study, Symptom Management after Reducing Therapy (SMART-1), 327 patients with BPH were treated with the combination of a α1-blocker (tamsulosin, 0.4 mg/d) plus a 5α-reductase inhibitor (dutasteride, 0.5 mg/d). One arm of the study received combination therapy for 36 weeks and the other arm received combination therapy for 24 weeks, after which placebo was substituted for tamsulosin for the remaining 12 weeks of the study. Overall, 91% of patients in the arm in which tamsulosin therapy was continued for 36 weeks felt the same or better at week 30 as they did at week 24, compared with 77% of patients who had tamsulosin withdrawn at week 24. In patients with moderate symptoms (IPSS < 20), the relative percentages were 93% and 84% and in patients with severe symptoms (IPSS ≥ 20), the percentages were 86% and 58%. These data suggest that tamsulosin can be withdrawn from a tamsulosin-dutasteride combination after 24 weeks of therapy, but that men with severe symptoms may need a longer period of combination treatment.

It has been suggested that this might reflect the possibility that short-term benefits from α1 -blockers, namely, the relaxation of the smooth muscle to relieve urinary tension, are negated by continued prostate growth, which itself can be halted and reversed by 5α-reductase inhibition.

Combination therapy with doxazosin and finasteride has been shown to provide fast symptom relief, reduced prostate growth, reduced risk of AUR and the need for BPH-related surgery. [39]

All the guidelines published after the Medical Therapy of Prostatic Symptoms (MTOPS) trial discussed the option to offer 5α-reductase inhibitors or combination therapy of 5α-reductase inhibitors and α-blockers as appropriate treatment for patients with LUTS with demonstrated prostatic enlargement. [23] By combining the beneficial effects of each class, the use of α1 -ARA/5ARI therapy has the potential to address concerns associated with monotherapy. [40] The 4-year Combination of Avodart and Tamsulosin (CombAT) data provide support for the long-term use of dutasteride and tamsulosin combination therapy in men with moderate-to-severe LUTS due to BPH and prostatic enlargement. [41]

One more study [42] concluded that the combination of terazosin and finasteride was no more effective than the a-blocker terazosin used alone. As described by the authors, a limitation of this study was the failure to include men with prostate volumes similar to those in other trials in which finasteride was shown to improve AUA symptom scores and peak urinary flow rates (UFRs) over placebo.

Cyclooxygenase-2 (COX-2) was found to be expressed in basal epithelial cells with 60% BPH and 94% peripheral zone of the prostate. There are multiple mechanisms through which COX-2 may play a role in prostate growth. The advantage of the combination therapy compared to finasteride alone is significant in a short-term interval (4 weeks). It can be hypothesized that the association of rofecoxib with finasteride induces a more rapid improvement in clinical results until the effect of finasteride becomes predominant. [43]

Kaplan et al.[44] conducted a randomized, double-blind, placebo-controlled trial and reported that the man who received a combination of tolterodine (antimuscarinic agent) and tamsulosin had better symptom control and QOL than men treated with either of medications or the placebo.

Desmopressin

Nocturia is one of the bothersome LUTS and also most difficult to eliminate in aging men. Nocturnal polyurea associated with circadian change of arginine vasopressine and atrial natriuretic peptide in the elderly has been suggested as the most dominant type of nocturia. Desmopressin is effective in treating nocturia to improve the patients' QOL, although a few adverse events such as hypernatremia might occur. [45]

Minimally invasive therapies

Minimally invasive therapies (MITs) usually involve heating the prostate gland by various means (electrical, microwave, laser). Insertion can be directly into the prostate via a needle or into the urethra via a catheter, probe, or endoscope.

  • Heating can be relatively low energy (e.g. microwave, laser, or electrical methods) when the effects are thought to be due to α-adrenoceptor blockade or damage and the net effect is akin to α-blockers.
  • It can be high energy, usually requiring anesthesia, when there is a more direct thermal coagulating or vaporizing effect on prostatic tissue with the intention of destroying or removing obstructing prostatic tissue, but with less bleeding than conventional surgery (e.g. potassium titanyl-phosphate (KTP) laser or holmium laser vaporization).


Long-term data and large-scale studies are rare; they are expensive and are rarely supported by healthcare systems. Re-treatment rates appear higher than conventional surgery, thereby reducing their cost-effectiveness. [46] Microwave treatment offers greater versatility than drug therapy, allowing patients with severe baseline symptoms and small prostates to be treated successfully. Medical management improves the symptoms to a more modest extent than does microwave treatment. [47]

According to different clinical studies, transurethral microwave thermotherapy (TUMT) proved to be an effective, safe, and durable therapy for the treatment of LUTS secondary to BPH. However, transurethral resection of prostate (TURP) still holds the steadier long-term results and is more effective to reduce obstruction as well as other LUTS. Other treatment options are transurethral needle ablation of the prostate (TUNA), high-intensity focused ultrasound (HIFU), interstitial laser thermotherapy (ILTT), water-induced thermotherapy (WITT), intraprostatic injection therapy with ethanol or hyperosmolar sodium chloride, and transurethral enzyme ablation of the prostate. [48]

Phytotherapy

Cernilton, prepared from the rye-grass pollen Secale cereale, is one of several phytotherapeutic agents available for the treatment of BPH. It is used by millions of men worldwide and is a registered pharmaceutical product throughout Western Europe, Japan, Korea, and Argentina. The Cernilton trials analyzed were limited by their short duration, limited number of enrollees, omissions in reported outcomes, and the unknown quality of the preparations used. The comparative trials had no confirmed active control. The available evidence suggests that Cernilton is well tolerated and modestly improves overall urological symptoms, including nocturia. [49]

Shao et al. studied herbal Saxifrage tablet prepared with extraction from the Chinese herb Saxifraga stolonifera Meerb. It mainly contains bergenin, quercitrin, quercetin, protocatechic acid, gallic acid, succinic acid, and mesoconic acid. Traditional Chinese medicine (TCM), herbal Saxifrage tablet (HST) is a potentially effective treatment in improving the QOL, prostate volumes, and maximum UFR for patients with BPH, though it is less effective in ameliorating the IPSS score when compared with terazosin hydrochloride (Hytrin). [50]

The Zi-Shen Pill (ZSPE) was originally reported in the Secret Record of the Chamber of Orchids, which was written by Li Gao (1279-1368 AD, Yuan Dynasty of China). It consisted of three kinds of medicinal plants: Anemarrhena asphodeloides Bge (Liliaceae, rhizome), Phellodendron amurense Rup. (Rutaceae, bark), and Cinnamomum cassia Presl (Camphoraceae, bark) in a ratio of 10:10:1 by weight. Investigation demonstrates that ZSPE can inhibit BPH in experimentally induced rats. In addition, treatment with ZSPE can enhance the expression of transforming growth factor beta-1 (TGF-ß 1 ) in prostate, which can induce cell apoptosis. [51]

Babassu is the common name of a Brazilian native palm tree called Orbignya speciosa, whose kernels are commonly used (eaten entirely or as a grounded powder) in parts of Brazil for the treatment of urinary disorders. O. speciosa nanoparticle (NanoOse) extract shows no toxicity in animals and acts incisively by promoting morphological cell changes, reducing cell proliferation, as well as inducing necrosis/apoptosis on BPH cells and tissues. [52]

Phellodendron or cork tree is a genus of deciduous trees in the family Rutaceae. The bark of the plant is used in TCM to clear heat, purge fire, and moisten dryness. Studies showed that Phellodendron amurense is able to inhibit prostatic contractility, suggesting that it may be useful in the treatment of urological disorders caused by prostatic urethral obstruction such as in the case of BPH. [53]

The extract of Ganoderma lucidum Fr. Krast (Ganodermataceae) showed the strongest 5α-reductase inhibitory activity. The treatment of the fruit body of G. lucidum or the extract prepared from it significantly inhibited the testosterone-induced growth of the ventral prostate in castrated rats. These results showed that G. lucidum might be a useful ingredient for the treatment of BPH. [54]

Sexual function is one of the aspects in the treatment of LUTS associated with BPH, which has gained increasing attention, and Permixon, a lipido-sterolic extract of Serenoa repens, has no negative impact on male sexual function. [55] The magnitude of the actual clinical benefit, the identification of the active compound, and the mechanism of action of S. repens products all have yet to be determined. [56]

Bach et al.[57] randomized 476 men 1:1 to placebo or a pumpkin extract. Two extracts have been tested against standard therapy: saw palmetto against tamsulosin and a combination product (saw palmetto/stinging nettle root) against finasteride. Both trials revealed similar outcomes regarding symptoms, Qmax, and postvoid residual (PVR) between the plant extract and standard therapy.

Freeze-dried aqueous extract of the red variety of Lepidium meyenii (Red Maca) on testosterone-induced BPH in adult rats of the Holtzman strain was investigated and compared with finasteride. Study suggested that finasteride was able to reduce both prostate and seminal vesicles weight, but Red Maca was specific to prostate weight. Authors suggested this may be an interesting alternative in the treatment of prostatic diseases. [58]

Transurethral resection of the prostate

In the case of TURP, short-term (mainly perioperative) complications include death, bleeding, clot retention, transurethral resection (TUR) syndrome (hyponatremia resulting in mental confusion, nausea, vomiting, and raised blood pressure), urinary tract infection, and inability to void, among which bleeding is the most common. Some of these complications (e.g. bleeding and TUR syndrome) may be serious and life-threatening. Short-term complications of TURP include death, bleeding, clot retention, TUR, urinary tract infection, and inability to void. Long-term complications of TURP include failure to void, retrograde ejaculation, impotence, partial or complete incontinence, and re-treatment. [27]

Miscellaneous

One study suggested the protective effect of carotene on the risk of BPH. The risk tended to decrease also with the intake of vitamin C and iron and tended to increase with the intake of sodium and zinc. Study further concluded that other antioxidants, including folic acid, lycopene, lutein/zeaxanthin, vitamins D and E, and retinol were not related to the risk for this disease. [59]

A series of phenoxyisoquinolines, N-phenoxyethyl-1-(2-nitrophenyl)-1, 2, 3, 4-trihydroisoquinolines, N-phenoxyethyl-1-benzyl-1, 2, 3, 4-trihydroisoquinolines, N-phenoxyethyl-1-(2-aminophenyl)-1, 2, 3, 4-trihydroisoquinolines, N-phenoxyethyl-1-(2-phenoxyethylaminophenyl)-1, 2, 3, 4-trihydroisoquinolines, have been synthesized and tested in isolated rat vas deferens a-adrenoreceptors. [60] Authors recommended α1 -blocker property in these compounds. Another report describes an improved synthesis of enantiomerically pure (S)-2-[4-(dimethylamino)phenyl]-2,3-dihydro-N-[2-hydroxy-3-[4-[2-(1-methylethoxy)-phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-isoindole-5-carboxamide (RWJ 69442), a potent and selective αla -AR antagonist, for the treatment of BPH. [61]

Botulinum neurotoxins (BoNTs) are well known for their ability to potently and selectively disrupt and modulate neurotransmission. BoNT is currently undergoing regulatory evaluation for urological disorders in the United States and the European Union and is not FDA approved for urologic use. Several case studies (level III evidence) have looked at specific BPH patient sub-populations to determine if BoNTA treatment was also effective. [62] Kuo (2005) [63] treated 10 patients who were either in frank urinary retention or carried a large PVR, who had already failed combination medical therapy (finasteride and α-blockers), and who had morbid medical conditions that prohibited them from having conventional TURP surgery. [62]

LASSBio-772, a 1,3-benzodioxole N-phenylpiperazine derivative, a novel potent and selective α1 A -/1 D -AR antagonist was selected after screening of functionalized N-phenylpiperazine derivatives in phenylephrine-induced vasoconstriction of rabbit aorta rings. The affinity of LASSBio-772 for α1 A - and α1 B -AR subtypes was determined through displacement of [ 3 H]prazosin binding. This compound presents pharmacological features with higher affinity for the α1 A /1 D than alpha 1 B -AR, being therefore putatively useful for the treatment of the LUTS, including the BPH in mammals. [64]

A case report suggests that carvedilol may be considered for the management of heart failure (HF) with systolic dysfunction in patients with concomitant BPH, thus eliminating the need for an α1-adrenergic blockers. [65]


  Conclusion Top


The condition known as BPH may be defined as a benign enlargement of the prostate gland resulting from a proliferation of both benign epithelial and stromal elements. It might also be defined clinically as a constellation of LUTS in aging men. [66] α-Adrenoreceptor antagonists are frequently used to treat patients with LUTS and benign prostatic enlargement because of their significant effect on storage and voiding symptoms, QOL, flow rate, and post-void residual urine volume. [67] Silodosin has been recently approved for marketing in India (23/06/2011). The α1 -blockers are the first line of treatment for symptomatic relief. More and more specific α1A -adrenoreceptor antagonists are under development for improving the prostate selectivity of α1 -blockers. Other medications, 5α-reductase inhibitors, combination therapies, and phytotherapies (in some respect), are also popular among the medical practitioners. The presented review is helpful for researchers involved in the development of new formulations in the field of BPH and to make the practitioners aware of the recent improvements.


  Acknowledgments Top


Authors acknowledge the support given by Indian Institute of Technology, Roorkee, for granting permission for literature survey which made this study possible. They also acknowledge the support given by Mr. Santosh Prajapati, Assistant Librarian (IIT, Roorkee) for assistance in the collection of articles. This review is part of research work for the grant of Doctoral in Philosophy in Pharmaceutical Science from Jodhpur National University.

 
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