Double-Blind Placebo-Controlled Study of PR-2000 in the Management of Benign Prostatic Hyperplasia

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1 [The Antiseptic (2002): (99), 1, 8-11] Double-Blind Placebo-Controlled Study of PR-2000 in the Management of Benign Prostatic Hyperplasia Garg, S.K., M.S., D.N.B. (Surgery), M.Ch., D.N.B. (Urology) Bombay Urologist and Transplant Surgeon, Garg Urological Clinic, B-51, Brij Enclave Colony, Varanasi , Uttar Pradesh, India and Kala Suhas Kulkarni*, M.D., Medical Advisor, R&D Center, The Himalaya Drug Company, Makali, Bangalore, India [*Correspondence author] ABSTRACT A double-blind placebo controlled study was planned in 40 patients with symptomatic benign prostatic hyperplasia (BPH). The patients were in the age group. The patients were subjected to pelvic ultrasonography to measure at the prostatic weight. The symptoms were evaluated according to the American Urological Association (AUA) symptom score. The PSA value was also estimated. They were dispensed a polyherbal preparation known as PR-2000 at a dose of 2 tablets, twice a day for 6 months. After 6 months, when these patients were evaluated, it was found that the AUA symptom score was reduced significantly in 90% of the patients in the PR-2000 group, with a moderate reduction in 10%, while in the placebo group, there was a significant reduction in 6.7% and a moderate reduction in 6.7%, and no effect in 86.4%. In the PR-2000 group, the prostatic weight reduced in 80% and moderately reduced in 20%, while in placebo group, it was significantly reduced in 6.7% and moderately reduced in 6.7%, no effect in 86.4%. The post-void residual volume was reduced in 50%, moderately reduced in 35% and hardly reduced in 15% in the PR-2000 group, while in the placebo group, only 10% showed reduction and 90% were not effected. The PSA values also showed reduction on an average of 0.31 mg/ml. Thus, PR-2000 provided a significant medical therapy in patients with BPH. Key words: PR-2000, ultrasonography, AUA symptom score, PSA value INTRODUCTION The prostate gland is an accessory male sex organ situated between the base of bladder and the external striated urethral sphincter. A benign enlargement of the prostate associated with voiding dysfunction has been recognized for centuries. Eight percent of men of years of age or older have benign prostatic hyperplasia (BPH). Benign prostatic hyperplasia is not necessarily a progressive process, and not all patients required immediate surgery. The causative factors of BPH in man have been studied and several theories have been putforth. In general, the 2 most important factors are aging and the presence of functional testes. These factors are the key to development of BPH, although they appear to be nonspecific 1.

2 The prostate consists of a network of glandular elements embedded in stroma, with androgen being the most important factor for prostatic growth. Free plasma testosterone enters prostatic cells, where at least 90% is converted into dihydrotestosterone (DHT) by 5α-reductase. The process of androgen conversion to DHT is irreversible and is followed by DHT binding to receptors on the nucleus. The breakthrough discovery that DHT is the active factor in the prostate is the rationale for the use of 5α-reductase inhibitors in the treatment of BPH, particularly the static component of the disease caused by the prostate mechanically obstructing the bladder neck. The paradox of continuing prostatic growth with declining androgen levels suggests that other factors, secreted by the testis, can stimulate prostate growth or perhaps sensitize prostatic cells to androgen 2. Estrogen androgen synergism as well as the role of other steroidal hormones have also been suggested as mechanisms for BPH. The final treatment for symptomatic BPH may be surgery. But in few patients, who are very high-risk cases, the desired line of treatment is medical therapy. The medical treatment includes blockade of α-adrenergic receptors by Phenoxybenzamine, Prazocin, Terazocin, Doxazocin etc. and hormonal manipulation by androgen deprivation, i.e. Estrogen and α 1 -reductase inhibiter like finastride. Mainly α 1 -antagonist and finastride were found effective in symptomatic treatment of BPH, but these drugs have a number of side effects also. So naturally occurring plant extracts have come into the forefront of research to treat BPH. With aging, there is a gradual accumulation of prostate mass as a result of continuing glandular stromal interactions, which may be enhanced by various growth factors provided systemically via the circulation or locally via the urethra. The effect of androgen is mediated through the stromal cells and results in proliferation. The impact of stromal cells on epithelial growth and function is mediated through production of specific growth factors 3-5. Another theory suggests a disturbance of the balance between the rate of prostate cell death and the rate of replication caused by hormonal factors, growth factors and oncogenes. PR-2000 also has 5α-reductase activity and has been documented in experimental studies to reduce the prostatic weight in experimentally-induced prostatic hyperplasia 6. Clinical studies of PR-2000 in patients with prostate hyperplasia have shown results that after PR-2000 treatment, there was a reduction in the American Urological Association (AUA) symptom score, prostatic weight and PSA values 7. In this double-blind study, the PR-2000 drug has been compared with placebo and PR-2000 has been found effective in symptomatic BPH. PR-2000 is a polyherbal formulation manufactured by The Himalaya Drug Company, Bangalore, India. MATERIALS AND METHODS A double-blind placebo controlled trial was carried out at Garg Urological Clinic and Heritage Hospital, Varanasi, India. Forty patients, diagnosed with symptomatic BPH, were

3 included in study after a thorough physical examination and complete urological history. The patients were between years of age. The efficacy parameters were subjective evaluation as per AUA symptom scoring index and objective evidence in the form of changes in prostate volume measured by ultrasonography and post-void residual urine. Assessment and follow-up was done every month. These included history with AUA scoring and digital rectal examination (DRE). Ultrasonography of the bladder (USG) was done to measure the prostate weight and post-void residual urine was measured initially and after 6 months. The serum PSA was also done initially and after 6 months. PR-2000 was administered at a dose of 2 tablets, thrice times a day, in 20 patients with a similarly looking placebo in another 20 patients. Both drug treatments continued for six months. RESULTS All patients of both the drug and placebo groups were followed every month and the final analyses were done after 6 months. The criteria of improvement was as follows: Significant improvement in AUA score 7. Average improvement in AUA score = Poor improvement in AUA score >14. Results showed that in the PR-2000 group, 10 patients (50%) showed significant improvement, while 4 (20%) showed average improvement and 6 (30%) showed poor improvement. In the placebo group, 1 patient (5%) each showed significant and average improvement and 18 patients (90%) displayed poor improvement (Table 1). Improvement with respect to severity of symptoms indicated that out of 20 patients in the PR-2000 group, 10 patients were severely symptomatic with AUA score 30 and another 10 patients were less symptomatic with AUA score < 30. Less symptomatic patients with AUA score <30 showed a significant improvement in 90% of cases, while only 10% of severely symptomatic patients showed a significant improvement. In the placebo group, 7 patients were severely symptomatic with AUA score 30 and 17 patients were less symptomatic with AUA score < 30. Less symptomatic patients with AUA score <30 displayed significant improvement in 7.7% of cases and none of the patients of the severely symptomatic patients shown significant improvement (Table 2). Abdominal ultrasonography showed that in the PR-2000 group, 80% of patients with prostate weight <80 gm displayed significant reduction while only 20% Improvement Improvement Table 1: Overall improvement PR-2000 group No. of patients Percentage Placebo group No. of patients Percentage Significant 10 50% 1 5% Average 4 20% 1 5% Poor 6 30% 18 90% Total % % Table 2: Improvement with respect to severity of symptoms Less symptomatic (AUA score < 30) PR-2000 group Severely symptomatic group (AUA score 30) Less symptomatic group (AUA score < 30) Placebo group Severely symptomatic group (AUA score 30) Significant 9 (90%) 1 (10%) 1 (6.7%) - Average 1 (10%) 3 (30%) 1 (6.7%) - Poor - 6 (60%) 11 (86.4%) 7 (100%) Total

4 patients with prostate weight 80 gm displayed significant improvement. In the placebo group, 6.7% of patients with prostate weight 80 gm showed a significant improvement and none of the patients with prostate weight <80 gm showed any improvement (Table 3). In all the patients in the PR-2000 group, ultrasonography showed a decrease in prostate weight, ranging from 4 to 20 gm with an average of 9.8 gm. In the placebo group, the weight of the prostate increased in most patients with an average of 8.3 gm in 16 patients while in 4 cases, weight decreased with an average of 8 gm. There was an improvement in respect to post-void residual volume in the treated group. In the PR-2000 group, 50% patients showed a significant decrease in post-void residue and 35% patients had average improvement whereas Improvement Significant (Final AUA score <7) Average (Final AUA score 8-14) Poor (Final AUA score >14) 15% had poor improvement. In the placebo group, 10% patients showed a significant decrease in post-void residue and 90% patients a poor improvement (Table 4). In PR-2000 group, serum PSA levels were reduced in all the cases ranging from mg/ml with an average of 0.31 mg/ml. In the placebo group, no significant changes in serum PSA levels were found. Table 3: Improvement in respect to prostatic weight Prostate weight <80 gm PR-2000 group Prostate weight 80 gm Prostate weight <80 gm Placebo group Prostate weight 80 8 (80%) 2 (20%) 1 (6.7%) - 2 (20%) 2 (20%) 1 (6.7%) (60%) 13 (86.4%) 5 (100%) Total Table 4: Improvement in respect to post-void residue Improvement Significant (PVR <40 ml) Average (PVR ml) Poor (PVR >60 ml) PR-2000 group No. of patients Percentage Placebo group No. of patients Percentage 10 50% 2 10% 7 35% % 18 90% Total % % DISCUSSION The idea of triphasic evolution of bladder behavior in BPH has been reviewed with traditional grouping of the associated symptoms as irritative (frequency; nocturia; urgency; and urge incontinence) or obstructive (hesitancy; difficulty of voiding; weak urinary stream; postvoiding dribble; sensation of incomplete emptying; and residual urine) In this clinical trial, it was found that there was a significant reduction in 9 patients who were less symptomatic and the one patient who was severely symptomatic as assessed by AUA symptoms score when compared to the placebo group, which showed that there was only one patient who responded out of 20 patients.

5 Post-voiding (post-void) residual urine (PVR) has been a time-honored measure of the degree of prostatism, and the traditional indicator of detrusor decompensation that presumably progresses to the end-stage of urinary retention 13,14. Post-void residual urine volume is considered significantly (ie, abnormally) elevated if it is >25% of the normal adult physiologic bladder capacity (after normal, ie, not overfill voiding), >10% of premicturitional bladder volume, or >50 to 100 ml 15,16. In this clinical trial, it was found that 50% had significant improvement (PVR<40 ml), 35% had average improvement (PVR ml) and there was poor improvement in 15% (PVR >60 ml). In the placebo group, 10% had significant improvement (PVR<40 ml) and there was no improvement in 90% (PVR >60 ml). In prostatic weight there was significant reduction in 10 patients, average reduction in 4 patients and poor reduction in 6 patients in the PR-2000 group. In the placebo group, only one patient each displayed significant and average reduction, while 18 patients showed no reduction of the prostatic weight. The anatomic location of the prostate at the bladder neck enveloping the urethra plays an important role in the pathophysiology of BPH, but it is known that the severity of obstructive voiding symptoms is not correlated only with the size of the prostate. Two prostatic components play a role in bladder outlet obstruction (BOO) and development of lower urinary tract symptoms: dynamic and static. The static component of BPH is related to increased prostate tissue mass. Progressive nodular proliferation leads to increased prostatic size and consequent boo. The result is symptomatic BPH with its classic symptoms such as weak stream, post-void dribbling, frequency and nocturia, which might affect the upper urinary tract if not properly managed. The ratio of stroma to epithelium increases from 2:1 in the healthy prostate to 5:1 in BPH The dynamic component of BPH is related to prostatic smooth muscle tone. Smooth muscle accounts for 39% of the cellular volume and 51% of the total stromal volume in BPH. Alpha 1 -adrenoceptors are the main receptors of stromal cells whereas α 2 -adrenoceptors are localized to the epithelium and blood vessels: 98% of α 1 -adrenoceptor binding sites may be in the prostatic stroma, which expresses 6-fold as much of this receptor as glandular cells. The predominance of α 1 -adrenoceptors in the prostate and the recognition of the role of neuromuscular tone in the prostate in BOO is the basis for the use of α-adrenergic receptor inhibitors in the treatment of voiding dysfunction. Failure to respond or poor response to α-adrenergic receptor inhibitors suggests variable mechanisms of autonomic activity 20. Post-void residual urine is the measurement of the urine volume remaining in the bladder immediately after completion of micturition. However, it is a helpful tool that can be used for follow-up and evaluation of response to therapy. Medical therapy is the first-line management option preferred by both physicians and patients due to its reversibility, less invasive nature, and the significant symptomatic improvement

6 and safety demonstrated in several studies of both α-blockers and 5α-reductase inhibitors. Medical therapy has the potential to prevent retention and obviate the need for surgery. Open prostatectomy is the oldest, most invasive, most efficient BPH treatment and produces a reported 98% symptom improvement. Compared with transurethral resection of the prostate (TURP) and transurethral incision of the prostate (TUIP), strictures and retrograde ejaculations are more common after open prostatectomy, but the mortality is lower than with TURP. However, TURP is the gold standard surgical treatment, although it should not be performed in patients who want to remain fertile. Side effects include incontinence (approximately 3% of patients), impotence (5 10%), retrograde ejaculation (60 80%), and bladder neck contracture (3 5%). The symptom improvement rate is % and the mortality risk is 2% PR-2000 is also useful in the treatment of BPH. CONCLUSION In this double-blind trial, the use of PR-2000 showed a significant improvement in 70% of patients according to the AUA score, while according to post-void residue 85% showed a significant improvement. In all the patients, serum PSA levels reduced with an average of 0.31 mg/ml and prostate weight decreased significantly with an average of 9.8 gm, while there was no change in placebo-treated patients. ACKNOWLEDGEMENT We are thankful to The Himalaya Drug Company, Bangalore, India for arranging the trial drug. REFERENCES 1. Partin A.W., Page W.F. and Lee B. et al. (1994). Concordance rates for benign prostatic hyperplasia among twins suggests hereditary influence. Urology, 44, Grayhack J.T. (1961). Changes with aging in human seminal vesicle fluid fructose concentration and seminal vesicle weight. Journal of Urology, 86, Cunha G.R. and Lung B. (1979). The importance of stroma in morphogenesis and functional activity of urogenital epithelium. In Vitro, 15, Cunha G.R., Chung L.W.K. and Shannon J.M. et al. (1983). Hormone induced morphogenesis and growth: role of mesenchymal epithelial interactions. Recent Progress in Hormone Research, 39, Steiner M.S. (1993). Role of peptide growth factors in the prostate. A review. Urology, 42, Sundaram R., Mohan A.R., Gopumadhavan S., Venkataranganna M.V., Venkatesha Udupa, Seshadri S.J., Anturlikar S.D. and Mitra S.K. (1999). Protective effect of Prostane in experimental prostatic hyperplasia in rats. Asian Journal of Andrology, 1(4), 175.

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