Medicine Update 2004: 12(6), 33-42

Evaluation of clinical efficacy and safety of Himplasia in BPH: A prospective, randomized, placebo-controlled, double blind, phase III

clinical trial

Dr. Pranjal R. Modi1, DNB (Urology) and Dr. S.A. Kolhapure2*, MD 1Department of Urology and Transplantation Surgery, Institute of Kidney Diseases & Research Centre,

BJ Medical College & Civil Hospital, Ahmedabad, India. 2Senior Medical Advisor, R&D Center, The Himalaya Drug Company, Bangalore, India.

[*Corresponding author]

ABSTRACT Benign prostatic hypertrophy/ hyperplasia occurs in about half of men in their 50’s and about 90% of men over 85 years of age and affects the quality of life. Currently available treatment options for the management of BPH have various drawbacks, such as low clinical efficacy and associated adverse effects. Due to these limitations, phytotherapy has been extensively researched and some polyherbal formulations have been proven beneficial in the management of BPH. Himplasia is a polyherbal formulation recommended for the clinical management of BPH and this study was planned to evaluate clinical efficacy and safety of Himplasia in BPH. This study was a prospective, randomized, placebo-controlled, double blind, phase III clinical trial and was approved by the “Institutional Ethics Committee”. A total of 60 patients who were diagnosedgive informed consent were included incarcinoma, acute and chronic prostatitis, calculus and patients on those drugs, whexcluded from the study. Also, patients withpatients indicated for surgery (refractory retand those patients who were not willing tstudy. At the initial randomization visit, a detapatients. All the patients underwent a thobiochemical blood tests and specific tests winvestigated by uroflowmetry and USG. Al

ABBREVIATIONS AUA : American urological association BPH : Benign prostatic hypertrophy/hyperplasiaCOX : Cyclooxygenase DLC : Differential leucocyte count DRE : Digital rectal examination FT : Flow time Hb : Hemoglobin HS : Highly significant IL : Interleukin LFT : Liver function test LP : Latent period LUTS : Lower urinary tract symptoms NS : Not significant PF : Peak flow PV : Prostate volume PVR : Post-void residual volume RFT : Renal function test TLC : Total leucocyte count TNF-α : Tumor necrosis factor-alpha USG : Ultrasonography VT : Voiding time VV : Void volume

as suffering from BPH and who were willing to the study. Patients with prostate and bladder neurogenic bladder, stricture urethra, vesicular

ich were likely to affect bladder function were severe cardiovascular, renal or hepatic disorders,

ention and recurrent or persistent gross hematuria) o give informed consent were excluded from the

iled medical history was obtained from all the rough systemic examination and DRE. Routine ere done for all the patients. All the patients were l the patients in the drug and placebo groups were

advised to consume 1 capsule of Himplasia and placebo respectively, once daily, for a period of 6 months. All the patients were followed for a period of 6 months (during the treatment period). The predefined primary efficacy endpoints were: decrease in total AUA score at the end of 6 months, decrease in prostate size, decrease in PV and improvement in uroflowmetry parameters. The predefined secondary safety endpoints were assessed by the reduced incidence of adverse events, improvements in laboratory parameters and overall patient compliance to the drug therapy. All adverse events reported by the patients or observed by investigators were recorded. Statistical analysis was done according to intention-to-treat principles. The mean age of the enrolled patients was 60.93 and 62.37 years in the Himplasia and placebo group, respectively and there was no statistical difference between the 2 groups. There was a highly significant reduction in the mean AUA symptom score, PV, PVR urine volume, LP and urinary FT, and a significant increase in PF rate and voided urinary volume, in the Himplasia group, at the end of 6 months. There were no significant changes in the hematological and biochemical parameters in the Himplasia group. This beneficial clinical efficacy of Himplasia in BPH might be due to the synergistic action of its ingredients. Therefore, it may be concluded that the use of Himplasia is clinically effective and safe in the management of BPH. INTRODUCTION Benign prostatic hyperplasia occurs in about half of men in their 50’s and about 90% of men over 85 years of age. Benign prostatic hypertrophy/hyperplasia is the increase in size of the prostate inside its capsule, which exerts pressure on the urethra, leading to the obstruction to urine flow. Benign prostatic hyperplasia is characterized by a slowdown in the urine stream build up of urine in the bladder and a frequent (and urgent) need to urinate. Unlike prostate cancer, BPH is not a life-threatening disease, however, it affects the quality of life (QOL). Untreated BPH may lead to urinary retention causing damage to kidneys, which may result in renal failure. In addition, BPH may lead to reduction in sexual ability, painful orgasm and impotence.1,2 Currently available treatment options for the management of BPH include medications (to reduce the amount of prostatic tissue and increase the urinary flow) and surgery. Few treatments are without any adverse consequences and this is particularly true of the available treatments for BPH, where there is a delicate balancing act between the benefits and risks. The adverse events following the treatment for BPH include headache, dizziness, hypotension, fatigue, reduced libido, impotence, breast tenderness and enlargement, oligospermia and the need for re-treatment. Due to these limitations, phytotherapy has been extensively researched and some polyherbal formulations have been proven beneficial in the management of BPH.3-11 Himplasia is a polyherbal formulation recommended for the clinical management of BPH and it contains the powders of Asparagus racemosus, Tribulus terrestris, Crataeva nurvala, Areca catechu, Caesalpinia bonducella, and Akika pishti. This study was planned to evaluate clinical efficacy and safety of Himplasia in BPH. Study Aim This study was planned to evaluate the clinical efficacy and safety (short- and long-term) of Himplasia in the management of BPH.

Study Design This study was a prospective, randomized, placebo-controlled, double blind, phase III, clinical trial, conducted at the Department of Urology and Transplantation Surgery, Institute of Kidney Diseases & Research Centre, BJ Medical College & Civil Hospital, Ahmedabad, India, as per the ethical guidelines of Declaration of Helsinki, from September 2001 to March 2003. The study protocol, case report forms, regulatory clearance documents, product related information and informed consent form (in Gujrathi and English) were submitted to the “Institutional Ethics Committee” and were approved by the same. MATERIALS AND METHODS Inclusion Criteria A total of 60 patients, divided into 2 groups of 30 each, who were diagnosed as suffering from BPH and who were willing to give informed consent were included in the study. The patients were categorized by the “AUA symptom score index” as either mild (0-7 points), moderate (8-19 points) or severe (20-35 points) cases of BPH.12 Exclusion Criteria Patients with prostate and bladder carcinoma, acute and chronic prostatitis, neurogenic bladder, stricture urethra, vesicular calculus and patients on those drugs, which were likely to affect bladder function were excluded from the study. Also, patients with severe cardiovascular, renal or hepatic disorders, patients indicated for surgery (refractory retention and recurrent or persistent gross hematuria) and those patients who were not willing to give informed consent were excluded from the study. Study Procedure At the initial randomization visit, a detailed medical history, with special emphasis on history of urinary symptoms (urgency, frequency, nocturia, hesitancy, straining, intermittency, terminal dribbling and sensation of incomplete voiding) was obtained from all the patients. All the patients underwent a thorough systemic examination, which was followed by DRE to determine the prostate size, presence of nodules, asymmetry, and tenderness. Routine biochemical blood tests (Hb, TLC and DLC) and specific tests (LFTs and RFTs) were done for all the patients. These patients were investigated by uroflowmetry and PF, FT, VV, LP and VT was recorded. The PV and PVR volume was determined by USG. All the patients in the drug and placebo groups were advised to consume 1 capsule of Himplasia and placebo respectively, once daily, for a period of 6 months. Follow-up and Assessment All the patients were followed up for a period of 6 months (during the treatment period). At each monthly follow-up visit, the AUC symptom score and prostate size was evaluated. Uroflowmetry examination was done at the end of the 3rd and 6th month and a complete clinical, biochemical and ultrasonographic examination was carried out at the end of the 6th month. Primary and Secondary Endpoints The predefined primary efficacy endpoints were decrease in total AUA score at the end of 6 months, decrease in prostate size, decrease in PV and improvement in uroflowmetry parameters. The predefined secondary safety (short- and long-term) endpoints were assessed by reduced incidence of adverse events, improvements in laboratory (hematological and biochemical) parameters and overall patient compliance to the drug therapy.

Adverse Events All the adverse events reported by the patients or observed by the investigators were recorded with information about severity, date of onset, duration and action taken regarding the study drug. Relation of adverse events to the study medication was predefined as “Unrelated” (a reaction that does not follow a reasonable temporal sequence from the time of administration of the drug), “Possible” (follows a known response pattern to the suspected drug, but could have been produced by the patient’s clinical state or other modes of therapy administered to the patient), and “Probable” (follows a known response pattern to the suspected drug that could not be reasonably explained by the known characteristics of the patient’s clinical state). Patients were allowed to voluntarily withdraw from the study, if they experienced serious discomfort during the study or sustained serious clinical events requiring specific treatment. For patients withdrawing from the study, efforts were made to ascertain the reason for dropout. Non-compliance (defined as failure to take less than 80% of the medication) was not regarded as treatment failure and reasons for non-compliance were noted. Statistical Analysis Statistical analysis was done according to intention-to-treat principles. “Repeated Measures ANOVA Test” and “Post-Test for Linear Trend” evaluated the changes in various parameters from baseline values and the values after each month. The changes in various parameters from baseline values and at 6 months were evaluated by “Paired ‘t’ Test” and the variances were compared by using “F Test”. The minimum level of significance was fixed at 99% confidence limit and a two-sided “p” value of <0.0001 was considered as highly significant. RESULTS A total of 60 patients were enrolled in the study. The mean age of the enrolled patients was 60.93 and 62.37 years (Minimum=50 and 50, Maximum=78 and 74, SD=6.913 and 6.921, SEM=1.262 and 1.264, Lower 99% CI of M=58.35 and 59.78, Upper 99% CI of M=63.51 and 64.95) in the Himplasia and placebo groups respectively. There was no statistical difference between the Himplasia and placebo groups (Difference between means= -1.433 ± 1.786, 99% CI= -6.192 to 3.325, R2=0.01098, t=0.8026, p=0.4255; NS) (Table 1).

Table 1: Age (in years) distribution of included patients Parameter Himplasia Placebo

Minimum 50 50 Maximum 78 74 Mean 60.93 62.37 Std. Deviation 6.913 6.921 Std. Error 1.262 1.264 Lower 99% CI of mean 58.35 59.78 Upper 99% CI of mean 63.51 64.95

Unpaired ‘t’ Test Mean ± SEM of Himplasia Group 60.93 ± 1.262 Mean ± SEM of Placebo group 62.37 ± 1.264 Difference between means -1.433 ± 1.786 99% CI -6.192 to 3.325

R2=0.01098, t=0.8026, df=58, p=0.4255; NS F test to compare variances: F=1.002, DFn=29, Dfd=29, p=0.9952; NS

There was a highly significant reduction in the “mean AUA symptom score” in the Himplasia group from 22.8 at the time of enrollment to 16.57 at the end of study (F=30.9, R2=0.516, p<0.0001; HS), in the Himplasia group and the mean AUA symptom score reduction from 19.23 at the time of enrollment to 18.07, at the end of study was nonsignificant in the placebo group (F=1.583, R2=0.052, p=0.155; NS) (Table 2 and Figure 1).

Table 2: AUA symptom score of included patients Himplasia Placebo

Parameter Baseline 3rd month 6th month Baseline 3rd month 6th month

Minimum 12 7 10 4 7 7 Maximum 32 26 26 29 26 25 Mean 22.8 17.5 16.57 19.23 18.3 18.07 Std. Deviation 5.561 5.009 3.181 5.752 4.219 4.448 Std. Error 1.015 0.9144 0.5807 1.05 0.7704 0.8122 Lower 99% CI of mean 20 14.98 14.97 16.34 16.18 15.83 Upper 99% CI of mean 25.6 20.02 18.17 22.13 20.42 20.31 Reported measures ANOVA test statistics F=30.9, R2=0.516, p<0.0001; HS F=1.583, R2=0.052, p=0.155; NS

Figure 1: AUA symptom score of included patients

Table 3: Changes in the PV (cm3) of included patients

Himplasia Placebo Parameter Before treatment After treatment Before treatment After treatment

Minimum 17 12 10 0 Maximum 46 44 41 40 Mean 29.9 27.72 27.41 27.93 Std. Deviation 9.17 8.514 8.479 9.447 Std. Error 1.703 1.581 1.575 1.785 Lower 99% CI of mean 25.19 23.36 23.06 22.98 Upper 99% CI of mean 34.6 32.09 31.76 32.88

Paired ‘t’ Test Mean of differences 2.172 -1 99% confidence interval 0.7535 to 3.591 -2.858 to 0.8583 R2; t; p value; significance

R2=0.3899; t=4.230; p=0.0002; HS

R2=0.07609; t=1.491; p=0.1475; NS

There was a highly significant reduction in the “mean PV” from 29.9 cm3 at the time of enrollment to 27.72 cm3 at the end of study in the Himplasia group (R2=0.3899, t=4.230, p=0.0002; HS), and the mean PV increase from 27.41 cm3 at the time of enrollment to 27.93 cm3, at the end of study was nonsignificant in the placebo group (R2=0.07609, t=1.491, p=0.1475; NS) (Table 3 and Figure 2).

Figure 2: Changes in the PV of included patients

Table 4: Changes in the PVR volume (ml) of included patients Himplasia Placebo Parameter

Before treatment After treatment Before treatment After treatment Minimum 10 0 0 0 Maximum 160 140 160 140 Mean 61.97 47.97 40.75 42.38 Std. Deviation 36.39 35.22 48.33 45.65 Std. Error 6.643 6.43 9.134 8.478 Lower 99% CI of mean 43.66 30.25 15.44 18.96 Upper 99% CI of mean 80.28 65.69 66.06 65.8

Paired ‘t’ Test Mean of differences 14 -2.429 99% confidence interval 3.823 to 24.18 -17.01 to 12.16 R2; t; p value; significance

R2=0.3314; t=3.791; p=0.0007;HS

R2=0.007822; t=0.4614; p=0.6482; NS

There was a highly significant reduction in the “mean PVR volume” from 61.97 ml at the time of enrollment to 47.97 ml at the end of study in the Himplasia group (R2=0.3314, t=3.791, p=0.0007; HS), and the mean increase in PVR volume from 40.75 ml at the time of enrollment to 42.38 ml at the end of study was nonsignificant in the placebo group (R2=0.007822, t=0.4614, p=0.6482, NS) (Table 4 and Figure 3).

Figure 3: Changes in the PVR volume of included patients

Table 5: Changes in the LP (sec) of included patients

Himplasia Placebo Parameter

Baseline 3rd month 6th month Baseline 3rd month 6th month Minimum 6 3 0 0 0 0 Maximum 53 47 45 255 20 25 Mean 20.2 15.6 10.7 19.43 12.3 12.57 Std. Deviation 14.15 10.88 9.48 44.88 4.542 4.717 Std. Error 2.583 1.987 1.731 8.194 0.8293 0.8613 Lower 99% CI of mean 13.08 10.12 5.93 -3.149 10.01 10.19 Upper 99% CI of mean 27.32 21.08 15.47 42.02 14.59 14.94 Reported measures ANOVA test statistics

F=19.02; R2=0.396; p<0.0001; HS

F=0.7789; R2=0.0262; p=0.4637; NS

Post-test for linear trend Slope; R2; p value; significance

Slope=4.75; R2=0.1026; p<0.0001; HS

Slope= -3.433; R2=0.0117; p=0.2937; NS

There was a highly significant reduction in the “mean LP” from 20.2 secs at the time of enrollment to 10.7 secs at the end of study in the Himplasia group (R2=0.396, F=19.02, p<0.0001; HS), and the mean LP reduction from 19.43 secs at the time of enrollment to 12.57 secs at the end of study was nonsignificant in the placebo group (R2=0.0262, F=0.7789, p=0.4637; NS) (Table 5 and Figure 4).

Figure 4: Changes in the LP of included patients

Table 6: Changes in the FT (sec) of included patients Himplasia Placebo

Parameter Baseline 3rd month 6th month Baseline 3rd month 6th month

Minimum 34 30 24 25 45 0 Maximum 180 168 60 141 132 160 Mean 58.5 50.4 40.33 71.30 73.73 71.67 Std. Deviation 31.99 25.13 10.62 22.32 18.29 25.22 Std. Error 5.84 4.589 1.94 4.074 3.34 4.605 Lower 99% CI of mean 42.4 37.75 34.99 60.07 64.53 58.97 Upper 99% CI of mean 74.6 63.05 45.68 82.53 82.94 84.36 Reported measures ANOVA test statistics

F=9.19; R2=0.2406; p<0.0003; HS

F=0.6632; R2=0.0224; p=0.5191; NS

Post-test for linear trend

F; R2; p value; significance Slope=9.083; R2=0.088; p<0.0001; HS

Slope=0.1833; R2=0.00004723; p=0.2937; NS

There was a highly significant decrease in the “mean FT” from 58.5 secs at the time of enrollment to 40.33 secs at the end of study in the Himplasia group (R2=0.2406, F=9.19, p<0.0003; HS), and the mean FT score increase from 71.30 at the time of enrollment to 71.67 at the end of study was nonsignificant in the placebo group (R2=0.0224, F=0.6632, p=0.5191; NS) (Table 6 and Figure 5).

Table 7: Chan

Parameter Baseli

Minimum 5.4Maximum 16.2Mean 10.2Std. Deviation 2.97Std. Error 0.543Lower 99% CI of mean 8.72Upper 99% CI of mean 11.7Reported measures ANOVA test statistics

Slope; R2; p value; significance

Slo

There was a highly significant increase in the “mean PF rate” from 10.23 ml/sec at the time of enrollment to 12.05 ml/sec at the end of study in the Himplasia group (R2=0.3044, F=12.69, p<0.0001; HS), and the mean PF reduction from 10.97 ml/sec, at the time of enrollment to 10.82 ml/sec at the end of study, was nonsignificant in the placebo group (R2=0.03918, F=1.183, p=0.3137; NS) (Table 7 and Figure 6).

Figure 5: Changes in the FT of included patients

ges in the PF rate (ml/sec) of included patients Himplasia Placebo

ne 3rd month 6th month Baseline 3rd month 6th month 6.1 7.6 3.7 6 6.3 19.3 19.5 19.7 19.9 18 3 11.46 12.05 10.97 11.41 10.82 7 3.009 2.447 3.337 2.875 2.277 5 0.5493 0.4468 0.6092 0.5248 0.4157 9 9.949 10.82 9.291 9.967 9.678 2 12.98 13.28 12.65 12.86 11.97 F=12.69; R2=0.3044;

p<0.0001; HS F=1.183; R2=0.03918;

p=0.3137; NS Post-test for linear trend

pe=0.9133; R2=0.06715; p<0.0001; HS

Slope= -0.07333; R2=0.000449; p=0.7148; NS

Figure 6: Changes in the PF rate of included patients

Table 8: Changes in the VV (ml) of included patients

Himplasia Placebo Parameter

Baseline 3rd month 6th month Baseline 3rd month 6th month Minimum 150 160 165 132 148 132 Maximum 384 520 520 542 516 470 Mean 253.10 283.3 309.60 218.10 224.4 214.40 Std. Deviation 66.32 84.76 94.08 95.17 87.48 76.41 Std. Error 12.11 15.47 17.18 17.37 15.97 13.95 Lower 99% CI of mean 219.7 240.7 262.3 182.5 191.7 185.8 Upper 99% CI of mean 286.4 325.9 357 253.6 257.1 242.9 Reported measures ANOVA test statistics

F=14.9; R2=0.3394; p<0.0001; HS

F=0.3508; R2=0.01195; p=0.7056; NS

Post-test for linear trend

F; R2; p value; significance Slope= 28.28; R2=0.0749; p<0.0001; HS

Slope= -1.85; R2=0.000313; p=0.7612; NS

There was a highly significant increase in the “mean VV” from 253.10 ml at the time of enrollment to 309.6 ml, at the end of study in the Himplasia group (R2=0.3394, F=14.9, p<0.0001; HS); and the mean decrease in VV score from 218.10 ml at the time of enrollment to 214.40 ml at the end of study was nonsignificant in the placebo group (R2=0.01195, F=0.3508, p=0.7056; NS) (Table 8 and Figure 7).

Figure 7: Changes in the VV of included patients

There were no significant changes in the hematological and biochemical parameters, in the Himplasia group. There were no clinically significant adverse events (either reported by the patients or observed by the investigators) and the overall compliance to the drug treatment was excellent in the Himplasia group.

DISCUSSION The prevalence of moderate to severe symptoms of BPH (measured by the AUA symptom score), varies from 26% to 46% in men aged between 40 to 79 years. These symptoms worsen with advancing age and maximum urinary flow rates tend to decrease faster in older men. Prostatic volume is strongly associated with age, which increases at the rate of 0.6% to 1.6% a year. Older age, severe symptoms and low flow rate increase the chances of acute urinary retention. A 60-year-old man with moderate to severe symptoms would have a one in seven chance of developing acute retention in the following 10 years.13

Lower urinary tract symptoms of BPH are classified into storage/irritative symptoms (increased urinary frequency, urgency and nocturia) and voiding/obstructive symptoms (hesitancy, terminal dribbling, dysuria, straining to void and a feeling of incomplete voiding). Post-micturition dribble, hemospermia and nocturnal polyuria are the other commonly associated symptoms.14 “International Consultation on BPH” guidelines for the assessment of LUTS include symptom analysis, clinical examination, urine and blood tests, urodynamics, endoscopy and radio imaging.15 Laboratory investigations play an important role in the management of BPH. Measurements of serum creatinine and urea are recommended because a significant number of patients with BPH have renal impairment.16 Prostate-specific antigen has been shown to be a useful tumor marker, but it is not a cancer-specific marker, as it lacks sufficient specificity.17 Some recent reviews concluded that there was no role for routine screening for prostate cancer.18,19 Uroflowmetry is the simplest non-invasive urodynamic test for recording the urinary flow rate. Interpretation of a flow trace involves analysis of the flow (Q) pattern and determination of the maximum flow rate (Qmax) (a low Qmax usually indicates bladder outlet obstruction). The ultrasound scan is a non-invasive method of checking the upper urinary tract for evidence of obstructive uropathy, the bladder for residual urine and the prostate for size and consistency. Measurement of PVR urine can be readily measured by an ultrasound and large post-void residual urine suggests bladder outlet obstruction. Pressure flow studies are the only accurate method of diagnosing bladder outlet obstruction by measuring the detrusor pressure and flow rate during voiding. Detrusor pressure is the component of bladder pressure produced by the bladder wall itself and is derived by subtraction of the rectal pressure from the bladder pressure. Bladder outlet obstruction can be defined by several methods like the “Abrams–Griffith’s number”20-22, the group-specific urethral resistance factor (URA) and Schafer’s linear passive urethral resistance ratio (L-PURR).23 Patients with mild to moderate symptoms that are not particularly bothersome are given a period of conservative management (“watchful waiting”), during which they are advised on the amount and type of fluid intake and bladder training (particularly if storage symptoms predominate with the passage of small and frequent volumes). The frequency and volume chart is used as a measure to assess the efficacy of the drug. The patient is encouraged to restore the bladder as a storage tank, passing urine by the clock rather than the urge, and gradually extending the intervals between each void. The aims of intervention in BPH are to alleviate LUTS, prevent complications and minimize the adverse effects of treatment. The goal of the treatment of BPH is essentially either reassurance or the relief of obstruction. Alpha-Blockers act by blocking the sympathetic adrenergic nerves in the smooth muscle of the bladder neck and prostate, and therefore act on bladder-neck obstruction as well as BPH. The reported incidence of side effects with other alpha-1 blockers is about 15% (includes headaches, dizziness, drowsiness and hypotension).24 5α-reductase inhibitors reduce the production of dihydrotestosterone and act by reducing prostatic growth; but the patient needs to take the drug at least for 6 months to ensure efficacy, which is rather costly. The common documented adverse effect of 5α-reductase inhibitors is impotence, occurring in about 10 % of patients.25 The various operative treatment options include prostatectomy (transurethral, retropubic or open), transurethral incision of the prostate (TUIP), laser prostatectomy, transurethral electrovaporization, balloon dilatation of the prostate, thermotherapy, high-intensity focused

ultrasound, transurethral needle ablation of the prostate, long-term catheterization of the bladder, prostatic stent or partial catheter and intermittent self catheterizations. Transurethral resection of the prostate remains the optimum treatment for BPH, but less invasive procedures are being developed which may provide a wider choice of treatment for elderly men. This study observed a highly significant reduction in the mean AUA symptom score, prostate volume, PVR urine volume, LP, urinary FT, and a significant increase in PF, and voided urinary volume in the Himplasia group, at the end of 6 months, which indicate the clinically beneficial effects of Himplasia in BPH. There were no significant changes in the hematological and biochemical parameters in the Himplasia group, which indicates the excellent short- and long-term safety profile of Himplasia. This beneficial clinical efficacy of Himplasia in BPH might be due to the synergistic action of its ingredients, which has been well documented in various experimental and clinical studies. Mitra et al. studied the efficacy of Himplasia on 5α-reductase inhibition, α-adrenergic antagonistic activity and testosterone-induced prostatic hyperplasia and observed that, Himplasia inhibited the 5α-reductase activity in a dose-dependent manner and exhibited α-adrenergic antagonistic activity. Treatment with Himplasia significantly reduced the prostatic weight, the epithelial height and the stromal proliferation in experimental prostatic hypertrophy.5 Garg et al. conducted a randomized, double blind, placebo-controlled study with Himplasia in BPH and observed significant reduction in AUA symptom score, prostatic weight and PVR volume.6 Upadhyay et al. evaluated the clinical efficacy of Himplasia in BPH and observed a significant improvement in the symptom score as per the AUA symptom index rating. Uroflowmetry studies showed increase in the PF and VV, with decrease in the LP, FT and PVR urine.7 Shukla et al. evaluated the efficacy of Himplasia in BPH and documented a significant improvement in the AUA score, peak flow rate and a decrease in ultrasonographic prostate size.8 Singh et al., Arora et al. and Sahu et al. reported that Himplasia significantly improved all the efficacy parameters of BPH with reduction of prostatic weight. There was an increase in the PF, with significant reduction in the PVR.9-11 The active ingredients of Asparagus racemosus are isoflavones namely 8-methoxy-5,6,4’-trihydroxyisoflavone and 7–O–β–D-glucopyranoside.26 Muruganadan et al. reported the revival of macrophage chemotaxis and IL-1 (IL-1) and TNF-α production by Asparagus racemosus, with the enhancement of humoral and cell mediated immunity.27 Dhuley et al. reported significant inhibition of chemotactic activity and production of IL-1 and TNF-α by macrophages on with pretreatment with Asparagus racemosus.28 Kamat et al. demonstrated the potent antioxidant properties of Asparagus racemosus in mitochondrial membranes.29 Asparagus racemosus has been reported to produce leucocytosis, neutrophilia with enhanced phagocytosis by macrophages and polymorphs (immunomodulatory property).30,31 Rege et al. and Thatte et al. reported the potent immunostimulant properties of Asparagus racemosus.32,33 Rege et al. observed increased phagocytic and killing capacity of macrophages with Asparagus racemosus treatment.34 Sairam et al. and Datta et al. demonstrated the cytoprotective actions (increased mucus secretion, cellular mucus and life span of cells) of Asparagus racemosus.35,36 The active ingredients of Tribulus terrestris are furostanol saponin (tribol), spirostanol saponin`s, sitosterol glucoside,37 terrestrinins A and B,38 protodioscin,39 neohecogenin galactopyranosides40 and tribulusamides.41 Hong et al. showed the potent inhibition of COX-2 activity by Tribulus terrestris.42

The principle active ingredient of Crataeva nurvala is a triterpene, lupeol. Geetha et al. demonstrated the potent anti-inflammatory activity of Crataeva nurvala (greater than that of indomethacin), which was attributed to their anticomplementary activity.42 Geetha et al. documented the anticomplement and hence anti-inflammatory activities of Crataeva nurvala.43. In another study, lupeol reduced the elevated levels of superoxide dismutase, glutathione peroxidase and catalase, which indicate the potent antioxidant action of Crataeva nurvala.44 Malini et al. reported the renoprotective effect of lupeol and observed the reduction of the urinary marker enzymes, which indicate renal tissue damage (lactate dehydrogenase, inorganic pyrophosphatase, alkaline phosphatase, gamma glutamyl transferase, β-glucuronidase and N-acetyl β-D glucosaminidase).45 Varalakshmi et al. documented the reversal of increased urinary excretion of the crystalline constituents along with lowered magnesium excretion by Crataeva nurvala46 and postulated that this action might be mediated through (Na+, K+)-ATPases affecting the transport of metabolites.47 The active ingredients of Areca catechu are alkaloids (arecoline, guvacoline, arecaidine, guvacine and arecolidine). Arecoline acts as a parasympathomimetic and muscarinereceptor agonist in vivo and the agonist properties are ascribed to the resemblance to acetylcholine, which arises after protonation of arecoline's nitrogen atom. Arecaidine and guvacine are strong inhibitors of GABA-uptake into the nerve endings and increase the plasma concentrations of adrenaline and noradrenaline. The principle active ingredients of Caesalpinia bonducella are triterpenoidal glycosides and these active ingredients have potent antioxidant activity.48 CONCLUSION Benign prostatic hyperplasia, which affects the quality of life, occurs in about half of men in their 50’s and about 90% of men over 85 years. Currently available treatment options for management of BPH have various limitations such as low clinical efficacy or associated adverse effects. Due to these limitations, phytotherapy has been extensively researched and some polyherbal formulations have been proven beneficial in the management of BPH. This study was planned to evaluate clinical efficacy and safety of Himplasia, a polyherbal formulation in BPH. This study observed a highly significant reduction in the mean AUA symptom score, prostate volume, PVR urine volume, LP, urinary FT and a significant increase in PF, and voided urinary volume in the Himplasia group, at the end of 6 months, which indicate clinically beneficial effects of Himplasia in BPH. There were no significant changes in the hematological and biochemical parameters in the Himplasia group, which indicates the excellent short- and long-term safety profile of Himplasia. This beneficial clinical efficacy of Himplasia in BPH might be due to the synergistic action of its ingredients. Therefore, it may be concluded that use of Himplasia is clinically effective and safe in the management of BPH. REFERENCES 1. Welch G. et al. Quality-of-life impact of lower urinary tract symptom severity: Results

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