[Phytotherapy Research (2001): (15), 411-415] A Study of Prostane in the Treatment of Benign Prostatic Hyperplasia Lokesh Upadhyay and Tripathi, K., Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India [Correspondence to: Dr. Kala Suhas Kulkarni, Medical Advisor, R&D Center, The Himalaya Drug Company, Makali, Bangalore, India] ABSTRACT A clinical trial was conducted in a study group of 70 males diagnosed with symptomatic Benign Prostatic Hypertrophy (BPH) (synonym of benign prostatic hyperplasia). They were administered Prostane, a herbal formulation, at a dose of 2 tablets a day for one year and monitored every 4 months during the study period. Analysis of results showed improvement in symptom score as per the American Urological Association symptom index rating. There was total relief in pain and haematuria in all the patients (100%); dribbling of urine decreased in 67%, dysuria in 50%, urgency in 60% and hesitancy in 40%. Blood urea levels were within normal range in 70% of the patients and in the range of 31-40 mg/dl in the remaining patients of the study group. Serum prostate specific antigen levels returned to normal in 56% of patients and were in the range of 4.1-5.0 ng/ml in 25% of patients. There was a decrease in prostate specific antigen values which were >6 ng/ml in 9 patients at the commencement of the trial. Uroflowmetry studies showed that the peak flow increased from 12.6 to 30.7 secs (p<0.001) and the void volume from 60.72 to 660 ml (p<0.001), the latent period reduced from 12.78 sec to 2.61 sec; the flow time from 57.01 sec to 20.17 sec and the residual volume from 620 ml to 20 ml (p<0.001). From these results, it is evident that Prostane was effective in alleviating symptoms, reducing prostate specific antigen values and normalising uroflow dynamics in patients with Benign Prostatic Hypertrophy. Keywords: Benign prostatic hypertrophy; prostatic hyperplasia; prostate specific antigen; Prostane. INTRODUCTION Benign Prostatic Hypertrophy (BPH) is an ailment commonly encountered in aged males. It is prevalent in 25% of those above 55 years of age. It usually reaches 50-73% by the age of 90 years. The standard line of therapy for BPH is surgery. However, the risk factor is high for patients in this age group who undergo prostatectomy. Hence, the preferred line of treatment is medical therapy. Advances in the medical field in the coming years are bound to result in increased longevity and thereby the probable incidence of BPH will increase. Benign Prostatic Hypertrophy is a proliferative process that involves both the stromal and epithelial elements of the prostate (Bartsch et al., 1979; Shapiro et al., 1992). Its clinical manifestations include obstructive and irritative urinary tract symptoms, urinary retention, urinary tract infection and haematuria (Madsen and Bruskewitz, 1995). In most patients with this disorder, the goal of therapy is to relieve the aggravating urinary symptoms (Mebust et al., 1989). Malignant transformation has been found in 9.51% of patients with BPH and often these changes are predicted by the presence of markers such as rise in the levels of prostate specific antigen (PSA) and acid phosphatase (De-Biasi et al., 1996). A wide disparity exists between obstructive symptoms and the size of the prostate. Since the advent of ultrasonography, an increasing number of asymptomatic cases with non-specific symptoms are now being diagnosed. Recently, prostatectomy and watchful waiting were the only widely accepted options for treatment of BPH. However, recent studies have reported that 5α-reductase inhibitors and long acting α1-adrenergic antagonist drugs have been found effective in the treatment of this disorder (De-Biasi et al., 1996; Gormley et al., 1992). These drugs though widely used to treat BPH have many adverse effects. Considering the above limitations, herbal remedies have come into the forefront of research to treat various disorders of the prostate (Palevitch et al., 1993; Jain and Dave, 1987). S. repens with or without other phytotherapeutic agents improves urinary tract symptoms by 28%, nocturia by 25%, peak urine flow by 24%, mean urine flow by 28% and residual urine volume by 43% (Wilt et al., 1998). In this perspective, the effect of Prostane, an herbal compound was analysed to evaluate its safety and to ascertain its effect in the lowering of concentration of PSA and reducing other obstructive symptoms of BPH. PATIENTS AND METHODS Seventy men diagnosed with symptomatic BPH were selected for the study after a thorough physical examination and complete history were noted. The study was conducted at the Institute of Medical Sciences, Banaras Hindu University, Varanasi (India). All the patients were selected from the general medical outpatient department over a period of 6 months. The majority of patients in this study were in their 50s or 60s (Table 1) with symptoms varying from mild thinning of the urine stream to dysuria, urgency, hesitancy, pain in the loin and groin, heaviness in the perineum, pain in the calf muscles, haematuria and fever (Table 2). Patients with an episode of unstable angina pectoris, myocardial infarction, history of an ischaemic attack or a cerebrovascular accident in the past 6 months, insulin-dependent diabetes mellitus, severe hypertension or blood Table 1: Distribution of age pressure <90/70 mm Hg, carcinoma of the prostate, No. of % urethral stricture, active urinary tract disease, prior Age group in years patients pelvic surgery likely to interfere with normal bladder 51-55 18 25.71 function and renal or hepatic impairment, were 56-60 26 37.14 excluded from the trial. Other exclusions were 61-65 20 28.57 unwillingness or inability to give informed consent or 66-70 3 4.28 intake of an experimental drug less than 4 weeks prior >71 3 4.28 to being screened. Patients were assessed according to the American Urological Association Symptom Index, which is a reliable indicator of symptoms characteristic of BPH. At each assessment, their symptoms were scored on a scale from 0 (absent) to 5 (severe), the total score reflecting the overall severity of the patient’s condition, ie. 1-7 (mild), 8-19 (moderate) and 20-35 (severe). At each follow up visit, uroflowmetry was performed to measure the voided volume, residual urinary volume and peak urinary flow rate and time. Eligibility for the study required a mean symptom score of at least 8, a mean peak urinary flow rate of <15 ml/sec and >4 ml/sec with a minimal voided volume of 125 ml and a mean residual volume after voiding of <300 ml. The grading of hyperplasia was done by ultrasonography and serum mean residual volume after voiding of <300 ml. The grading of hyperplasia was done by ultrasonography and serum concentrations of PSA were measured. Ultrasonography evaluation was reported by the radiologist. Evaluation for any evidence of prostate cancer by X-ray, ultrasonography and C.T. scan was also done. Other investigations were conducted for renal and liver functions along with electrocardiogram, serum lipid profile, electrolytes, creatinine and urine analysis. The glomerular filtration rate was also estimated. The patients were then administered the drug, Prostane, to be taken at a dose of 2 tablets, twice a day. On completion of the12th, 24th, 36th and 48th weeks of therapy, they were evaluated and the above investigations repeated. This was an open clinical trial. All the patients received Prostane tablets. Each patient served as his own control and the assessment of response was done before and after completion of the stipulated therapy, i.e. 48 weeks. Each tablet of Prostane contains the following: Gokshura (Tribulus terrestris) 140 mg; Putikaranja (Caesalpinia bonducella) 120 mg; Puga (Areca catechu) 100 mg; Shatavari (Asparagus racemosus) 80 mg; Akik pisthi 80 mg and Vanga bhasma 80 mg. These are standardized in the R&D Centre of The Himalaya Drug Company, Bangalore, India. The analgesic, antibacterial and diuretic properties of Tribulus terrestris that are described in Ayurveda have been found useful in treating genitourinary symptoms such as painful micturition, dysuria, haematuria and prostatic enlargement. Caesalpinia bonducella has diuretic and urinary antiseptic properties. Asparagus racemosus also has diuretic property which is beneficial in treating nephropathy. Areca catechu is useful in urinary disorders. This prompted us to evaluate the polyherbal formulation, Prostane, in prostatic enlargement. RESULTS Seventy patients were examined and assessed for inclusion in the trial. All of them completed the treatment and made themselves available for follow-up examination. There were no dropouts in the study. Hesitancy and urgency were symptoms dominant in 35 patients (50%), dribbling of urine in 21 cases (30%), dysuria and calf muscle tenderness in 14 cases (20%) and mild grade fever in 49 patients (70%). At the end of the trial, the subjective symptoms of calf muscle tenderness, pain in the loin and groin during micturition and perineal heaviness improved completely, ie. 100%, whereas 85.5% of patients in the study group showed resolution of mild grade pyrexia. The symptoms of prostatism (urgency and hesitancy) were corrected in 60% and 40% of the cases respectively and there was improvement in dysuria and dribbling of urine in 50% and 40% respectively. Haematuria also resolved in all patients, i.e. 100% (Table 2). Statistical analysis was done using Student’s paired ‘t’ test. Table 3: Ultrasonography findings at 48 weeks Table 2: Improvement in Symptoms Before therapy After therapy No. of patients (n=70) % No. of patients (n=70) % Dribbling of urine 21 30 14 Dysuria 14 20 Urgency 35 Hesitancy Grading of BPH Before therapy After therapy I 30% 50% 40 II 40% 40% 7 50 III 30% 10% 50 21 60 35 50 14 40 Pain in loin and groin 7 10 0 100 Heaviness in perineum 7 10 0 100 Calf muscle tenderness 14 20 0 100 Haematuria 3 42 0 100 Mild grade fever 49 70 42 85 Symptom Wilcoxon Signed Ranks Test performed to assess the significant changes in hypertrophy between the groups. p<0.0001 Table 5: Range of Prostate Specific Antigen Values No. of patients Range (ng/ml) Before therapy After therapy (At 48 weeks) <4.0 20 39 4.1 – 5.0 15 17 5.1 – 6.0 26 14 Table 4: Blood Urea, Serum Creatinine and Glomerular Filtration Rate Values No. of patients Parameter Blood Urea (mg/dl) Serum Creatinine (mg/dl) Glomerular filtration rate (ml/min) Before therapy After therapy (At 48 weeks) >6.0 9 - Total (n) 70 70 20-30 42 49 Mean S.E. 31-40 14 21 3.824 ± 1.3429 2.6760a ± 1.1012 41-60 7 0 61-80 7 0 0.9-1.2 14 42 1.3-1.5 49 21 1.6-2.0 7 7 100-119 35 56 90-99 14 7 50-69 14 7 20-49 7 0 Range 80% improvement in all the patients (Table improvement. a p<0.001 At the commencement of the study, ultrasonographic findings confirmed grade I BPH in 30% of the patients, grade II BPH in 40% and grade III BPH in 30% of the cases under study. Hydronephrosis was present in 20% of the cases. After completion of the treatment, ultrasonography showed an 3). Patients with hydronephrosis showed 100% Blood urea in all the patients at the commencement of the study ranged from 20-80 mg. Patients with blood urea level on the higher side (41-60 and 61-80) showed 100% improvement, while there was 50% improvement in serum creatinine and 80% improvement in the glomerular filtration rate (Table 4). When the study commenced, 20 patients (28%) had a PSA reading of <4.0 ng/ml, 15 patients (21.42%) had a PSA level ranging from 4.1-5.0 ng/ml, 26 cases (37.14%) had PSA values of 5.1-6.0 ng/ml and 9 patients (12.85%) had high PSA values (>6 ng/ml) (Table 5). The mean value was 3.824 ± 1.3429 ng/ml and after treatment, it was 2.6760 ng/ml, showing significant reduction. A significant improvement was noticed in the peak flow rate, latent period, voided volume and residual volume (Figs. 1-a & b). Residual volume improved by 62% and voided volume by >85%. The peak flow and voided volume improved from 12.6 to 30.7 sec and from 60.72 ml to 660 ml Figure 1: Uroflowmetry studies: effect of obstructive indices. respectively. The latent period (a) *p≤0.02, zp≤0.05, # p≤0.01 compared with initial value. reduced from 12.78 to 2.61 sec, (b) zp≤0.05, #p≤0.01 compared with initial value. the flow time from 57.01 to 20.17 sec and the residual volume was only 20 ml compared with the initial volume of 620 ml. As the treatment was sustained over a period of 48 weeks, there was a gradual reduction in residual volume of urine and was negligible at 48 weeks. Similarly, the quantity of voided urine increased gradually showing the sustained effect of Prostane. As the residual volume of urine decreased, it was reflected by increase in the amount of voided urine. To confirm the disappearance of residual volume, the therapy may have had to be continued beyond 48 weeks. No regression analysis could be carried out. The maximum response was observed from 32 weeks onwards. Patient compliance was high as all the patients completed the study. None of them reported any side effects or adverse effects on administration of Prostane orally. DISCUSSION Obstructive urinary symptoms are a common occurrence in the majority of males above 50 years of age, of whom 20-30% undergo prostatectomy (Chirikos and Sanford, 1996). Advances in medical therapy for the management of BPH represent the long-awaited development of a formulation to overcome these symptoms (Di-Silverio et al., 1995). Currently-used drugs such as 5α-reductase inhibitors cause a decrease in libido and sexual potency (Steiner, 1996), while α-adrenergic antagonist drugs can result in a host of untoward ailments such as vertigo, fatigue, palpitation, headache, tachycardia, asthenia, nausea, diarrhoea, nasal congestion and impotence on prolonged use (Chapple, 1996). Herbal medicines have been used in the past for the effective management of several incurable diseases. Throughout the world, research is in progress to find a remedy for BPH that is safe and free from side-effects even on prolonged use (Carraro et al., 1996; Paubert et al., 1996). An herbal compound, Prostane, manufactured by The Himalaya Drug Company, Bangalore, India, contains extracts of various herbs that have different modes of action: Aloe vera increases blood circulation, helps in the healing process of damaged tissues (Heggers et al., 1993) and has anti-cancer properties (Jeong et al., 1994). Acacia nilotica is very effective against gram-positive and gram-negative organisms (Abd El Nabi et al., 1992). Tribulus terrestris possesses diuretic property. The diuretic, analgesic and antibacterial properties found in Tribulus terrestris are utilised and found beneficial in treating the symptoms of prostatic enlargement such as haematuria, painful micturition and dysuria (Singh et al., 1991; Tomova, 1987). Asparagus racemosus has an immunomodulatory effect on the prostate (Thatte et al., 1987). Areca catechu has antimicrobial properties (Iwamoto et al., 1991). It was observed in this study that on account of its antispasmodic, diuretic, androgen blocking, antibacterial and anticarcinogenic properties, Prostane displayed a multi-dimensional effect in patients with BPH, especially in those with increased levels of PSA. The treatment with Prostane decreased PSA levels; similar effects could be further studied in a randomised controlled trial in patients of prostate cancer with raised PSA compared with that of placebo. It was also perceived that Prostane alleviated the other symptoms of BPH and displayed a significant improvement in urine flow dynamics. Ultrasound findings showed a significant reduction in the prostate size. The symptomatic relief of dysuria and urgency of urine may be due to the astringent action of Acacia catechu. Tribulus terristris has diuretic property which potentiates the diuretic effect of other herbs. It is feasible to carry out a randomised controlled double blind clinical trial of Prostane, a polyherbal formulation to ascertain its efficacy in improving urologic symptoms and urinary flow measures. This approach would justify our views that Prostane alleviates the obstructive urological symptoms of benign prostatic hyperplasia. Since this was an open clinical trial, the efficacy of Prostane was observed in terms of relief of symptoms of prostatic hyperplasia. 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