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Lower Urinary Tract Symptoms in Men for GPs

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Talk by Dr. Peter Ng, SJMC

Talk by Dr. Peter Ng, SJMC
Audio track available at Dobbs Forum. CME Talks listed here: http://forum.mydobbs.net/cme/cme-talks

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  • In the Olmsted County Study Rhodes et al used repeat ultrasound measures in a 7-year period and found that average prostatic growth rates were 1.6% yearly in men between ages 40 and 79 years (fig. 1, A).4 Another important finding in this study was that the percent growth of the prostate yearly depends on baseline volume, in that the larger the prostate at baseline, the greater the percent of growth every year thereafter. Similar findings were also reported in men participating in the Baltimore Longitudinal Study of Aging.7,8 Thus, while prostate volume correlates poorly with symptoms and urinary flow at any given time point, the larger the prostate, the greater the likelihood of future clinical deterioration. <br />
  • Jacobsen SJ, Jacobsen DJ, Girman CJ, et al. Treatment for benign prostatic hyperplasia among community dwelling men: the Olmsted County study of urinary symptoms and health status. J Urol 1999; 162:1301–1306 <br /> Emberton M. Definition of at-risk patients: dynamic variables. BJU Int 2006; (97 Suppl 2):12–15 [discussion 21–22]. <br /> Djavan B, Fong YK, Harik M, et al. Longitudinal study of men with mild symptoms of bladder outlet obstruction treated with watchful waiting for four years. Urology 2004; 64:1144–1148. <br />
  • 8 <br /> Various factors were considered by Astellas in designing the ideal alpha blocker formulation for treating LUTS/BPH. <br /> The absorption of current controlled release -A antagonists, such as conventional tamsulosin and alfuzosin XL, are food dependent. To improve on this, the ideal formulation would eliminate the effect of food on absorption, thus providing controlled release with no dose dumping. <br /> Current formulations are also dependent on the presence of water in the GI tract to release the active ingredient. As a result, drug release is impeded in the colon where water content is limited. The ideal formulation would provide controlled release over 24 hours with no peaks or troughs in plasma levels, irrespective of water levels throughout the GI tract. <br />
  • 9 <br /> Taking these factors into consideration, Astellas developed and patented OCAS®, the Oral Controlled Absorption System. <br /> The Ocas® formulation is a gel matrix comprising a gel-forming agent and a gel-enhancing agent. Gel formation is rapid and does not agitate the GI tract. Ocas® technology also ensures consistent drug release, independent of pH. <br /> Importantly, this unique new formulation overcomes the problem of low-level drug absorption from the colon. It does this by achieving rapid and complete hydration before reaching the colon. In this way, the gel matrix has sufficient water available to provide continuous, consistent drug release, even in areas of low water content, such as the colon. <br />
  • 10 <br /> Tamsulosin Ocas® has an improved pharmacokinetic profile compared with conventional tamsulosin MR. <br /> This graph shows the steady-state pharmacokinetic profiles for conventional tamsulosin MR (in blue) and Tamsulosin Ocas® (in green) from 2 separate studies. <br /> Conventional tamsulosin MR shows a peak in plasma levels at 8 to 10 hours followed by a drop in plasma levels that continues towards the end of the 24-hour dosing period. <br /> In contrast, Tamsulosin Ocas® shows a reduced peak plasma level and maintenance of consistent plasma levels across the 24-hour dosing period. <br />
  • 11 <br /> Absorption of Tamsulosin Ocas® is not affected by food intake. <br /> These data are from a crossover study of multiple doses of Tamsulosin Ocas®, including Tamsulosin Ocas® 0.4 mg in the fasted and fed state. Steady state was achieved after 5 days of dosing; crossover dosing periods were separated by washout periods that lasted a minimum of 7 days. Each plasma concentration versus time curve represents the average values obtained from 24 study subjects. <br /> Feeding did not affect the mean tmax (4.16 hours in fed state vs 4.75 hours in fasted state) or Cmax (11.1 ng/mL fed vs 10.7 ng/mL fasted). Mean t1/2 was approximately 15 hours in both the fasted and fed states. <br /> For both Cmax and AUC 0-24h, the 90% confidence interval fell between 0.80 and 1.25. Therefore, the pharmacokinetic parameters obtained under fasted and fed conditions can be considered equivalent. <br /> The pharmacokinetics of Tamsulosin Ocas® appear to be unaffected by concomitant food intake. <br />
  • 12 <br /> Thus, to summarize these pharmacokinetic data, Tamsulosin Ocas® has a superior pharmacokinetic profile vs conventional formulation. <br /> Tamsulosin Ocas® delivers consistent drug levels for 24-hour symptom control. In addition, Tamsulosin Ocas® has reduced peak plasma levels compared with conventional tamsulosin, which minimizes potential side effects.1 <br /> Tamsulosin Ocas® also has a lower maximum plasma concentration than conventional tamsulosin MR.1 <br /> Unlike conventional tamsulosin, Tamsulosin Ocas® drug absorption is not affected by food.2 <br /> Tamsulosin Ocas® was approved in August 2004 in The Netherlands, and in December 2004 by European health authorities.2 It is available in most European countries.2 <br /> 1. Djavan B, et al. Eur Urol Suppl 2005;4:61-68.2. Michel MC, et al. Eur Urol Suppl 2005;4:15-24. <br />
  • 23 <br /> In this double-blind, randomized, phase IIIa study, the 0.4-mg and 0.8-mg doses of Tamsulosin Ocas® were further evaluated against placebo and conventional tamsulosin. This slide shows the study design. <br /> After a 2-week, placebo run-in period, men aged 45 years or older with LUTS/BPH were randomized to receive 12 weeks of once-daily treatment with: <br /> Tamsulosin Ocas® 0.4 mg (n=361); <br /> Tamsulosin Ocas® 0.8 mg (n=724); <br /> Conventional tamsulosin 0.4 mg (n=710); or <br /> Placebo (n=357). <br /> The primary efficacy variable was mean change in total IPSS score from baseline. <br /> Secondary variables were mean change in IPSS quality of life (QoL) score and global assessment of change. <br />
  • 24 <br /> Patient enrolment and randomization for the European phase IIIa study is shown here. <br /> 2,152 patients were randomized to receive placebo (n=357), Tamsulosin Ocas® 0.4 mg (n=361), Tamsulosin Ocas® 0.8 mg (n=724) or tamsulosin MR 0.4 mg (n=710) once daily. <br /> The majority of randomized patients completed the study. The discontinuation rate after randomization was very low (107 patients; 5%) with no major differences between the 4 treatment groups. Discontinuation due to treatment-emergent adverse events (TEAEs) was the most frequent reason for withdrawal (57 patients; 2.6%). <br /> In addition, 18 patients (0.8%) discontinued due to insufficient response and 32 patients (1.5%) for other reasons, including: <br /> Lost to follow up (n=9); <br /> Protocol violations (n=3); <br /> AEs starting during the placebo run-in period (n=3); <br /> Death (n=3); <br /> Abnormal laboratory values (n=1); and <br /> Other non-specified reasons (n=13). <br /> Patient demographics and baseline characteristics are presented in the next slide. <br />
  • 25 <br /> Demographics and baseline characteristics of each treatment arm are shown here. There were no relevant differences between the treatment groups for any of the baseline characteristics. <br /> Mean age of patients was approximately 65 years. <br /> Mean total IPSS was around 18.5 points. <br /> Mean Qmax was almost 10 mL/s. <br /> Mean prostate volume was 43–45 mL. <br />
  • 26 <br /> This slide shows the results for the primary efficacy variable of the European phase IIIa study – mean change in total IPSS score from baseline. <br /> At the end of the study, the mean reduction with Tamsulosin Ocas® 0.8 mg (8.0 points or 42.4%) was not statistically significantly different from that with tamsulosin MR 0.4 mg (8.0 points or 43.2% difference 0.0; P=0.9909). <br /> The reduction with both Tamsulosin Ocas® 0.4 mg (7.7 points or 41.7%) and tamsulosin MR 0.4 mg (8.0 points or 43.2%) was statistically significantly greater than with placebo. (5.8 points or 32%; difference respectively 1.7 and 2.0 points; P&lt;0.0001 for both comparisons). The mean change in total IPSS for Tamsulosin Ocas® (0.4 and 0.8 mg) and tamsulosin MR 0.4 mg was comparable. <br />
  • 27 <br /> In terms of the effect on total IPSS over time: <br /> For the mean reduction in total IPSS from baseline to study end, there was no statistically significant difference between Tamsulosin Ocas® 0.8 mg (8.0 points or 42.4%) and conventional tamsulosin MR 0.4 mg (8.0 points or 43.2%; P=0.9909). Both Tamsulosin Ocas® 0.4 mg (7.7 points or 41.7%) and conventional tamsulosin MR 0.4 mg were similarly superior to placebo (5.8 points or 32.0%; P&lt;0.0001 for both comparisons). The absolute mean change and, in particular, the percentage mean change in total IPSS for Tamsulosin Ocas® (0.4 mg and 0.8 mg) and conventional tamsulosin MR 0.4 mg was comparable. <br /> Both Tamsulosin Ocas® 0.4 mg and 0.8 mg and conventional tamsulosin MR 0.4 mg had rapid and comparable onsets of action. At the first assessment after 4 weeks of treatment, approximately 75% of the total improvement was achieved. Further improvement was seen with continuation of treatment. <br />
  • 30 <br /> This slide shows the mean change in supine SBP & DBP from baseline to week 12. The greater reductions in supine SBP and DBP with tamsulosin MR 0.4 mg and Tamsulosin Ocas® 0.8 mg, compared with Tamsulosin Ocas® 0.4 mg, were statistically significant (P&lt;0.05). <br />
  • 31 <br /> In terms of side effects, the European phase III trial showed that Tamsulosin Ocas® 0.4 mg had the lowest incidence of the most common adverse events (AEs). <br /> The 2 most commonly reported AEs were dizziness and abnormal (retrograde) ejaculation. <br /> With regard to dizziness, there were no statistically significant differences between any of the treatment arms. The incidence of dizziness for Tamsulosin Ocas® 0.4 mg was the same as that for placebo (1.4%). <br /> In terms of abnormal ejaculation, the incidence was not significantly higher for Tamsulosin Ocas® 0.4 mg vs placebo. The incidence of abnormal ejaculation was significantly higher with conventional tamsulosin MR 0.4 mg than with placebo (P=0.014). It was also significantly higher in the Tamsulosin Ocas® 0.8 mg group than in the placebo (P=0.0002) or Tamsulosin Ocas® 0.4 mg groups (P=0.0399). <br />
  • 32 <br /> In conclusion, the European Tamsulosin Ocas® phase IIIa study found that: <br /> Tamsulosin Ocas® 0.8 mg provided no significant clinical benefit over conventional tamsulosin 0.4 mg or Tamsulosin Ocas® 0.4 mg. <br /> Tamsulosin Ocas® 0.4 mg exhibited the most favourable tolerability profile, comparable to placebo, for most common AEs. <br /> Thus, Tamsulosin Ocas® 0.4 mg is the optimal dose and formulation for the treatment of LUTS/BPH. <br />
  • 56 <br /> This randomized, crossover study evaluated the effects of Tamsulosin Ocas® 0.4 mg vs conventional tamsulosin 0.4 mg on orthostatic stress in 40 healthy men aged 60 years or older with no abnormal cardiovascular findings. The study results showed that the percentage of patients with positive orthostatic stress tests (OTs) was lower with Tamsulosin Ocas® than with conventional tamsulosin. <br /> Orthostatic stress tests were performed by measuring vital signs of subjects while lying down, sitting and standing. <br /> A positive test was defined by symptoms of orthostatic hypotension or reductions in BP upon changes in position. <br /> At all postdose time-points, fewer subjects receiving Tamsulosin Ocas® 0.4 mg had a positive orthostatic stress test than those receiving conventional tamsulosin. <br /> Across all postdose time-points, 17.5% of subjects receiving Tamsulosin Ocas® had a positive OT compared with 31.7% of subjects receiving conventional tamsulosin – this difference was statistically significant (P0.05). <br />
  • 57 <br /> This slide shows the results of a randomized, double-blind, single-dose, two-way crossover study designed to evaluate the orthostatic cardiovascular effects of Tamsulosin Ocas® against alfuzosin XL 10 mg. The results showed that there was a lower percentage of positive orthostatic stress tests (OTs) among men treated with Tamsulosin Ocas® than in those treated with alfuzosin XL. <br /> The study was conducted in 40 elderly males, aged 60 years or older, under fed conditions. <br /> The primary efficacy variables were the results of OTs performed 4, 6 and 8 hours after dosing. <br /> A positive OT result was defined by symptoms of orthostatic hypotension or reductions in BP upon change in position. <br /> The overall percentage of positive OTs was significantly higher (P0.05) in the alfuzosin XL 10 mg group than in the Tamsulosin Ocas® group. <br />
  • In the Olmsted County Study Rhodes et al used repeat ultrasound measures in a 7-year period and found that average prostatic growth rates were 1.6% yearly in men between ages 40 and 79 years (fig. 1, A).4 Another important finding in this study was that the percent growth of the prostate yearly depends on baseline volume, in that the larger the prostate at baseline, the greater the percent of growth every year thereafter. Similar findings were also reported in men participating in the Baltimore Longitudinal Study of Aging.7,8 Thus, while prostate volume correlates poorly with symptoms and urinary flow at any given time point, the larger the prostate, the greater the likelihood of future clinical deterioration. <br />
  • The type 2 5AR is the predominant isoenzyme in reproductive tissues, especially the prostate, while the type 1 isoenzyme is also responsible for testosterone conversion in the skin, liver and brain, as well as in the prostate. <br />
  • The rationale for the development of 5ARIs is that prostate gland development and growth is dependent on DHT, which is derived from testosterone via the actions of the enzyme, 5AR. 5ARIs competitively bind to the 5AR enzyme, but do not themselves bind to androgen receptors. Inhibition of 5AR suppresses conversion of testosterone to DHT. Research has demonstrated that there are two isoenzymes (types 1 and 2) of 5AR. Type 2 is the dominant isoenzyme in the prostate, while type 1 is present in the smaller amounts in the prostate. Testosterone is converted to DHT by both enzymes in the skin, liver, and prostate. <br />
  • Avodart® is a competitive and specific inhibitor of both type 1 and type 2 5AR isoenzymes. Competitive inhibitors compete with natural substrates, such as testosterone, for binding sites on the enzyme. Specific inhibitors bind with one type of enzyme (5AR) and tend not to affect the activity of other enzymes. In comparison with finasteride, Avodart® is a 45-fold greater inhibitor of type 1 5AR, and a 2.5-fold greater inhibitor of type 2 5AR. Once Avodart® binds with 5AR, it forms a stable complex with the enzyme, inhibiting its activity for prolonged periods of time. The drug does not bind to human androgen receptors, and thus, is not an androgenic or anti-androgenic compound. <br />
  • Combination therapy with a 5ARI and an alpha-blocker leads to rapid improvements in symptoms and significant reductions in the risk of long-term outcomes such as AUR and BPH-related surgery. <br /> Avodart in combination with an alpha-blocker targets the alpha1-adrenoceptors, 5AR1 and 5AR2. Combination therapy with the type 2-selective 5ARI, finasteride, and an alpha-blocker targets only the 5AR2 receptors and alpha1-adrenoceptors. <br />   <br />
  • This slide shows the study design. <br /> This study was a randomized, double-blind, parallel group study to investigate the efficacy and safety of treatment with Dutasteride (0.5mg) and Tamsulosin (0.4mg), administered once daily for 4 years, alone and in combination, on the improvement of symptoms and clinical outcome in men with moderate to severe symptomatic benign prostatic hyperplasia (Year 2 analysis). <br /> Patients and investigators will remain blinded for another 2-years at which point the primary measures of efficacy will be AUR and BPH related surgery. <br /> The primary objective at 2 years is to assess the efficacy of combination treatment in providing superior symptomatic improvement to BPH patients compared with dutasteride and/or tamsulosin monotherapy after 2 years of treatment. The 2 year data have been summarized and are presented in this slide deck. <br /> The primary objective at 4 years is to assess efficacy of combination treatment in providing superior improvement in the clinical outcomes of AUR or BPH-related prostatic surgery to BPH patients compared with tamsulosin or dutasteride monotherapy after 4 years of treatment. 4 year data will be available in 2009. <br />
  • This slides shows the diagnosis and main criteria for inclusion <br /> This slide outlines the major inclusion criteria which include. <br /> Males aged 50 years <br /> Clinically diagnosed BPH <br /> An International Prostate Symptom Score (IPSS) screening score of 12 points, <br /> Prostate volume 30cc, <br /> A total serum Prostate Specific Antigen (PSA) level 1.5ng/mL, <br /> A maximum flow rate (Qmax) &gt;5mL/sec and 15mL/sec, and minimum voided volume of 125mL at Screening. <br /> Subjects with a history or evidence of prostate cancer, previous prostatic surgery or with a screening serum total PSA &gt;10.0ng/mL were excluded. <br /> Subjects selected for this trial were those most likely to experience clinical progression of BPH <br />
  • This slide summarizes the major Year-4 Endpoints <br /> Unlike the Year-2 Endpoints, the majority of analysis are focused on AUR and BPH-related surgery and other significant outcomes. <br /> The primary analysis at Year 4 is the: Time to Event / Proportion of subjects with AUR or undergoing BPH-related prostatic surgery (combined endpoint) <br /> A number of secondary endpoints at Year 4 include: <br /> • Time to BPH clinical progression, defined as one of the following: <br /> -Symptom deterioration by IPSS ≥4 points (i.e. sum score of first 7 questions) on two consecutive visits <br /> -Acute urinary retention (AUR) related to BPH (defined as the inability to urinate requiring catheterisation) <br /> -Incontinence (overflow or urge) (defined as socially or hygienically unacceptable involuntary leakage of urine) <br /> -Recurrent urinary tract infection (UTI) or urosepsis (where recurrence is defined as 2 or more episodes of symptomatic infection of 105 cfu/mL during the study) <br /> -Renal insufficiency related to BPH (defined as ≥50% sustained rise in baseline serum creatinine and ≥1.5mg/dL) <br /> • Proportion of subjects with symptom deterioration of IPSS ≥4 points (i.e. sum score of first 7 questions) on two consecutive visits post-baseline <br /> • Time to event/proportion of subjects with AUR <br /> • Time to event/proportion of subjects undergoing BPH-related prostatic surgery <br /> • Proportion of patients with macroscopic haematuria (BPH-related) post-baseline <br /> • Proportion of patients with macroscopic haematospermia (BPH-related) postbaseline <br />
  • Source: Figure F1_Y4 <br /> This slide shows the cumulative probability of AUR or BPH-related surgery. <br /> The data in this slide includes patients who might have reported and AUR or BPH-surgery after 48-months and are included in the month 48 time point and the patient could have been on or off treatment. <br />
  • Clinical Progression: Table E25_Y4 Summary of BPH Clinical Progression (crude rate)., Table E23_Y4 Summary of Time to BPH Clinical Progression (for risk reduction values) <br /> Table E26_Y4 Summary of BPH Clinical Progression For Component = Symptom Deterioration (crude rate); Table E28_Y4 Summary of BPH Clinical Progression For Component = BPH-Related AUR (crude rate); Table E30_Y4 Summary of BPH Clinical Progression For Component = BPH-Related Urinary Incontinence (crude rate); Table E32_Y4 Summary of BPH Clinical Progression For Component = Recurrent BPH-Related UTI/Urosepsis (crude rate); Table E34_Y4 Summary of BPH Clinical Progression For Component = BPH-Related Renal Insufficiency (crude rate); Proofed by PG Apr 06, 2009 <br /> Risk Reduction E23_Y4. <br /> A secondary analysis of BPH clinical progression was also performed. Time to BPH clinical progression was defined as the first occurrence of one of the following: <br /> Symptom deterioration by IPSS &gt;4 points (i.e. sum score of first 7 questions) on two consecutive visits, Acute urinary retention (AUR) related to BPH (defined as the inability to urinate requiring catheterisation), Incontinence (overflow or urge) (defined as socially or hygienically unacceptable involuntary leakage of urine), Recurrent urinary tract infection (UTI) or urosepsis (where recurrence is defined as 2 or more episodes of symptomatic infection of 105 cfu/mL during the study), Renal insufficiency related to BPH (defined as &gt;50% sustained rise in baseline serum creatinine and &gt;1.5mg/dL) <br /> The data in this slide shows the number of events and the incidence based on the overall population for clinical progression, and the subcomponents. <br /> Combination therapy was associated with a statistically significant lower incidence of Clinical Progression compared with tamsulsoin (12.6% for combination vs 21.5% for tamsuloin, p&lt;0.001, 44.1% risk reduction [95%CI 33.6%;53.0%]) or dutasteride and (12.6% for combination vs 17.8% for dutasteride, p&lt;0.001, 31.2% risk reduction [95%CI 17.7%;42.5%]). <br />
  • Source: Table E9 Summary of Qmax Change From Baseline (LOCF) (Note: Used the Adjusted Mean Change values) <br /> Data entered by PG April 07, 2006, Proofed Apr 09, 2009 <br /> The analysis specified that testing start at Month 24 and work backward, then again starting at Month 48 and work backward. <br /> Since Month 48 was not significant at p&lt;0.01, the statistical interpretation must be evaluated with caution. <br /> At month 48, the adjusted mean change from baseline (LOCF) in Qmax were 2.4 mL/sec combination therapy, 2.0 mL/sec dutasteride and 0.7 mL/sec for tamsulosin, respectively <br /> In the Phase 3 trials dutasteride/dutasteride group, the mean change after 48 months in Qmax was 2.8 mL/s (Roehrborn , 2004). <br />
  • Anwser is D as there is no bother and PSA showed prostate not enlarged. Just watch for progression as risk if Qmax &lt; 9 ml /sec <br />
  • The primary efficacy outcomes measure was a change of &gt;3 points in the IPSS. Results of the primary end point did not meet statistical significance. <br /> Among men in the BOO plus DO group, at the end of the initial 3-month treatment period with doxazosin alone, only 35% reported improvement in symptoms. <br /> The remainder (65%) were then given Detrusitol® IR in addition to doxazosin. At the end of the 2-month treatment phase, 73% of those patients assigned to therapy with Detrusitol IR plus doxazosin reported improvement in symptoms (measured by &gt;3-point decrease in IPSS). <br /> Reference <br /> Lee JY, Kim HW, Lee SJ, Koh JS, Suh HJ, Chancellor MB. Comparison of doxazosin with or without Detrusitol in men with symptomatic bladder outlet obstruction and overactive bladder. BJU Int. 2004;94:817-820. <br />
  • Fonda BJU Int 1999;84(Suppl):13–5. <br /> van Kerrebroeck et al. Neurourol Urodyn 2002;21(2):179–83. <br /> Wein et al. BJU Int 2002;90(Suppl 3):28–31. <br /> BPH = benign prostatic hyperplasia. <br />
  • Weiss et al. Neurourol Urodyn 1998;17:467–72. <br /> Mattiasson et al. BJU Int 2002;89:855–62. <br /> Nocturnal polyuria refers to a condition in which the rate of urine output is excessive only at night; the total 24-hour urine output is within normal limits. <br /> Nocturnal polyuria is considered to be one of the main causes of nocturia (Asplund et al. General Pharmacol 1995;26:1203–1209). <br /> Nocturnal polyuria is defined as the production of an abnormally large volume of urine during sleep. What is ‘over production’ of urine? Various definitions have been used in the literature, as shown in this slide (Robertson BJU Int 1999;84(Suppl 1):17–19). <br /> However nocturnal polyuria is defined, nocturnal polyuria is believed to play a significant role in the pathogenesis of nocturia. Up 70% of nocturia cases is believed to be due to nocturnal polyuria. <br /> When evaluating the patient, the measurement of nocturnal urine output should include all the urine produced after going to bed and the first void after arising. <br />
  • Weiss et al. Neurourol Urodyn 1998;17:467–72. <br /> Mattiasson et al. BJU Int 2002;89:855–62. <br /> Nocturnal polyuria refers to a condition in which the rate of urine output is excessive only at night; the total 24-hour urine output is within normal limits. <br /> Nocturnal polyuria is considered to be one of the main causes of nocturia (Asplund et al. General Pharmacol 1995;26:1203–1209). <br /> Nocturnal polyuria is defined as the production of an abnormally large volume of urine during sleep. What is ‘over production’ of urine? Various definitions have been used in the literature, as shown in this slide (Robertson BJU Int 1999;84(Suppl 1):17–19). <br /> However nocturnal polyuria is defined, nocturnal polyuria is believed to play a significant role in the pathogenesis of nocturia. Up 70% of nocturia cases is believed to be due to nocturnal polyuria. <br /> When evaluating the patient, the measurement of nocturnal urine output should include all the urine produced after going to bed and the first void after arising. <br />
  • Asplund & Åberg J Intern Med 1991;229:131–134. <br /> Miller & Shock J Gerontol 1953;8:446–50. <br /> Bauer Drugs Ageing 1993;3:238–45. <br /> Cugini et al Gerontol 1992;47:B14–19. <br /> The rate of urine production is regulated by the kidneys. Normally, about 90% of the 180 L filtered is reabsorbed in the proximal tubule and Henle’s loop. The remaining 10% passes to the distal/collecting tubules where variable amounts of salt and water are removed under the control of the hormones aldosterone and the antidiuretic hormone (AVP). Vasopressin decreases urine production and increases urine concentration. <br /> In healthy adults urine flow follows a circadian rhythm. During the night, AVP levels increase and urine production decreases, minimizing the need to wake to void. In adults, night-time urine production comprises just 25% of the total daily amount. <br /> As a person ages, nocturnal AVP secretion reduces so that day- and night-time levels become similar. This causes an increase in night-time urine production which can result in nocturia. <br /> In addititon, the renal response to AVP falls and the renal concentrating capacity reduces. <br />
  • Vilhardt Drug Investigation 1990; 2 (Suppl 5):2–8. <br /> Desmopressin is a pure V2-agonist. This means that desmopressin retains the anti-diuretic effect of vasopressin and produces little or no vasoconstriction, no increase in blood pressure and no contraction of the uterus or gastrointestinal tract. <br /> When bound to the V2 receptors in the distal tubules in the nephrons of the kidney, desmopressin increases the permeability of the collecting ducts and tubules thereby enhancing water re-absorption. Consequently, the urine becomes more concentrated and the urine volume is reduced. <br />
  • The recommended initial dose of MINIRIN is 0.1 mg at bedtime. If this dose is not sufficiently effective after 1 week, it may be increased weekly, to 0.2 mg and 0.4 mg, by step-up doses. <br /> It is important to start at the lowest possible dose and titrate upwards as tolerated and needed. <br /> Fluid intake shall be limited to the least possible during the period of 1 hour before and 8 hours after administration. <br /> The initiation of treatment in the elderly is not recommended. If clinical circumstances dictate the use of desmopressin in patients aged 65 years and over, serum sodium should be measured before commencing MINIRIN treatment, 3 days after treatment initiation or any increase in dose, and at other times during treatment as deemed necessary by the treating physician. <br /> If signs or symptoms of water retention and/or hyponatraemia are observed (e.g. headache, nausea/vomiting, weight gain) MINIRIN treatment should be stopped until the patient has fully recovered. <br />
  • The initiation of treatment in the elderly is not recommended. If clinical circumstances dictate the use of desmopressin in patients aged 65 years and over, serum sodium should be measured before commencing MINIRIN treatment, 3 days after treatment initiation or any increase in dose, and at other times during treatment as deemed necessary by the treating physician. <br /> If signs or symptoms of water retention and/or hyponatraemia are observed (e.g. headache, nausea/vomiting, weight gain) serum sodium should be monitored and MINIRIN treatment should be stopped until the patient has fully recovered. <br />
  • Abrupt withdrawal <br />

Lower Urinary Tract Symptoms in Men for GPs Lower Urinary Tract Symptoms in Men for GPs Presentation Transcript

  • Lower Urinary Tract Symptoms Workshop PETER NG
  • Lower Urinary Tract Symptoms (LUTS)
  • LUTS Are a Constellation of Storage and Voiding Symptoms Straining Urgency incontinence IntermittencyNocturia Sense of incomplete emptying Poor flowFrequency Post-void dribbleHesitancyUrgency Post-micturitionVoidingStorage Symptoms Often Relate to Bladder and ProstateSymptoms Often Relate to Bladder and Prostate Abrams P et al. Neurol Urodyn. 2002;21:167-178. Terminal dribbleTerminal dribbleOther incontinenceOther incontinence
  • Overall Prevalence of LUTS in MenLUTS were experienced by 6 of 10 men in the general population 38.7%38.7% 61.3%61.3% Men with LUTS Men without LUTS N = 5460 Irwin DE et al. Abstract. EAU 2006.
  • Prevalence of LUTS in Men Prevalence,% Incomplete emptying Post-micturitiondribble Irwin DE et al. Abstract. EAU 2006. Storage Voiding Post- micturition Nocturia 47.2 Terminaldribble 14.8 13.3 Urgency 11.1 Slow stream 8.9 5.1 Frequency 6.4 Straining 6.4 Incontinence 5.1 Intermittency 2.8 0 5 10 15 20 25 30 35 40 45 50 Nocturia: waking to void ≥1 times per night Frequency: subject feels he/she urinates too often during the day
  • Overall Prevalence of LUTS in Subang Jaya Men LUTS were experienced by 8 of 10 men in the general population N =351 Khoo EM ,Tan HM ,Low WY J Sex Med 2008;5:2925–2934.
  • Prevalence of LUTS in Asians Homma Y, Kawabe K, Tsukamoto T, et al. Epidemiologic survey of lower urinary tract symptoms in Asia and Australia using the international prostate symptom score. Int J Urol 1997;4:40–6[27]
  • Despite the bother of symptoms, most men with LUTS do not seek medical help Garraway et al. Br J Clin Pract 1993;43:318–21 While 48.4% of men reported ‘urgency’, and 28.3% found urgency bothersome, but only 4.5% consulted a doctor
  • Prevalence of Nocturia Men Women 48.6 20.9 11.9 8.2 5.2 54.5 24.0 13.4 8.9 6.2 0 10 20 30 40 50 60 Prevalence,% ≥1 ≥2 ≥3 ≥4 ≥5 Times Wake per Night to Void, n Irwin DE et al. Abstract. EAU 2006. EPIC Study. Data on file. Pfizer Inc.
  • Not Specific to Any Lower Tract Pathology BPH
  • Overactive Bladder Bladder Cancer Cystitis Bladder stones Neurogenic bladder-DM, Spinal Urethral stricture STD BPO Prostate cancer Prostatitis Constipation Excessive Urine Output Osmotic diuresis-DM Diuretics CCF
  • BPH – histological process 50% of men aged 50 and 80% of men older than 70
  • Terminology BPHBPH BPEBPE BPOBPO 50% No obstruction LUTS 50% Non enlargement
  • The lower urinary tract symptoms in BPH BPH Bladder Outlet Obstruction (BOO) Bladder Outlet Obstruction (BOO) Impaired detrusor contractility Impaired detrusor contractility Detrusor Overactivity Detrusor Overactivity • Voiding symptoms - hesitancy - weak stream - prolonged voiding - post voiding dribbling - feeling of incomplete emptying • Decreased flow rates • Post void residual urine • Voiding symptoms - hesitancy - weak stream - prolonged voiding - post voiding dribbling - feeling of incomplete emptying • Decreased flow rates • Post void residual urine • Storage symptoms - urge - frequency - nocturia - urge incontinence • Decreased bladder capacity • Storage symptoms - urge - frequency - nocturia - urge incontinence • Decreased bladder capacity DHICDHIC OAB Sensory OAB Sensory
  • Crucial points in History
  • The International Prostate Symptom Score (IPSS)  The I-PSS is based on the answers to 7 questions concerning urinary symptoms.  Each question is assigned points from 0 to 5 indicating increasing severity.  The total score can therefore range from 0 to 35 (asymptomatic to very symptomatic). Mild 0-7 Moderate 8-19 Severe 20-35
  • Patient name: Date 1. Incomplete emptying Over the past month, how often have you had a sensation of not emptying your bladder completely after you finish urinating? 2. Frequency Over the past month, how often have you had to urinate again less than two hours after you finished urinating? 3. Intermittency Over the past month, how often have you found you stopped and started again several times when you urinated? Less than 1 time in 5 Not at all Less than half in the time About half the time More than half the time Almost always 0 1 0 0 1 1 2 2 2 3 3 3 4 4 4 5 5 5 The International Prostate Symptom Score (1)
  • Patient name: Date 4. Urgency Over the past month, how often have you found it difficult to postpone urination? 5. Weak stream Over the pas month, how often have you had a weak urinary stream? 6. Straining Over the past month, how often have you had to push or strain to begin to urinate? 7. Nocturia Over the past month, how many times did you most typically get up to urinate from the time you went to bed until the time you got up in the morning? Less than 1 time in 5 Not at all Less than half in the time About half the time More than half the time Almost always 0 1 0 0 1 1 2 2 2 3 3 3 4 4 4 5 5 5 0 1 2 3 4 5 The International Prostate Symptom Score (2)
  • Patient name: Date 1. If you were to spend the rest of your life with your urinary condition just the way it is now, how would you feel about that? PleasedDelighted Mostly satisfied Mixed about equally satisfied and dissatisfied Unhappy Terrible 0 1 2 3 4 5 BOTHER SCORE (BS) = The bother score (IPSS 8th question)
  • 22 DRE •Size •Assymetery •Nodules •Tenderness •Anal Tone
  • Urinalysis -Haematuria, - Proteinuria, - Pyuria, Microhematuria = 5rbc/ul 4-5% of men with microscopic haematuria will be found to have a cancer or other urological disease within the first 3 years following the test.
  • 24 PSA Level GENERAL PRACTICE ASSESSMENT • Detection of Prostate Cancer Estimation of Prostate Size
  • 25
  • 26 Flowmetry Only This is the basicbasic Non-InvasiveNon-Invasive urodynamic test Flow Transducer Flow Recorder Flowmeter Recording Flow
  • 27 Results of Flowmetry Delay Time s 2.5 Max. Flow Rate ml/s 23.5 Time to Max. Flow s 3.5 Flow Time s 11.3 Voiding Time s 13.5 Voided Volume ml 120 Average Flow Rate ml/s 10.6 Residual Volume ml 90 Flowmeter-Rate ml/s Time s 10 20
  • 28
  • 29
  • 30
  • 31 Max flow rate % risk of obstruction <10ml/sec 90 10-14ml/sec 76 >=15ml/sec 30
  • Indications for urodynamics • younger person who is about to undergo surgical intervention • patient with a large residual volume indicating a possible hypocontractile bladder as well • patient where there doubt about the presence of obstruction • concomitant neurological disease like Parkinsons disease which will make the pathophysiology of the LUTS more complicated 32
  • 33 VLPP (Cough) Recording Vesical & Abdominal Pressures and Flowmetry 215 3710 cmH2O L L L 2 ml / s Delay 0,8 s 37 cmH2O Pves Pump PabdFlowmeter My bladder is filled up to 200 ml before VLPP testing
  • 34
  • Upper urinary tract function assessment creatinine measurement and/or ultrasonographic examination PV determination the method of choice is transrectal ultrasonograph transabdominal ultrasound is also acceptable
  • 36  Severe IPSS  Hematuria  Elevated PSA  Elevated Creatinine  Abnormal DRE  Recurrent UTI  Palpable Bladder  Young Patient <45  Neurological Disease  Unresponsive to Mx
  • 37 GENERAL PRACTICE MANAGEMENT • LUTS Bothersome YES NO Large Prostate >30ml PSA>1.4ng/mlActive Treatment Watchful Waiting
  • Indications of watchful waiting  Uncomplicated BPH  Symptoms not bothersome (usually IPSS ≤7)  Symptoms significantly bothersome but after being informed of various treatment options and their consequences, the patient chooses watchful waiting
  • Watchful waiting Fluid restriction Bowel habit Care with flu meds Beverages
  •  The patient’s symptoms and clinical course should be monitored, usually annually. Definition of watchful waiting
  • Prostate growth Rhodes, T, Girman, C. J., Jacobsen, S. J., Roberts, R. O., Guess, H. A., Lieber, M. M.: J Urol, 161: 1174, 1999 Average prostatic growth rates were 1.6% yearly in men between ages 40 and 79 years, faster rate in larger baseline prostate glands
  • Placebo cohorts Variable ALTESS (2yrs) MTOPS (4.5yrs) Patients 757 735 IPSS worse>=4 127(16.8%) 97(14%) AUR 14(1.8%) 18 (2%) BPH surgery 49(6.5%) 37(5%) Incontinence Not done 6(0.8%) Sepsis No done 1(0.1%) Wiygul, Jeremy; Babayan, Richard K Watchful waiting in benign prostatic hyperplasia. Current Opinion in Urology. 19(1):3-6, January 2009.
  • Predictive of progression  IPSS>=8(1)  Qmax <12ml/sec(1)  Age >70(1)  Increasing PVR(2) medical Tx arm MTOPS  Worsening symptoms(2)  PSA>1.5ng/ml(2)  Transitional zone volume >25ml(3) 1.Jacobsen SJ, Jacobsen DJ, Girman CJ, et al. T Urol 1999; 162:1301–1306 2. Emberton M. BJU Int 2006; (97 Suppl 2):12–15 [discussion 21–22]. 3. Djavan B, Fong YK, Harik M, et al. Urology 2004; 64:1144–1148.
  • Indications of medical treatment  Uncomplicated BPH  Symptoms are bothersome (usually IPSS>7) and after being informed of various treatment options and their consequences, the patient chooses medical treatment  Progression from watchful waiting
  • 45 GENERAL PRACTICE MANAGEMENT • LUTS Bothersome YES NO Large Prostate >30ml PSA>1.4ng/ml Active Treatment Watchful Waiting OAB BPH obstructionPrimary Nocturia
  • There are 3 pharmacological classes used in BPH Plant extractsPlant extractsα1-blockersα1-blockers 5α-reductase inhibitors5α-reductase inhibitors
  • α1-blockers in the Treatment of BPH
  • They are sparse in the bladder body α1-receptors are abundant in the bladder neck, prostate and urethra
  • α1-blockers are expected to reduce the sympathetic tone of the prostate and the urethra. α1-blockers act on the dynamic component of BOO •50% intraurethral pressure of normal person •98% receptors in prostatic stroma
  • α1A α1B α1D α1 α2 α2A α2B α2C Predominant in human prostate α 1995 1974 1948 α-adrenoceptor classification 3.9 :1
  • Effects of Alpha1 Subtypes α1B α1D α1A Systemic vasculature Bladder Prostate Older person Alpha 1B upregulated
  • 52
  • α1-blockers may have local but also systemic effects Prostate Urethra Bladder Neck Prostate Urethra Bladder Neck ↓ Outflow resistance ↓ Outflow resistance ↑ Flow Rates ↑ Flow Rates ↓ Voiding Symptoms ↓ Voiding Symptoms ↓ Residual Urine ↓ Residual Urine ↓ Filling Symptoms ↓ Filling Symptoms BladderBladder Blood vesselsBlood vessels ↓ Bladder Instability ↓ Bladder Instability ↓ Blood Pressure ↓ Blood Pressure Postural Hypotension Dizziness Postural Hypotension Dizziness URINARY TRACT EFFECT SYSTEMIC EFFECT α1A α1B α1D
  • Non Selective Alpha 1 blockers Terozosin , Doxasosin, Proazosin α1B α1D α1A Systemic vasculature Bladder Prostate Older person Alpha 1B upregulated
  • Selective Alpha 1 blockers Tamsulosin, α1B α1D α1A Systemic vasculature Bladder Prostate Efficacy the same but far less systemic side effects
  • Designing the ideal formulation Michel MC, et al. Eur Urol Suppl 2005;4:15-24. Eliminate effect of food on absorption Control release – no dose dumping Consistent release continues despite low water content Absorption of conventional tamsulosin and alfuzosin XL are food- dependent Current formulations are water dependent – this impedes consistent drug release in colon Current controlled-release α1-A antagonists Ideal characteristics
  • OCAS® : The ideal formulation • Carries water throughout the entire GI tract, including to the colon, where water content is lowest • Consistent drug release Rapid gelation & complete hydration Stevens HNE & Speakman M. Curr Med Res Opin 2006;22:2323-2328.
  • Tamsulosin Ocas® : Improved pharmacokinetic profile *YM12617. †617C1302. Adapted from Djavan B, et al. Eur Urol Suppl 2005;4:61-68. Steady-state; Tamsulosin Ocas® vs conventional 0.4 mg capsule
  • Tamsulosin Ocas® absorption NOT affected by food intake N=24. Adapted from Michel MC, et al. Eur Urol Suppl 2005;4:15-24.
  • Tamsulosin Ocas® : Superior pharmacokinetic profile • Delivers consistent drug levels over 24 hours1 • Lower maximum plasma concentration (Cmax)1 • Irrespective of food intake2 Tamsulosin Ocas® delivers consistent drug levels for optimal 24-h control of symptoms while minimizing side effects 1. Djavan B, et al. Eur Urol Suppl 2005;4:61-68. 2. Michel MC, et al. Eur Urol Suppl 2005;4:15-24. Tamsulosin Ocas® vs conventional tamsulosin
  • Tamsulosin Ocas® : European phase IIIa study design • Double-blind, randomized, placebo- and active comparator-controlled, parallel-group study placebo (N=57) tamsulosin Ocas® 0.4 mg (N=361) -2 4 8 Screening Randomization Final assessment Weeks 0 placebo run-in conventional tamsulosin 0.4 mg cap (N=710) tamsulosin Ocas® 0.8 mg (N=724) 12 Adapted from Chapple CR, et al. Eur Urol Suppl 2005;4:33-44.
  • European phase IIIa: Patient enrolment Adapted from Chapple CR, et al. Eur Urol Suppl 2005;4:33-44.
  • European phase IIIa: Demographic & baseline characteristics IPSS=International Prostate Symptom Score. Qmax, prostate volume and PSA data at enrolment instead of baseline visit. Adapted from Chapple CR, et al. Eur Urol Suppl 2005;4:25-32.
  • European phase IIIa: Mean change in total IPSS -5.8 -7.7* -8.0* -8.0** -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 placebo (N=350) tamsulosin Ocas® 0.4 mg (N=354) conventional tamsulosin 0.4 mg (N=700) tamsulosin Ocas® 0.8 mg (N=707) MeanchangeintotalIPSS *P<0.0001 vs placebo; **P=0.9909 vs conventional tamsulosin. IPSS=International Prostate Symptom Score. Adapted from Chapple CR, et al. Eur Urol Suppl 2005;4:33-44.
  • European phase IIIa: Effect on total IPSS over time *P<0.0001 vs placebo. IPSS=International Prostate Symptom Score. Adapted from Chapple CR, et al. Eur Urol Suppl 2005;4:33-44.
  • European phase IIIa: Mean change, supine SBP & DBP From baseline to week 12 SBP=systolic blood pressure; DBP=diastolic blood pressure. *P<0.05 vs tamsulosin Ocas 0.4 mg. Adapted from Chapple CR, et al. Eur Urol Suppl 2005;4:33-44.
  • European phase IIIa: 0.4 mg Tamsulosin Ocas® , lowest incidence of most common AEs * significant vs placebo. † significant vs Tamsulosin Ocas® 0.4 mg. Adapted from Chapple CR, et al. Eur Urol Suppl 2005;4:33-44.
  • Tamsulosin Ocas® European phase IIIa: Conclusions • Increasing the Tamsulosin Ocas® dose to 0.8 mg does not improve IPSS score • Conventional tamsulosin has a confirmed favourable efficacy/safety ratio • Tamsulosin Ocas® 0.4 mg has tolerability comparable to placebo • Tamsulosin Ocas® 0.4 mg is the optimal formulation & dose for treating LUTS/BPH Chapple CR, et al. Eur Urol Suppl 2005;4:33-44.
  • Tamsulosin Ocas® : Less orthostatic stress *P≤0.05 vs Tamsulosin Ocas® . N=40. OT=orthostatic stress tests. Adapted from Michel MC, et al. Eur Urol Suppl 2005;4:45-52. % Patients with positive OT vs conventional tamsulosin
  • % Positive OTs reduced with Tamsulosin Ocas® vs alfuzosin XL 10 mg *P≤0.05 vs Tamsulosin Ocas® based on discordant pairs testing. N=40. OT=orthostatic stress tests. Data on file, 2005. Yamanouchi Pharmaceuticals Co.
  • 1 Marks et al. Urology 2003, 62, 888-893 2 Lepor Urology 1998, 51, 892-900 3 AUA Practice Guidelines Committee, J.Urol 2003, 170, 530-547 4.Djavan B et al. Eur Urol 1999;36:1–13; Schulman CC et al. Eur Urol 1996;29:145–54 MTOPS Steering Committee. J Urol 2002; 167:265 Benefits of α1-blockers in BPH  Rapid onset of action – From the first dose on peak flow rate for alfuzosin1 and tamsulosin2 , – From the first days on LUTS, – Typically established within 2 weeks  Majority respond – Typically 50–70% of patients respond (4)  Best monotherapy for relief of LUTS3 – Improvement of IPSS of 4 to 6 points – Improve symptom score by 30-40% (4) – Improve Qmax by 16-26% (4)
  • 1 Marks et al. Urology 2003, 62, 888-893 2 Lepor Urology 1998, 51, 892-900 3 AUA Practice Guidelines Committee, J.Urol 2003, 170, 530-547 Benefits of α1-blockers in BPH  Effective irrespective of prostate size  Improve quality of life and respect sexual function – Except tamsulosin which is associated with ejaculatory dysfunction (EjD)
  • Phytotherapy
  • Popular preparations • Hypoxis rooperi (South African star grass), • Serenoa repens/Sabal serrulata (saw palmetto berry), • Pygeum africanum (African plum), • Seceale cereale (rye pollen) • Cucurbita pep (Pumpkin seeds), Stephan Madersbacher, Ingrid Berger, Anton Ponholzer and Martin Marszalek Current Opinion in Urology 2008, 18:16–20
  • Components Discovered • Phytosterols, • [Beta]-sitosterols, • Fatty acids • Lectins More common ones Stephan Madersbacher, Ingrid Berger, Anton Ponholzer and Martin Marszalek Current Opinion in Urology 2008, 18:16–20
  • Possible mechanisms of Phytotherapy • 5[alpha]-reductase inhibition, • Aromatase activity, • Androgen blockade, • [Alpha]1-blockade, • Inhibition of prostaglandin synthesis, • Anti-inflammatory • Inhibit growth factors • Improve detrusor function • Free radical scavenger • Alteration cholesterol metabolism In Vitro activity seen but not confirmed invivo There is no change in prostate volume or PSA
  • Trials so far • In 2006, two clinical trials meeting the WHO benign prostatic hyperplasia consensus conference criteria (randomized against placebo/standard therapy, study duration 12 months) were published • Placebo vs saw palmetto – no diff • Saw Palmetto vs Tamsulosin – improvement identical but no detailed on Qmax, postvoid residual or prostate volume
  • Improvement in symptoms score Stephan Madersbacher, Ingrid Berger, Anton Ponholzer and Martin Marszalek Current Opinion in Urology 2008, 18:16–20
  • Improvement in flow rate
  • AUA BPH Guidelines 2003 Phytotherapeutic agents cannot be recommended for treatment of BPH at this time … mechanisms of action, effectiveness, and safety of these agents have not been well documented in multicenter, clinical trials with independent data monitoring American Urological Association 2003 BPH Guidelines (1st Revision Since 1994) Phytotherapy: recommendations AUA Guideline Committee J. Urol 2003, 170, 530-47
  • EAU BPH Guidelines 2004 These drugs are not recommended for the treatment of elderly men with LUTS suggestive of benign prostatic obstruction benign prostatic hyperplasia’ Eur. Urol 2004, 46, 547-54 Combination therapy: recommendations
  • Case 2   59 yr old Chinese gentleman  presented with acute difficulty in  passing water as well as urinary  incontinence  on coughing or  straining.  No hematuria nor fever or  pain
  •   He had a history of hypertension and  maturity onset diabetes treated with  oral hypoglycaemics and had a recent  bout of influenza. 
  • DRE  showed a  45g  prostate  smooth
  •  What is your diagnosis ? What are the possible triggers for this event?  What would you do next
  •  Bladder overdistension  Imobility, constipation, Long journey,surgery  Meds like anticholinergics or opiods-decrease  bladder fullness, flu meds -symphaticomimetic  ETOH symphatetic stimulator  Diabetic cystopathy  Prostatic inflammation  Prostatic infarction  BPH progression
  •  Urethral  catheterisation  done with 16f  Foley catheter.   
  • 800 ml of urine  was drained What is  significance of  the urine  volume? What  investigations?
  •  UFEME  UCS  Serum Creatinine  US Urinary tract
  • Upper urinary tract function assessment creatinine measurement and/or ultrasonographic examination PV determination the method of choice is transrectal ultrasonography transabdominal ultrasound is also acceptable
  •  Hb 16.0  Creatinine 110 umol/L  PSA 15 ng/ml  Urine 50 rbc/ul wbc 12/ul  What is your next move?
  • 96  BPH   Prostatitis  Prostatic  massage  (1.5-2  times  the  normal  PSA)   Prostate biopsy  (rise by 8ng/ml)  TURP                 ( rise by 6ng/ml)  Urinary retention  Ejaculation recent within 48-72h   DRE?
  • Alpha Blocker  Trial off Catheter in 1-3 days  Refer for Surgery a sudden stimulation of [alpha]1- adrenergic receptors
  • TURP
  • Thullium Laser
  • POST OP 3 MONTHS
  •  Haematuria  UTI and urosepsis,   Urine leak, catheter obstruction   Double the rate of prolonged hospitalization  than in men catheterized for <= 3 days
  • McNeill SA, Hargreave TB; members of the ALFAUR study group. Alfuzosin once daily facilitates return to voiding I n patients in acute urinary retention. J Urol 2004; 171: 2316–20 P=0.012
  •  What else need to be done? For his PSA?
  •  Antibiotics for the PSA  4 weeks of Ciprofloxacin  Repeat  PSA level 3.8ng/ml  What is the next step?
  • Prostate growth Rhodes, T, Girman, C. J., Jacobsen, S. J., Roberts, R. O., Guess, H. A., Lieber, M. M.: J Urol, 161: 1174, 1999 Average prostatic growth rates were 1.6% yearly in men between ages 40 and 79 years, faster rate in larger baseline prostate glands
  • 108 Size is Predictor of progression Marberger MJ, Andersen JT, Nickel JC et al prostate volume and PSA as predictors of AUR, Combined experience from 3 large multinational placebo controlled trials Eur Urol 2000; 38:563-8
  •  The risk of complications increases with  age (a 70-year old male has a 8x the risk of a 40-year old)  symptom severity (IPSS > 7 means a 4x risk increase)  PV (> 30cc means a 3x risk of AUR 1 )  decreased Qmax (< 12mL/second means a 3x risk)  antihypertensive (not diuretics) or anti-arrhythmic drug use 1 Jacobsen SJ et al. J Urol 1997;158:481–7
  • 13.7 8.9 4.9 5.4 7.2 5.1 10-yearcumulativerisk(%) 20 15 10 5 0 Risk of AUR versus other diseases (60 year old male) AUR Hip fx Hip fx Diabetes Stroke MI (women) (men) Jacobsen S. Urology 2001;58(6A):5
  • Scalp, hair follicle Sebaceous glands Liver Liver Prostate (mainly in stroma) Chest/skin Beard Type 1 Type 2 Brain Brain (low levels in hypothalamus and hippocampus) Skin Prostate (mainly in epithelium) Type 1 and type 2 isoenzyme distribution Genital tissues Seminal vesicles
  • 5AR in the prostate  Two distinct isoforms of 5AR – type 1 and type 2  Type 1 is also expressed in the prostate (mainly epithelium)  Type 2 is the dominant isoenzyme in the stroma of normal human prostate
  • FOR INTERNAL USE ONLY Inhibitors of 5AR • Finasteride (ProscarTM ) - MSD – inhibitor of type 2 • Dutasteride (AvodartTM ) - GSK – inhibitor of both type 1 and type 2 AvodartTM is 2.5x more potent against type 2 isoenzyme than finasteride Increased potency and dual inhibition may be warranted to enhance suppression of DHT
  • FOR INTERNAL USE ONLY • Finasteride reduces systemic DHT by 65-70% • Dutasteride reduces systemc DHT by 90% • Both reduce intraprostatic DHT by 90% • With Dutasteride the uro-flowrates improving at a month earlier at 3 months instead of 4 months with Finasteride and the symptoms score improving two months earlier at 6 months compared with 8 months with Finasteride. • No clinical difference demonstrated yet
  • Rationale for Combination Therapy (2) 5AR2 5AR1 Finasteride Avodart Reduced PV 5ARIs α-blockers 5AR2 Combination therapy offers rapid onset and durable symptom relief and long-term reductions in progression Smooth Muscle Relaxation
  • 116 Study design (n=3,047 randomised) Combination Treatments: MTOPS MTOPS Steering Committee. J Urol 2002;167:265 Screen and placebo run-in Placebo Doxazosin 4 or 8mg once daily Finasteride Combination 0 4 weeks 48 months
  • MTOPS: combination therapy is more effective in reducing overall progression Cumulative incidence of overall clinical progression Years from randomization 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 Placebo FinasterideDoxazosin Combination 0 5 10 15 20
  • 118 MTOPS: summary  Risk of progression reduced by – 39% for Doxasosin – 34% Finasteride – 67% Combination  Risk Retention reduced by – 31% doxaosin – 67% finasteride Monotherapy also significantly reduces the risk of BPH clinical progression – 79% combined  Doxazosin increases the time to progression of AUR and invasive therapy, but does not reduce the overall risk
  • AUA BPH Guidelines 2003 “Appropriate and effective treatments for patients with LUTS and demonstrable prostatic American Urological Association 2003 BPH Guidelines (1st Revision Since 1994) Combination ther recommendat AUA Guideline Committee J. Urol 2003, 170, 530-47
  • CombAT study designCombAT study design Tamsulosin 0.4 mg Dutasteride 0.5 mg Combination Placebo run-in Safety follow-up Screening Pre-screen Screen Baseline 4 years Follow-up (+16 weeks) Single-blind Double-blind Visits every 3 months, daily dosing 2 years IPSSPrimary endpoints: Siami et al. Contemp Clin Trials 2007;28:770–9 AUR / surgery
  • CombAT main entry criteriaCombAT main entry criteria  Men agedMen aged ≥≥50 years50 years  Diagnosis of BPH by history and DREDiagnosis of BPH by history and DRE  IPIPSSSS ≥≥12 (moderate to severe symptoms)12 (moderate to severe symptoms)  Two voids at screening with QTwo voids at screening with Qmaxmax >>5 and5 and ≤≤1515 mlml/s (at minimum voided volume of/s (at minimum voided volume of ≥≥125 ml)125 ml)  Prostate volumeProstate volume ≥≥30 cm30 cm33 byby TRUSTRUS  Serum PSA 1.5–10.0 ng/mlSerum PSA 1.5–10.0 ng/ml Siami et al. Contemp Clin Trials 2007;28:770–9
  • MeanMean ± S.D.± S.D. CombATCombAT11 (n=4844)(n=4844) MTOPSMTOPS22 (n=3047)(n=3047) Age (years)Age (years) 66.166.1 ± 7.01± 7.01 62.662.6 ± 7.3± 7.3 CaucasianCaucasian 4259 (88%)4259 (88%) 2509 (82%)2509 (82%) Total IPSSTotal IPSS 16.416.4 ± 6.16± 6.16 16.916.9 ± 5.9± 5.9 Prostate volume (cc)Prostate volume (cc) TotalTotal Transition zoneTransition zone 55.055.0 ± 23.58± 23.58 29.5 ± 21.97*29.5 ± 21.97* 36.336.3 ± 20.1± 20.1 16.416.433 Serum PSA (ng/mL)Serum PSA (ng/mL) 4.04.0 ± 2.08± 2.08 2.42.4 ± 2.1± 2.1 Qmax (mL/sec)Qmax (mL/sec) 10.710.7 ± 3.62± 3.62 10.510.5 ± 2.6± 2.6 Post-void residual volume (mL)Post-void residual volume (mL) 67.767.7 ± 64.87± 64.87 68.168.1 ± 82.9± 82.9 Baseline characteristics ofBaseline characteristics of CombAT relative to MTOPSCombAT relative to MTOPS 1. Roehrborn et al. Eur Urol 2008;179:616-21. McConnell et al. NEJM 2003; 349: 2387–98; 3. Roehrborn et al. Unpublished MTOPS data *Sub-group of 656 men
  •  PrimaryPrimary – Time to event/proportion of subjects with AURTime to event/proportion of subjects with AUR or BPH-related surgeryor BPH-related surgery  SecondarySecondary – Time to BPH-related clinical progression –Time to BPH-related clinical progression – First of:First of: – Symptom deterioration by IPSS ≥4 pointsSymptom deterioration by IPSS ≥4 points – Acute urinary retentionAcute urinary retention – IncontinenceIncontinence – Recurrent UTI or urosepsisRecurrent UTI or urosepsis – Renal insufficiency related to BPHRenal insufficiency related to BPH  All primary and secondary endpoints evaluated at Year 2All primary and secondary endpoints evaluated at Year 2 are secondary endpoints at Year 4are secondary endpoints at Year 4 CombAT 4-year endpointsCombAT 4-year endpoints Siami et al. Contemp Clin Trials 2007;28:770–9
  • CombAT: Time to first AUR or BPH-relatedCombAT: Time to first AUR or BPH-related surgerysurgery 0 12 24 36 48 Study month Combination Dutasteride Tamsulosin Risk reduction estimate combination vs. tamsulosin = 65.8% (95% CI: 54.7, 74.1%) Risk reduction estimate combination vs. dutasteride = 19.6% (95% CI: -10.9, 41.7%) 1010 PatientswithAURorBPH-related surgery(%) 16 14 12 8 6 4 2 0 p<0.001 p = 0.18 Roehrborn et al. In press with Eur Urol 67 84 191 Combination; dutasteride + tamsulosin
  • IncidenceIncidence *p<0.001 vs. combination ** Roehrborn et al. In press with Eur Urol CombAT: Crude incidence of AURCombAT: Crude incidence of AUR or BPH-related surgery at Year 4or BPH-related surgery at Year 4 Combination; dutasteride + tamsulosin
  • CombinationCombination (n=1610)(n=1610) DutasterideDutasteride (n=1623)(n=1623) TamsulosinTamsulosin (n=1611)(n=1611) At Year 4At Year 4 nn %% nn %% nn %% Clinical progressionClinical progression 203203 12.6%12.6% 289289 17.8%*17.8%* 347347 21.5%*21.5%* Risk reductionRisk reduction vs.vs. combinationcombination (95% CI)(95% CI) 31.2%31.2% (17.7–42.5%)(17.7–42.5%) 44.1%44.1% (33.6–53.0%)(33.6–53.0%) Crude rate based on ITT population *p<0.001 vs. combination CombAT 4-year BPH clinical progressionCombAT 4-year BPH clinical progression Roehrborn et al. In press with Eur Urol IPSS incr. ≥4-pointsIPSS incr. ≥4-points 139139 8.6%8.6% 212212 13.1%*13.1%* 229229 14.2%*14.2%* AURAUR 2626 1.6%1.6% 3737 2.3%2.3% 8282 5.1%*5.1%* IncontinenceIncontinence 4949 3.0%3.0% 6060 3.7%3.7% 6565 4.0%4.0% UTIUTI 33 0.2%0.2% 55 0.3%0.3% 55 0.3%0.3% Renal insufficiencyRenal insufficiency 11 <0.1%<0.1% 22 0.1%0.1% 77 0.4%0.4% Combination; dutasteride + tamsulosin
  • AdjustedmeanIPSSchange frombaseline (n = 1610) (n = 1611) p < 0.001 combination vs. tamsulosin p < 0.001 combination vs. dutasteride Study month (n = 1623) Roehrborn et al. In press with Eur Urol CombAT IPSSCombAT IPSS Adjusted mean change from baseline (LOCF)Adjusted mean change from baseline (LOCF) Combination; dutasteride + tamsulosin
  • p<0.001 combination vs. tamsulosin p≤ .006 combination vs. dutasteride Roehrborn et al. In press with Eur Urol CombAT QmaxCombAT Qmax Adjusted mean change from baseline (LOCF)Adjusted mean change from baseline (LOCF) Combination; dutasteride + tamsulosin
  • Combination therapy
  •  A 63 year old gentleman presented with LUTS for the past 9 months  His IPSS =6 QL = 2  There is no hematuria  He has diabetes  DRE showed a 30g prostate which was non tender and smooth
  •  USKUB showed 12mm cyst left lower pole of the kidney and enlarged prostate 46g  PSA 1.04ng/ml  Cret 69 umol/L  Uroflowmetery showed  Max Flow Rate 9 ml/secVol is 183ml and res 74ml and prolonged curve
  • Your management  5 alpha reductase inhibitor  Alpha blocker  Combination therapy  Watchful waiting
  •  A 50 year old gentleman presented with LUTS for the past 3 years but recently there is bladder pain and pain at the tip of his penis whenever he passes water.  His IPSS =23  There is obvious hematuria  He has diabetes as well as HT  DRE showed a 50g prostate which was tender
  •  How would you investigate him  What is your provisional diagnosis?
  •  RBC nil  WBC 15 /ul  Urine culture negative  PSA 31ng/ml  US urinary system normal
  •  How would you treat him?
  •  Done 6 weeks later on 1.2ng/ml  He still has IPSS of 15  How would you treat him?
  •  90 year old father of a local GP presented with acute retention of urine after a right hemicolectomy  He had denied any antecedant LUTS but his wife says he does get up out of bed often at night.  A CBD was inserted and even after the 7th post op day he could not pass water on trial off a catheter
  •  Physical examination showed distended bladder and 45g prostate gland which was non tender and there is severe pain on doing DRE and fecal impaction  What would you do next?
  •  PSA was 9 ng/ml  He developed a swinging fever  What test would you do next?
  •  Klebsiella 100000 org /ml  Sens to Ofloxacin and resistance to Cephalosporins  How would you treat him?
  •  Trial off CBD was done after giving alfuzosin for three days  He wet his pants in bed so had to use diapper  Discharged home well after 2 weeks in hospital  GP rings up and says he took another urine culture and this time grew E Coli
  •  E Coli culture  Resis to Augmentin and Cefuroxime but sens to Aminoglycoside and Imepenam  No fever  No pain  Apetite well  Wet pants- diappers  What would you do?
  • Assymptomatic Bacteriuria • Two consecutive clean voided specimens of 100,000org/ml Hooton TM. Recurrent urinary tract infection in women [Review]. Int J Antimicrob Agents 2001; 17:259-268.
  • ACTIVE Management of Assymptomatic Bacteriuria • Pregnant women • Urological instrumentation European Urology Association UTI guidelines 2006
  • Conservative Management of Assymptomatic Bacteriuria • pre-menopausal, non-pregnant women • diabetic women • older persons living in community • elderly institutionalized subjects • persons with spinal cord injury • catheterized patients while the catheter remains in situ. European Urology Association UTI guidelines 2006
  •  Alpha blocker or 5 alpha reductase inhibitor or both?
  •  63 year old Indian gentleman presented with a 3 year history of LUTS. His IPSS = 27 and QL = 5.There was recent constipation .  There was no dysuria nor hematuria nor bone pain or weight loss  DRE showed 35g prostate with impacted stools
  •  UFEME showed 2 rbc/ul otherwise clear  Serum creatinine 100umol/L  USKUB normal kidneys and enlarged prostate gland  PSA 2.5ng/ml
  •  How would you go about treating him?
  •  He gets on Doxasosin XL 4mg nocte and Dutasteride 0.5mg daily for 6 months  His return IPSS = 22 mainly irritative bladder symptoms  What would you do next?
  • Detrusitol® IR Added to Doxazosin in alpha-Blocker Non-responders Was More Likely to Improve Symptoms in Patients with BOO and DO Doxazosin + Detrusitol IR Doxazosin BOO ImprovedImproved n = 60n = 60 79%79% NOTNOT ImprovedImproved n = 16n = 16 21%21% ImprovedImproved n = 6n = 6 37.5%37.5% NOTNOT improvedimproved n = 10n = 10 62.5%62.5% BOO and DO ImprovedImproved n = 24n = 24 35%35% NOTNOT ImprovedImproved n = 44n = 44 65%65% ImprovedImproved n = 32n = 32 73%73% NOTNOT improvedimproved n = 12n = 12 27%27% Lee JL et al. BJU Int. 2004;94:817-820.Results of primary end point did not meet statistical significance. Improvement was defined as at least a 3-point reduction in IPSS
  • Case 6 • 68 year old gentleman presented with LUTS with and IPSS of 28 • There was no hematuria • There was DM • DRE showed a 45 g prostate smooth non tender with no nodules • PSA was 2ng/ml • Qmax 9ml/sec on a volume of 245ml and residual of 78ml
  • • How would you go about treating him?
  • • He responded to the alpha blocker and dutasteride • IPSS = 14 • He has great urinary flow but still has poor quality of life • He has to wake up 4 times at night to pass water and this causes day time sleepiness • What is your next course of action?
  • F/V informs about my diuresis (i.e. bladder capacity) This is the first urodynamic screening test. F/V Frequency Volume Chart Monday Thuesday Wednesday Thrusday Friday Saturday Date : ……………. Name : …………………………. FREQUENCY VOLUME CHART Number Time Volume 3 2 3 4 07:00 250 11:20 200 18:00 420 10:00 600 21:00 700 09:00 450 12:00 320 20:00 600 07:20 400 11:00 350 16:00 410 21:00 350
  • What causes nocturia? Nocturnal polyuriaNocturnal polyuria PRIMARY NOCTURIAPRIMARY NOCTURIA PsychologicalPsychological factorsfactors UntreatedUntreated diabetesdiabetes mellitusmellitus PrimaryPrimary polydipsiapolydipsia UnstableUnstable bladderbladder UntreatedUntreated diabetesdiabetes insipidusinsipidus UncompensatedUncompensated heart diseaseheart disease ReducedReduced bladderbladder capacitycapacity NocturiaNocturia Fonda 1999; van Kerrebroeck 2002; Wein 2002.
  • Multifactorial cause of Nocturia NP 20% SB 5% BOO 2% NP+SB 15% NP+BOO 20% SB+BOO 10% NP+SB+BOO 23% NP+SB+SA 5% NP SB BOO NP+SB NP+BOO SB+BOO NP+SB+BOO NP+SB+SA Sh Shyh-Chyi Chang, Alex TL Lin , Kuang Kuo Chen and Luke S Chang , Multifactorial Nature of Male Nocturia , Urology 2006: 67: 541-544
  • • 49 patients 51-78y with BPH in Sultanah Aminah Hsp JB • Nocturia 2-5 (3.4 mean) • Prevalance = 85.4% Yoong BF, Bala Sundaram M and Aida Z Med J Malaysia Aug 2005, Vol 60:3 p 294- 296 NocturnalNocturnal polyuria with BPHpolyuria with BPH
  • What causes nocturia? • Defined as a night-time urine production that is: – > 35% of 24-hour urine volume – > 50% of total 24-hour urine production from 19:00 to 07:00 hours – in excess of bladder capacity Weiss 1998; Mattiasson 2002.Weiss 1998; Mattiasson 2002. NocturnalNocturnal polyuria is a primary cause of nocturiapolyuria is a primary cause of nocturia
  • What is the role of the kidney? • Urine production by the kidney follows a circadian rhythm • At night, arginine vasopressin (AVP, the antidiuretic hormone) secretion increases; urine production therefore falls • With age: – nocturnal AVP production falls – renal response to AVP declines – renal concentrating capacity reduces Asplund & Åberg 1991; Miller & Shock 1953; Bauer 1993; Cugini 1992.Asplund & Åberg 1991; Miller & Shock 1953; Bauer 1993; Cugini 1992.
  • Vilhardt 1990.Vilhardt 1990.  Selective VSelective V22 receptorreceptor agonistagonist  Potent anti-diureticPotent anti-diuretic effecteffect  Concentrates the urineConcentrates the urine Desmopressin How does desmopressin work?How does desmopressin work? Desmopressin is a substitutional therapy inDesmopressin is a substitutional therapy in patients with deficient AVP productionpatients with deficient AVP production V2
  • How should MINIRIN tablets be used in nocturia? • Single night-time dosing with antidiuretic effect within 30min • Titrate dose at weekly intervals: 0.1→ 0.2→ 0.4 mg . Higher dose prolongs duration of action but no greater antidiuretic effect • Fluid intake must be limited from 1 hour before to 8 hours after administration as duration of action 6-8h • Monitor serum sodium level if increased risk of hyponatraemia
  • Important considerations whenImportant considerations when using MINIRIN tabletsusing MINIRIN tablets Measure serum sodium and stop treatment until the patient has fully recovered … patient experiences nausea and/or headache Monitor serum sodium… increased risk of hyponatraemia Stop treatment until patient has recovered … patient has a fever, gastroenteritis or systemic infection Limit fluid intake… patient drinks a lot RecommendationIf …
  • MINIRIN shifts nocturnal urine production towardsMINIRIN shifts nocturnal urine production towards normal circadian rhythmnormal circadian rhythm • MINIRIN significantly reduced the number of nocturnal voids • MINIRIN prolonged the sleep period before first void – by 2 hours • 1/3 of the patients had an undisturbed first period of sleep > 5 hours
  • Case 7 • 40 year old man who presented with LUTS as well as suprapubic discomfort, low back pain for the last 6 months • There was no hematuria • UFEME showed 12wbc/ul but UCS was clear • DRE - 20g normal prostate gland • What do you think is the diagnosis here?
  • What is the post probable cause? A. Prostatitis (Chronic Pelvic Pain Syndrome) B. Overactive bladder C. Bladder stone D. Interstitial Cystitis E. Recurrent Chronic UTI Case 14
  • NIH classification Definition Cat 1-Acute bacterial prostatitis Acute infection Cat11-Chronic bacterial prostatitis Recurrent infection Cat111-Chronic pelvic pain syndrome (CPPS)No demonstrable infection Cat 111A-Inflammatory CPPS No demonstrable infection; WBCs in semen EPS/VB3 Cat111B-Noninflammatory CPPS No demonstrable infection; no WBCs in semen, EPS/VB3 Cat1V-Asymptomatic inflammatory prostatitis No symptoms
  • Table 2.Screening for prostatitis using the PPMT Diagnosis Pre-M urine culture Post-M ur cult WBCs post-M Category11 - + + Category111A - - + Category111B - - - Cystitis (+/- Category 11) + + + PPMT Premassage and postmassage test Pre-M Premassage Post-M Postmassage
  • Management • Explanation • Manage expectations • Exclude other diagnosis • Antibiotics • Alpha blockers- Terozosin • Prostatic Massage • Gabapentin
  • IMPORTANT FEATURE-IN STERILE URINE • CHRONIC LUTS IN MEN • PAINFUL BLADDER ON HOLDING ON CHRONIC PROSTATITIS-Cat 3 INTERSTITIAL CYSTITIS BLADDER STONE
  • Case 8 • 35 year old gentleman presented with acute right loin pain and LUTS a day prior to seeing you. • There was nausea and vomiting as well at the time
  • • Temp 37.2 C • Comfortable at rest • Abdomen showed some deep tenderness over the RIF
  • UFEME • Rbc –Nil • Wbc –nil • Protein – nil • Serum Creatinine 135umol/L
  • IVP How would you treat him?
  • Management • Fluids 2-2.5L /day • Pain relief
  • Spontaneous passage rates • Stones size Passage rates • <=5mm 68% • >5<=10mm 47% European Urology Association Ureteral Stone Guidelines 2007
  • Medical tx passage rates • Agent Passage rates • Nifedipine 75% • Alpha Blockade 81% European Urology Association Ureteral Stone Guidelines 2007
  • Efficacy of [alpha]-Blockers for the Treatment of Ureteral Stones • 11 trials and 911 patients • “Compared to patients who received conservative management alone, patients who received [alpha]-blockers were 44% more likely to expel the stones.” Parsons, J. Kellogg *,+; Hergan, Lori Ann; Sakamoto, Kyoko; Lakin, Charles Efficacy of [alpha]-Blockers for the Treatment of Ureteral Stones. Journal of Urology. 177(3):983- 987, March 2007
  • Comparison of Efficacy of 3 different alpha 1 adrenergic blockers for distal ureteric stones • 114 patient ages 18-65 yrs • Followed up for a month • Weekly Xrays and US Yilmaz E, Batislam E, Basar MM. J Urol 2005; 173:2010–2012.
  • Stone Expulsion Rates P=0.03 P=0.03 Yilmaz E, Batislam E, Basar MM. The comparison and efficacy of 3 different alpha 1 adrenergic blockers for distal ureteral stones. J Urol 2005; 173:2010–2012.
  • Pain episodes P=0.004 P=0.018 Analgesic usage also less Number of pain episodes Yilmaz E, Batislam E, Basar MM. The comparison and efficacy of 3 different alpha 1 adrenergic blockers for distal ureteral stones. J Urol 2005; 173:2010–2012.
  • Average time to expulsion P=0.004 P=0.03 Number of pain episodes Yilmaz E, Batislam E, Basar MM. The comparison and efficacy of 3 different alpha 1 adrenergic blockers for distal ureteral stones. J Urol 2005; 173:2010–2012.
  • Criteria • Distal ureteral stones < 10mm • Absences of severe colic • Absence of colic last more than a day • Absence of infection • No evidence of renal failure • Absence of severe hydronephrosis or hydroureter • Dual Kidneys
  • Case 9 • A 56 year old gentleman presented with an incidentally raised PSA level of 6.7ng/ml • He has and IPSS = 7 • He has no difficulty with uroflow • No hematuria • No medical problems • DRE showed a normal 45g prostate which was smooth • What would you do next?
  • 189 • What is a raised PSA level? PSA level Prevalence of cancer Sensitivity Specificity 3.1 - 4.0 26.90% 20.50% 93.80% 2.1 - 3.0 23.90% 32.20% 86.70% 1.1 - 2.0 17.00% 52.60% 72.50% 0.6 - 1.0 10.10% 83.40% 38.90% < 0.5 6.60% Not reported Not reported
  • 190 Raised PSA level • BPH • Prostatitis • Prostatic massage (1.5-2 times the normal PSA) • Prostate biopsy (rise by 8ng/ml) • TURP ( rise by 6ng/ml) • Urinary retention • Ejaculation recent within 48-72h • DRE?
  • 191 TRUS biopsy • Negative biopsy does not mean absence of cancer • Sedation • Preop antibiotics • Septicaemia in 3% • Expect hematuria and hematospermia • Anal spasm
  • Reduce Trial AUA 2009 April
  • Reduce Criteria  Men 50-75 years old  PSA 2.5ng-10ng/ml (<60yrs ) or PSA 3-10 in men >=60 yrs  Single negative biopsy in the last 6 mths  80 ml prostate gland
  • Design Control-Placebo Dutasteride 2 year 10 core biopsy 4 year biopsy Prn biopsy if clinically indicated 6.4% Random 7 mths Biopsy 6726 men Placebo run in 1 month Andriole J Urol 2004; 172:
  • END POINT Dutasteride reduced the risk of cancer by 23% p<0.0001 Placebo 857 vs Dutasteride 659 No increase in high grade cancer
  • BPH related complications
  • Case 11 • 37 year old gentleman who presented with premature ejaculation since he has been sexually active for the last 3-4 years. • Ejaculates with seconds of penetration. Sometimes even before penetration. • No problems with erections. • Has loss of libido as well. • Exam : Normal genitalia, Female dist of hair. • IPSS is 4.
  • McMahon 2nd isced ,Committee 9b REPORT 2004 • WJHAT IS NORMAL INTRAVAGINAL EJACULATION LATENCY TIME? Normal men IELT 2-10mins No definite agreement on best PE vs non PE break point •Prepenetration (5-7%) In most large PE groups • 30-40% <20 sec • 80% <40 sec • 90% <60 sec • 95% <120sec
  • PREMATURE EJACULATION 3. psychological distress in the patient and/or partne 1. brief ejaculatory latency <1min 2. loss of control (inability to delay on vaginal penetration)
  • Diagnosis of PE Onset and duration Degree of distress Psychosocial hist Relationship issues Clinical assessment PE is due to ED PDE5 inhibitor Organic cause prostatitis Treat cause TREAT PE Richardson, Daniel BSc; et al Recommendations for the management of premature ejaculation: BASHH Special Interest Group for Sexual Dysfunction Int J of STD and AIDS Volume 17(1), January 2006, pp 1-6
  • COUPLANDETALJCLINPSYCHOPHARMACOL1996:356-362 SSRI WITHDRAWAL SYNDROME •Diziness •Parasthesia •Lethargy •Vivid dreams/insomnia •Irritability •Lowered mood Common Symptoms Men > Women Occurrence varies amongst SSRI’S Clomipramine>Paroxetine>Fluvoxa mine>Setraline>Fluoxetine
  • USINGTHEPITCHBOOKTEMPLATE Method Tramadol 50mg taken 2 hrs before sex self-administered IIEF, IVELT, mean weekly coitus episodes, and adverse drug effects. Patients and their wives were interviewed separately Results •Placebo controlled randomised trial •Tramadol vs Placebo •64 potent patient •mean age, 34 years; range, 20-52 years •IVELT<2min in 90% of coitus •Stable relationship 6 mths •No organic cause of PE • Safety and Efficacy of Tramadol in the Treatment of Premature Ejaculation: A Double-blind, Placebo-Controlled, Fixed- Safarinejad, Mohammad Reza MD; Hosseini, Seyyed Yoosof ,Journal of Clinical Psychopharmacology. 26(1):27-31, February 2006.
  • MEAN INTRAVAGINAL EJACULATORY LATENCY TIME P<0.001 Safarinejad, Mohammad Reza MD; Hosseini, Seyyed Yoosof ,Journal of Clinical Psychopharmacology. 26(1):27-31, February 2006.
  • Mean number of intercourse/week P<0.005 Safarinejad, Mohammad Reza MD; Hosseini, Seyyed Yoosof ,Journal of Clinical Psychopharmacology. 26(1):27-31, February 2006.
  • Mean satisfaction domain of IIEF P<0.005 Safarinejad, Mohammad Reza MD; Hosseini, Seyyed Yoosof ,Journal of Clinical Psychopharmacology. 26(1):27-31, February 2006.
  • SATISFACTIONWITHTHEMEDICATION % of pt or wives * p<0.01 * Safarinejad, Mohammad Reza MD; Hosseini, Seyyed Yoosof ,Journal of Clinical Psychopharmacology. 26(1):27-31, February 2006.
  • TRAMADOL MECHANISM OF ACTION •inhibition of neuronal reuptake of serotonin •inhibition of neuronal reuptake of noradrenaline, •enhancing serotonin efflux, antinociceptive effect, •inhibition of spinal somatosensory- evoked potentials. Completely absorbed after 30min Peak plasma concentrations (Cmax) are attained within 1.6 to 1.9 hours The mean elimination half-life is approximately 5 to 6 hours.
  • ADVERSE EVENTS No Tramadol patients (%) No of Placebo patients (%) p Adverse Events 9(28.1) 5(15.6) <0.05 Nausea 5(15.6) 1(3.1) <0.05 Vomiting 2(6.2) 2(6.2) ns Dizziness 1(3.1) 2(6.2) Constipation 1(2.6) 0
  • TRAMADOL MECHANISM OF ACTION •inhibition of neuronal reuptake of serotonin •inhibition of neuronal reuptake of noradrenaline, •enhancing serotonin efflux, antinociceptive effect, •inhibition of spinal somatosensory- evoked potentials. Completely absorbed after 30min Peak plasma concentrations (Cmax) are attained within 1.6 to 1.9 hours The mean elimination half-life is approximately 5 to 6 hours.