[Management of geriatric patients with benign prostatic hyperplasia]. / Das Management geriatrischer Patienten mit benignem Prostatasyndrom.

Multimorbid older men are increasingly more common in daily practice and present a challenge because they are often affected by lower urinary tract symptoms (LUTS) and age-associated benign prostatic hyperplasia (BPH). In order to identify possible risks in diagnostics, therapy and counselling at an early stage, screening for functional deficits or risk factors with standardized procedures is helpful. An initial screening with subsequent assessment of everyday skills using the Barthel Index, Timed up & Go Test, and a cognitive test are recommended. If frailty syndrome is detected, it should be taken into account during the pre-, peri-, and postoperative management, as it may indicate increased morbidity and mortality. Noninvasive methods for reducing the prostate volume without anesthesia can be a therapy option in older multimorbid patients, and with individual planning and consideration of risk factors, up to 70% of individuals become symptom-free. However, there is currently no gold standard for this vulnerable patient group. Number of medications and concomitant diseases and higher need for help are per se risk factors for unsatisfactory results after transurethral resection of the prostate (TURP) or laser vaporization. With drug therapy, concomitant medications and their interactions, especially in the cytochrome system, an existing multimorbidity and adherence to therapy must be taken into account. Combination therapies may complement each other and may bridge the time until surgery. Minimally invasive methods that can be performed without general anesthesia are suitable for geriatric patients, especially those with recurrent retention. Studies with the Rezüm® system (NxThera Inc., Maple Grove, MN, USA) and UroLift® (NeoTract Inc., Pleasanton, CA, USA) show that about 70% of patients can be relieved from the permanent catheter.

[Do benign prostatic hyperplasia drugs affect mood or cognition?] / Beeinflussen Medikamente gegen das benigne Prostatasyndrom Stimmung oder Kognition?

Based on new evidence, we discuss the risk of central nervous side effects, mainly reduced cognition/dementia and depressive symptoms during the use of drugs for the treatment of lower urinary symptoms suggestive of benign prostatic hyperplasia. Cognitive impairments during use of muscarinic antagonists are well documented and mechanistically well understood, but their occurrence differs quantitatively between members of this drug class. The occurrence of depressive symptoms while using 5α-reductase inhibitors only became known recently but has now been observed consistently in several studies and is mechanistically plausible; it appears to occur with similar incidence when using dutasteride and finasteride. A moderate increase in new diagnoses of dementia has recently been reported from a single study upon use of tamsulosin but not other α1-adrenoceptor antagonists. The plausibility of a mechanistic cause-effect relationship is only moderate, and the association could be explained based on selection bias. Overall, physicians should be alert for the occurrence of central nervous side effects during the treatment of lower urinary tract symptoms.

An observational study of patient satisfaction with fesoterodine in the treatment of overactive bladder: effects of additional educational material.

AIM: To compare the effects of additional educational material on treatment satisfaction of overactive bladder (OAB) patients treated with a muscarinic receptor antagonist. METHODS: In an observational study of OAB patients being treated by their physician with fesoterodine for 4 months (FAKTEN study), sites were randomised to providing standard treatment or additional educational material including the SAGA tool. Patient satisfaction was assessed by three validated patient-reported outcomes including the Treatment Satisfaction Question. Because of premature discontinuation of the study, descriptive statistical analysis was performed. RESULTS: A total of 431 and 342 patients received standard treatment or additional educational material, respectively. At study end, 76.1% [95% CI = 71.3, 80.4] of patients with standard care and 79.6% [95% CI = 74.4, 84.1] with additional SAGA tool were satisfied with treatment (primary end-point). Comparable outcomes with and without the additional educational material were also found in various patient subgroups, at the 1-month time point, and for the other patient-reported outcomes. A notable exception was the subgroup of treatment-naïve patients in which the percentage of satisfied patients was 77.2% vs. 89.5% with standard treatment and additional SAGA tool, respectively (post hoc analysis). DISCUSSION AND CONCLUSIONS: In an observational study, most overactive bladder patients were satisfied with fesoterodine treatment. Because of the small sample size, the study does not support or refute the hypothesis that adding the SAGA tool will improve patient satisfaction with treatment. The potential effect of additional educational material in treatment-naïve patients warrants further dedicated studies.

Does concomitant diabetes affect treatment responses in overactive bladder patients?

AIMS: To compare the efficacy and tolerability of a muscarinic receptor antagonist, darifenacin, in the treatment of overactive bladder (OAB) patients with concomitant diabetes as compared with those without comorbidities. METHODS: Post hoc exploratory analysis of a published, large, non-interventional study in OAB patients treated with darifenacin including 532 diabetics and 1315 controls. Associations of diabetes with treatment responses were evaluated by multiple regression models. RESULTS: Diabetics (largely type 2 patients) and controls differed in baseline age, body weight, duration of OAB symptoms and presence of co-medications. However, they exhibited similar OAB symptom episode frequency and problem rating and received similar starting doses of darifenacin. Presence of diabetes was associated with a significantly smaller reduction of OAB symptoms, but the effect attributable to diabetes was small relative to the overall treatment response. The presence of diabetes was not associated with differences in tolerability. DISCUSSION AND CONCLUSIONS: We conclude that a muscarinic receptor antagonist has comparable efficacy and tolerability in the treatment of OAB patients with and without concomitant diabetes.

Autonomic nervous control of the urinary bladder.

The autonomic nervous system plays an important role in the regulation of the urinary bladder function. Under physiological circumstances, noradrenaline, acting mainly on ß(3) -adrenoceptors in the detrusor and on α(1) (A) -adrenoceptors in the bladder outflow tract, promotes urine storage, whereas neuronally released acetylcholine acting mainly on M(3) receptors promotes bladder emptying. Under pathophysiological conditions, however, this system may change in several ways. Firstly, there may be plasticity at the levels of innervation and receptor expression and function. Secondly, non-neuronal acetylcholine synthesis and release from the urothelium may occur during the storage phase, leading to a concomitant exposure of detrusor smooth muscle, urothelium and afferent nerves to acetylcholine and noradrenaline. This can cause interactions between the adrenergic and cholinergic system, which have been studied mostly at the post-junctional smooth muscle level until now. The implications of such plasticity are being discussed.

[Dose-escalation of SSRIS in major depressive disorder. Should not be recommended in current guidelines]. / Dosisverhoging van SSRI'S bij depressie; niet aan te bevelen in richtlijnen.

BACKGROUND: In cases where patients with unipolar depression do not respond to a standard dose of selective serotonin reuptake inhibitors (SSRIS), treatment guidelines often recommend a higher dose. A systematic review of the literature revealed uncertainty about the efficacy of dose escalation and pointed to methodological weaknesses in earlier research. AIM: To review current practice and results concerning dose-escalation of SSRIS. METHOD: We made a summary of previously published English articles that systematically reviewed previous SSRI-dose-escalation studies in depressed patients and present the results of a recent double-blind randomised dose-escalation study of paroxetine. By means of a 123I-ß-cit-spect study in a subgroup of the patients in the recent dose-escalation study it was possible to measure the amount of paroxetine bound to serotonin transporters. This provided combined clinical and pharmacological outcomes. RESULTS: The study with paroxetine provided clinical evidence that dose-escalation of paroxetine in depression was not effective and that adverse effects increased. The occupancy of the serotonin-transporters did not increase significantly after dose-escalation, despite increases in paroxetine serum levels. CONCLUSION: Dose-escalation of ssris for patients with unipolar depression who did not respond to a standard dose, does not improve response or the chance of remission. The pharmacological explanation for this is that the occupancy of the serotonin-transporters does not increase following dose-escalation.

Do gender, age or lifestyle factors affect responses to antimuscarinic treatment in overactive bladder patients?

AIMS: Gender, age, obesity, smoking and alcohol or caffeine intake have been shown or proposed to be risk factors for the prevalence and/or severity of the overactive bladder symptom complex (OAB) or related parameters. We have explored whether any of these factors affect the therapeutic response to a muscarinic receptor antagonist during routine clinical use. METHODS: Data were analysed from 3766 OAB patients (77.1% woman, age 62.6 +/- 12.8 years) participating in an observational, open-label postmarketing surveillance study of the safety and efficacy of darifenacin. Multiple logistic regression models were applied to explore the effect of potential OAB risk factors on the darifenacin treatment-associated improvement of OAB symptoms, patient's subjective rating of bladder problems and global efficacy and tolerability. RESULTS: Age and (less consistently) gender were statistically significantly correlated with efficacy parameters, but the extent of their impact was judged to be too small to be clinically relevant. Except for a very small effect of body mass index on urgency episode improvement, none of the lifestyle-associated factors had significant effects on the efficacy of darifenacin. Except for a very small age effect, none of the potential risk factors had significant effects on global tolerability. DISCUSSION AND CONCLUSIONS: We conclude that the efficacy and tolerability of a muscarinic receptor antagonist, such as darifenacin is largely independent of potential OAB risk factors, such as gender, age, obesity, smoking and alcohol or caffeine intake.

Urinary urgency - translating the evidence base into daily clinical practice.

AIM: To consider the currently available knowledge and understanding of the symptom of urgency. MATERIALS & METHODS: Each faculty member reviewed the literature base of a different aspect of urgency and along with their personal clinical experience provided a base of evidence for discussion. RESULTS: This overview summarises relevant published literature and the current clinical experience of the authors. DISCUSSION: Whilst the mechanisms producing the sensation of urgency are still not fully understood and we are working within a definition that may complicate measurement and treatment, our pressing need is to effectively manage our patients for whom the practical nature of urgency can be all too apparent. CONCLUSION: Health care professionals have an important role to play today in helping to alleviate the widespread problem of urgency and its consequences.

How are women with SUI-symptoms treated with duloxetine in real life practice? - preliminary results from a large observational study in Germany.

BACKGROUND: Duloxetine was found safe and effective in the treatment of moderate to severe female stress urinary incontinence (SUI) in controlled clinical trials; complementary data from routine clinical practice are still wanted. OBJECTIVES: To explore the use of various initial duloxetine doses by physicians in the treatment of female SUI in routine clinical practice and its implications on drug safety and patients' subjective impression of effectiveness. METHODS: Adult women treated with duloxetine for SUI symptoms were documented as part of an ongoing large-scale observational study in Germany. Data collected at baseline, after 4 and 12 weeks, were evaluated by initial doses. Statistics were descriptive, 95% confidence intervals were calculated for adverse event (AE) rates. RESULTS: A total of 7888 adult women were treated with duloxetine; their mean age was 61.4 years, body mass index 27 kg/m(2), incontinence episode frequency (IEF) 14.0 per week. Previous SUI treatments were observed in 52.2%, comorbidities in 60.4% of the patients. A total of 90.7% reported reduced frequency of SUI-episodes, 12.1% any AE; nausea (5.7%) and vertigo (1.6%) were reported most frequently. In all, 52.2% of patients were initiated on a duloxetine dose of 40 mg/day. Only minor differences in patient characteristics, effectiveness and tolerability were associated with varying initial duloxetine doses. CONCLUSIONS: Many women received lower duloxetine doses than expected based on evidence-based dosing recommendations. Although SUI patients in this study had a higher health risk because of old age and multiple comorbidities than in previous controlled clinical trials, AE rates were lower, possibly because of the observational character of the study and/or the use of rather low doses. Similar AE rates for varying initial doses possibly reflect sensible dose-adjustment to individual needs.

The design and development of fesoterodine as a prodrug of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of tolterodine.

This review highlights the design and development of fesoterodine (Toviaz) as a prodrug of 5-hydroxymethyl tolterodine (5-HMT), which is also the active metabolite of tolterodine, for the treatment of overactive bladder (OAB). Tolterodine and 5-HMT are both potent antimuscarinic agents. A prodrug approach was necessary for systemic bioavailability of 5-HMT after oral administration. Fesoterodine was selected amongst a series of ester analogues of 5-HMT to develop an advanced OAB treatment with an optimum biopharmaceutics profile, while maintaining a pharmacological link to tolterodine. While tolterodine and 5-HMT have similar antimuscarinic activity, the logD value, a determinant of lipophilicity and permeability across biological interfaces such as the gut wall and blood-brain barrier, is considerably lower for 5-HMT (0.74) versus tolterodine (1.83). In contrast to the cytochrome P450 (CYP) 2D6-mediated metabolism of tolterodine, 5-HMT formation from fesoterodine occurs via ubiquitous nonspecific esterases. Consequently, treatment with fesoterodine results in consistent, genotype-independent exposure to a singular active moiety (5-HMT); treatment with tolterodine results in CYP2D6 genotype-dependent exposure to varying proportions of two active moieties (5-HMT and tolterodine). At least partially due to the avoidance of variations in pharmacokinetic exposures observed with tolterodine, it was possible to develop fesoterodine with the flexibility of two efficacious and well-tolerated dosage regimens of 4 and 8 mg daily.

Different response patterns of several ligands at the sphingosine-1-phosphate receptor subtype 3 (S1P(3)).

BACKGROUND AND PURPOSE: Recently, some ligands targeting the sphingosine-1-phosphate receptor subtype 3 (S1P(3)) have become available. The characterization of these compounds was mainly based on one functional read-out system, although S1P(3) receptors are known to activate different signal transduction pathways. Therefore, this study pharmacologically characterizes these compounds using different assays. EXPERIMENTAL APPROACH: Using CHO-FlpIn cells expressing the human S1P(3) receptor the potencies and maximal effects of S1P, FTY720-P, VPC23019, VPC23153 and VPC24191 were determined in three different assays [inhibition of cAMP accumulation, elevation of intracellular calcium concentrations ([Ca(2+)](i)) and S1P(3) receptor internalization]. KEY RESULTS: All compounds tested inhibited forskolin-induced cAMP accumulation, increased [Ca(2+)](i) and induced S1P(3) receptor internalization but with different potencies and maximal effects. S1P was the most potent compound in all assays followed by FTY720-P. The VPC compounds were generally less potent than S1P and FTY720-P. Regarding the maximal effects, all compounds except VPC23153, behaved as full agonists in the cAMP accumulation assay. In the calcium assay, FTY720-P, VPC23019 and VPC24191 displayed partial and VPC23153 weak partial agonist activity, relative to S1P. Interestingly, treatment with the G(i) inactivator Pertussis toxin, did not affect S1P-induced [Ca(2+)](i) elevations but inhibited those in response to the other compounds, by about 50%. CONCLUSIONS AND IMPLICATIONS: This study demonstrated differential response patterns at the S1P(3) receptor for a range of ligands. These differences could indicate the presence of functional selectivity at this receptor as FTY720-P and the VPC compounds seemed to signal predominantly via G(i)- whereas S1P activated G(i) and G(q)-coupled pathways.

[Drug-drug interactions in urology]. / Arzneimittelinteraktionen in der Urologie.

Many patients concomitantly receive multiple urological and nonurological medications. This practice can lead to drug-drug interactions (DDIs). These interactions can be pharmacodynamic (acting on the same body function) or pharmacokinetic (affecting each other's concentrations) and are a frequent cause of adverse drug reactions. Examples of pharmacodynamic DDIs include the use of overactive bladder drugs together with those prescribed for psychiatric or neurological indications that also have anticholinergic properties, or the use of PDE5 inhibitors together with vasodilating drugs, particularly nitrates. Pharmacokinetic DDIs are mainly due to effects on drug metabolism, specifically that involving CYP3A4 and 2D6, or on drug transporters. Drugs can both inhibit and induce the activity of many of these enzymes and transporters. CYP3A4 inducers can lower levels of cyclosporine or tacrolimus so much that transplant rejection occurs, and CYP3A4 inhibitors can increase their levels, leading to nephrotoxicity. Levels of the anticholinergic darifenacin can be increased so much by potent CYP3A4 inhibitors that this combination is contraindicated. These examples show that knowledge of DDI can help patients avoid undesirable side effects of drugs.

[Anticholinergic treatment of overactive bladder syndrome. Is it all the same?]. / Anticholinerge Therapie der überaktiven Blase. Ist alles dasselbe?

Anticholinergic therapy is the first-line therapy for overactive bladder (OAB) syndrome. Especially in the last years, the number of available substances has increased because of the launch of solifenacin, darifenacin, and fesoterodine. Additionally, slow-release and transdermal formulations have led to a large variety of available treatment options. The efficacy of all substances has been proven in randomised, double-blind studies, and reviews and meta-analyses have also underlined the efficacy of all available anticholinergics and have been updated regularly. All available drugs are efficacious for OAB treatment, and clinically relevant differences among them have not been proven consistently. Moreover, age, gender, and the type of OAB (dry vs. wet) seem to lack clinically relevant impact on the efficacy of OAB treatment. The various drugs are similar in tolerability, with the exception of more dry mouth and central nervous effects with slow-release oxybutynin. Knowledge of pharmacokinetic properties of the individual substances is important in order to choose the right therapy for each patient.

[Contemporary medical management of the benign prostatic syndrome]. / Aktuelle Aspekte der medikamentösen Therapie bei benignem Prostatasyndrom (BPS).

Two groups of drugs, alpha blockers and 5-alpha-reductase inhibitors (5ARI), are currently widely used for the medical treatment of benign prostatic syndrome (BPS). Alpha blockers are characterized by a rapid onset of efficacy. If given at an adequate dose, all alpha blockers have a similar efficacy, yet quantitative differences regarding side effects exist. The onset of clinical efficacy of 5ARIs is delayed and dependent on prostate volume. Symptom improvement is generally less pronounced than with alpha blockers, yet this difference declines with time. 5ARI, in contrast to alpha blockers, reduce prostate volume and the risk of long-term BPS complications such as prostate surgery or acute urinary retention. The combination therapy of alpha blockers and 5ARI is superior to either monotherapy; however, this superiority becomes evident only after prolonged (>1 year) therapy. Because of additive side effects, this combination should be reserved for BPS patients with a high risk of progression. Regarding plant extracts, no definitive recommendation can be given because of a limited number of high-quality clinical trials. The use of antimuscarinics in men with BPS with a dominance of storage symptoms and without significant obstruction is promising, although further trials, particularly with a longer study duration, are required.

[German guidelines for the assessment of BPH. What's new in 2007?]. / Deutsche Leitlinien zur Diagnostik des benignen Prostatasyndroms. Was ist neu in 2007?

The new version of the German guidelines for assessing benign prostatic hyperplasia (BPH) was written in 2006 and 2007 by experts of the BPH working group on behalf of the German Association of Urology and Federation of German Urologists. The full version is expected to be published in 2008. Recommendations for assessing BPH were modified and updated and include patient history, symptom questionnaires, physical examination, urine analysis, prostate-specific antigen, uroflowmetry, ultrasound examination of the urinary bladder (including postvoid residual urine), and ultrasound examination of the upper urinary tract or creatinine measurement. Optional tests are voiding diary, pressure-flow studies, ultrasound measurement of detrusor wall thickness, urethrocystography, and urethrocystoscopy. For the first time, tests for the differential diagnosis of bladder symptoms and BPH are described. Furthermore, the latest knowledge was added on disease progression, indications for urodynamic assessment, and ultrasound measurement of detrusor wall thickness for evaluating bladder outlet obstruction. International quality standards were applied in order to increase the guidelines' value; all tests were judged using the levels of evidence and grades of recommendation of the U.S. Department of Health and Human Services classification.

Effects of sphingosine-1-phosphate and sphingosylphosphorylcholine on intracellular Ca2+ and cell death in prostate cancer cell lines.

The sphingolipid metabolites sphingosine-1-phosphate (S1P) and sphingosylphosphorylcholine (SPC) can be involved in cellular growth and apoptosis, by both receptor-dependent and -independent mechanisms. We investigated the role of S1P and SPC in intracellular Ca2+ elevation, cell proliferation and cell death in DU 145 and PC3 hormone-refractory prostate cancer cell lines. S1P and SPC increased intracellular Ca2+ levels, most likely in a receptor-independent manner. Surprisingly, both S1P and SPC did not stimulate but rather reduced cell growth through induction of apoptosis. Therefore, antagonists targeted against S1P, SPC and their receptors do not appear to be promising new approaches in the treatment of hormone-refractory prostate cancer.

Alpha1-adrenoceptors and ejaculatory function.

The abnormal ejaculation of semen is a typical but infrequent side effect of some alpha(1)-adrenoceptor antagonists, particularly those with selectivity for alpha(1A)-adrenoceptors such as silodosin or tamsulosin. Recent clinical studies suggest that this represents a relative anejaculation rather than a retrograde ejaculation. An elegant study in this issue of the journal using alpha(1A) single and alpha(1A/B/D) triple knock-out mice reports a similar phenomenon in rodents. Using a multi-disciplinary approach, the reduced ejaculation and related male infertility is shown to be caused by an impaired function of the vas deferens rather than by alterations in sperm formation, number or function. Similarities and differences between mouse and human data are discussed, particularly why a complete inhibition of all three alpha(1)-adrenoceptor subtypes has the strongest effects in mice whereas apparently only alpha(1A)-adrenoceptor-selective drugs impair ejaculatory function in humans.