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.

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.

[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.

[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.

Plutonium-244: confirmation as an extinct radioactivity.

The mass spectrum of xenon from spontaneous fission in a laboratory sample of plutonium-244 is precisely what meteoriticists predicted it would be; this discovery completes a web of proof that this nuclide is a bona fide extinct radioactivity of galactic origin, that r-process nucleosynthesis was ongoing in the galaxy at the time of the birth of the sun, and that the early meteoritic abundances of plutonium-244, heretofore tentative, can be utilized with confidence in models for the chronology of galactic nucleosynthesis. The search for an explanation for anomalous fission-like xenon in carbonaceous chondrites can now be narrowed.

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.

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.

[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.

Adrenergic control of circulating lymphocyte subpopulations. Effects of congestive heart failure, dynamic exercise, and terbutaline treatment.

The current studies were undertaken to explore the relationship between enhanced sympathetic nervous activity and lymphocyte subset distribution in three settings: congestive heart failure, dynamic exercise, and beta-adrenergic agonist treatment. We compared the number and subset distribution of circulating lymphocytes in 36 patients with congestive heart failure and 31 age-matched control subjects. The number of circulating lymphocytes was lower in heart failure than in control. This was due to a reduction in Tsuppressor/cytotoxic and natural killer cells without significant alteration of Thelper cells. The extent of the alteration was similar in patients with idiopathic and ischemic heart failure, but the reduction was more pronounced in patients with New York Heart Association class III-IV than in class I-II. The plasma catecholamine elevation in heart failure was also independent of etiology but more pronounced in the more severely ill patients. We also assessed lymphocyte subsets after acute stimulation of sympathetic activity by dynamic exercise and after treatment with the beta-adrenergic agonist terbutaline. Dynamic exercise until exhaustion increased the number of circulating lymphocytes in healthy controls and heart failure patients in a subset-selective manner. By contrast, a 7-d treatment with terbutaline caused a reduction in the circulating number of lymphocytes in some subsets that was identical to that seen in heart failure patients. We conclude that prolonged sympathetic activity reduces the number of circulating lymphocytes by a beta-adrenergic mechanism. Such alterations might be involved in the pathophysiology of heart failure and other disease states involving increased activity of the sympathetic nervous system.

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.

Effect of short-term outlet obstruction on rat bladder nerve density and contractility.

1 The present study was designed to investigate the relationship between innervation density and contractile responses to field stimulation and exogenous agonists at early time points after induction of bladder outlet obstruction (BOO) in rats. 2 When compared with sham-operated animals, 1, 3 and 7 days of BOO were associated with a 75%, 80% and 90% increase of bladder weight. Field stimulation caused a frequency-dependent increase in force of contraction. The force of contraction was reduced at each frequency in BOO rats with the greatest decrease after 1 day and a gradual but incomplete recovery thereafter. In contrast, contractile responses to ATP, carbachol and KCl were markedly reduced after 1 day of BOO and fully recovered after 7 days. The neurofilament staining was not altered by 1 day of BOO, but gradually decreased with increasing duration of BOO reaching the lowest levels after 7 days. 3 We conclude that impaired cellular contractility seems to underlie the early reductions of field stimulation-induced contraction, possibly reflecting surgical trauma of the tissue. However, at later time points a reduced nerve density, possibly reflecting a partial denervation, appears to be the main reason for impaired contractile response to field stimulation.

BML-241 fails to display selective antagonism at the sphingosine-1-phosphate receptor, S1P(3).

BACKGROUND AND PURPOSE: The thiazolidine carboxylic acid, BML-241, has been proposed as a lead compound in development of selective antagonists at the sphingosine-1-phosphate receptor (S1P3), based on its inhibition of the rise in intracellular calcium concentrations ([Ca2+]i) in HeLa cells overexpressing S1P receptors. We have studied the antagonistic properties of BML-241 for the S1P(3) receptor in more detail. EXPERIMENTAL APPROACH: Chinese hamster ovary (CHO) cells stably transfected with the S1P3, S1P2 or alpha(1A)-adrenoceptors were used to investigate the effect of BML-241 on increases in [Ca2+]i mediated via different receptors. CHO-K1 cells were used to study ATP-induced [Ca2+]i elevations. Effects on S1P3 -mediated inhibition of forskolin-induced cAMP accumulation and on binding to alpha(1A)-adrenoceptors were also investigated. In addition, the effect of BML-241 on contractions of rat mesenteric artery induced by phenylephrine was studied in an organ bath. KEY RESULTS: High concentrations of BML-241 (10 microM) inhibited the rise in [Ca2+]i induced by S1P3 and S1P2 receptor stimulation; lower concentrations were ineffective. This high concentration of BML-241 also inhibited [Ca2+]i increases via P2 (nucleotide) receptor or alpha(1A)-adrenoceptor stimulation. Moreover, BML-241 (10 microM) inhibited alpha(1)-adrenoceptor-mediated contraction of rat mesenteric artery but did not displace [3H]-prazosin from alpha(1A)-adrenoceptors in concentrations up to 100 microM. BML-241 (10 microM) did not affect the S1P3 -mediated decrease of forskolin-induced cAMP accumulation. CONCLUSIONS AND IMPLICATIONS: We conclude that BML-241 is a low potency, non-selective inhibitor of increases in [Ca2+]i, rather than a specific antagonist at the S1P3 receptor.

[Anticholinergics for overactive bladder: does subtype selectivity play a role?]. / Anticholinergika bei überaktiver Blase: Spielt Subtypselektivität eine Rolle?

Anticholinergics act in the treatment of overactive bladder by blocking muscarinic receptors of which five subtypes exist. Their desired effects occur via M(3) receptors, but a role for M(2) receptors is being discussed. Adverse effects such as dry mouth and constipation occur also via M(3) receptors, but M(2) and M(1) receptors can mediate side effects in the heart or on cognitive function, respectively. Therefore, an M(3)-selective drug such as darifenacin could theoretically be less effective but also have fewer cardiac or central nervous side effects. However, the limited available clinical data do not support a smaller efficacy or better general tolerability. The lack of adverse effects on cognitive function is well documented for darifenacin, but it cannot yet be determined definitively whether this discriminates it from other modern anticholinergics.

Chronic mu-opioid receptor stimulation in humans decreases muscle sympathetic nerve activity.

BACKGROUND: Opioid-addicted patients undergoing detoxification provide a unique opportunity to assess the effects of chronic opioid receptor stimulation on the sympathetic nervous system. We tested the hypothesis that chronic oral methadone intake decreases resting efferent sympathetic nerve activity to muscle (MSA). Furthermore, we assessed whether this effect is reversed by mu-opioid receptor blockade during antagonist-supported detoxification under general anesthesia. METHODS AND RESULTS: Fifteen young patients (30+/-1 years old, mean+/-SEM) with a long history of mono-opioid addiction and under oral methadone substitution therapy (65+/-10 mg/d for 21+/-6 months) were selected. Peroneal MSA (microneurography) and catecholamine plasma concentrations (high-performance liquid chromatography) were assessed in the awake state and compared with those of age-matched healthy control subjects. The effects of mu-opioid receptor blockade by naloxone (12.4 mg IV) were determined during propofol anesthesia. Compared with healthy volunteers, resting MSA (4+/-2 versus 22+/-2 bursts/min, P<0.0001) and antecubital venous norepinephrine plasma concentration (100+/-64 versus 256+/-48 pg/mL, P=0.01) were markedly decreased in addicted patients despite similar arterial blood pressure and heart rate. Opioid receptor blockade markedly increased MSA (5+/-2 to 24+/-3 bursts/min) and norepinephrine (49+/-12 to 305+/-48 pg/mL) and epinephrine (13+/-2 to 482+/-67 pg/mL) arterial plasma concentrations as well as mean arterial pressure (82+/-4 to 108+/-3 mm Hg) and heart rate (70+/-3 to 86+/-4 beats/min). CONCLUSIONS: Chronic mu-opioid receptor stimulation by methadone decreases resting MSA in humans.

Receptors for neuropeptide Y: multiple subtypes and multiple second messengers.

Neuropeptide Y (NPY) can elicit numerous physiological responses by activating specific pre- and postsynaptic receptors. Different orders of potency for agonists in various model systems suggest that there are multiple subtypes of NPY receptors, described here by Martin Michel, but their pharmacological definition remains tentative, awaiting development of specific antagonists and receptor cloning studies. The coupling of NPY receptors to various signal transduction mechanisms is also reviewed, including inhibition of adenylyl cyclase and stimulation or inhibition of increases in intracellular Ca2+, but a link between individual NPY receptor subtypes and specific signal transduction pathways has not been established.

Emerging functions for neuropeptide Y5 receptors.

The Y5 subtype of neuropeptide Y (NPY) receptors has raised considerable interest as a mediator of NPY-stimulated food intake, but with the advent of recent data, this hypothesis has come into question. Moreover, Y5 receptor-selective drugs might not be specific for food intake because additional functions in the central and peripheral nervous systems, including endogenous anti-epileptic activity, attenuation of morphine withdrawal symptoms, enhancement of diuresis and natriuresis, lowering of blood glucose and reduction of acetylcholine release in the ileum, have recently been reported to occur via Y5-like receptors. Given that mRNA for the cloned Y5 receptor is apparently restricted to the CNS, Angela Bischoff and Martin Michel discuss the possible existence of additional NPY receptor subtypes with Y5-like recognition features and their presence in peripheral tissues.

Myocardial beta-adrenoceptor changes in heart failure: concomitant reduction in beta 1- and beta 2-adrenoceptor function related to the degree of heart failure in patients with mitral valve disease.

In patients suffering from end-stage congestive cardiomyopathy, cardiac beta 1-adrenoceptor function is markedly reduced, whereas cardiac beta 2-adrenoceptor function is nearly normal. To determine whether beta 1-adrenoceptor function is impaired in heart failure selectively, beta 1- and beta 2-adrenoceptor density and functional responsiveness in the right and left atria and the left papillary muscles from patients with mitral valve disease (functional class III to IV) were studied. In all three tissues concomitantly beta 1- and beta 2-adrenoceptor density gradually declined when the degree of heart failure increased from functional class III to IV. This decrease in beta 1- and beta 2-adrenoceptor density was accompanied by similar decreases in the contractile response of isolated electrically driven right atrial and left ventricular papillary muscles to beta-adrenergic agonists. It is concluded that a decrease in cardiac beta-adrenoceptor function is a general phenomenon in heart failure, and its extent is related to the degree of heart failure. However, in contrast to congestive cardiomyopathy, in mitral valve disease the decrease in cardiac beta-adrenoceptor function is due to a concomitant decrease in beta 1- and beta 2-adrenoceptors.

Is the glycogen synthase analogue C1-peptide a suitable fluorescent substrate for routine measurements of protein kinase C?

We have compared a new commercially available non-radioactive protein kinase C (PKC) activity assay based on the fluorescent [A9,10K11]glycogen synthase1-11 analogue C1-peptide with a classical radioactive assay based on myelin basic protein4-14 (MBP4-14) and other substrates. The C1-peptide had lower affinity for PKC from rat brain than substrates such as MBP4-14, [S25]PKC alpha 19-31, and [A9,10K11,12]glycogen synthase1-12. The sensitivity of the C1-peptide-based assay was considerably lower than that of the MBP4-14-based assay. The C1-peptide was readily degraded in an ATP-independent manner by crude and DEAE-column chromatography-purified cytosolic extracts from rat brain, rat kidney, SK-N-MC and L929 cells. In rat kidney this degradation was not prevented by many common protease inhibitors. Phenylsepharose column chromatography separated the C1-peptide degrading activity from PKC. We conclude that the C1-peptide-based fluorescent PKC assay is applicable to highly purified PKC preparations but has low sensitivity and is not applicable to crude extracts due to substrate degradation.

Is cyclic AMP formation desensitized in patients with end-stage renal failure?

1 Cyclic AMP formation has consistently been reported to be desensitized in various tissues including heart of animal models of end-stage renal failure (ESRF). In contrast, reports on desensitization of cAMP formation in ESRF patients remain contradictory. Whether this discrepancy results from a difference between human ESRF and its animal models or from the use of circulating blood cells in the human and various solid tissues in the animal studies, remains unclear. Therefore, we performed three studies with heart and platelets of ESRF patients undergoing haemodialysis or continuous ambulatory peritoneal dialysis and age- and gender-matched controls with normal renal function (n = 11-13 each). 2 In platelets from haemodialysis patients adenylyl cyclase activity in response to receptor-dependent and -independent agonists was reduced by approximately 30%, and this could be explained by an alteration at the level of adenylyl cyclase itself. However, no such desensitization was seen in platelets from peritoneal dialysis patients. 3 In hearts from ESRF patients undergoing haemodialysis, beta-adrenoceptor density and subtype distribution, cAMP formation in response to the beta-adrenoceptor agonist isoprenaline or various receptor-independent stimuli, were very similar to those in control patients but activity of G-protein-coupled receptor kinase was increased by approximately 20%. 4 We conclude that conflicting reports on the desensitization of cAMP formation between ESRF patients and ESRF animal models are not explained by the use of solid tissues in animal studies vs. circulating blood cells in patient studies. Rather desensitization of cAMP formation seems to be a less consistent feature of human ESRF than of its animal models.