Antimuscarinics for the treatment of overactive bladder: current options and emerging therapies

Antimuscarinic drugs have been the mainstay in the treatment of overactive bladder (OAB) for over two decades. An ideal antimuscarinic medicine is one that can normalize bladder function without interfering with parasympathetic regulation of other organs. Currently, extended-release formulations of tolterodine (tolterodine-ER) and oxybutynin (oxybutynin-ER and oxybutynin-TDS) serve as the cornerstone in the pharmacotherapy of OAB. Although these products represent a significant improvement over older agents, especially with respect to convenience of dosing schedule, their tolerability concerns and modest efficacy make them less than ideal therapies. Advances in our understanding of muscarinic receptor pharmacology have raised optimism in our ability to widen the therapeutic index and increase the efficacy of antimuscarinics by selectively targeting one or more of the five muscarinic subtypes. A structurally diverse group of molecules, having varying receptor-selectivity profiles (non-selective, M3 selective, M2 selective, M2 sparing and M5 sparing), are in development for OAB. Results of clinical trials with these drugs must be awaited before their therapeutic value can be accurately judged.     

Effects of oral prednisolone on biomarkers in synovial tissue and clinical improvement in rheumatoid arthritis

OBJECTIVE: To create greater understanding of the changes in synovial tissue parameters that occur in conjunction with clinical response by using an effective therapy, in order to facilitate the planning of future studies with therapeutic agents for rheumatoid arthritis (RA). METHODS: Twenty-one patients with active RA were randomized to receive either oral prednisolone (n = 10) or placebo (n = 11) for 2 weeks. In all patients, synovial tissue biopsy specimens were obtained by arthroscopy directly before treatment and after 14 days of treatment. Immunohistochemical analysis was performed to characterize the cell infiltrate and vascularity. Stained tissue sections were analyzed by digital imaging. Statistical analysis was performed using an analysis of covariance model. RESULTS: After treatment, the mean Disease Activity Score in 28 joints (DAS28) was 2.0 units lower (95% confidence interval [95% CI] 1.0-3.0) in patients who received prednisolone than in those who received placebo. In the prednisolone group, the mean (+/-SD) DAS28 decreased from 6.27 +/- 0.95 to 4.11 +/- 1.43 after therapy; minimal change was observed in the placebo group. For macrophages, the estimated effect of prednisolone was large. Patients receiving active treatment had fewer (mean 628 cells/mm(2) [95% CI 328-927]) macrophages after therapy compared with those receiving placebo. A reduction in the total number of CD68+ macrophages, from 1,038 +/- 283 cells/mm(2) before treatment to 533 +/- 248 cells/mm(2) after treatment, was observed in the prednisolone group. There were clear trends toward decreased infiltration by T cells, plasma cells, and fibroblast-like synoviocytes after active treatment. We observed a trend toward a reduction in alphavbeta3+ newly formed blood vessels and expression of vascular growth factors after prednisolone therapy. CONCLUSION: Prednisolone therapy in RA is associated with a marked reduction in macrophage infiltration in synovial tissue, suggesting that synovial macrophage numbers could be used as a biomarker for clinical efficacy.     

Fear activation and distraction during the emotional processing of claustrophobic fear

We tested several hypotheses derived from the emotional processing theory of fear reduction by manipulating claustrophobic participants' focus of attention during in vivo exposure. Sixty participants displaying marked claustrophobic fear were randomized to one of four exposure conditions. Each participant received a total of 30-min of self-guided exposure 2-weeks after pretreatment testing. One group attended to threatening words and images during exposure (TW) and was compared to a control group that attended to neutral words and images (NW). A third group performed a demanding cognitive load task--a modified Seashore Rhythm Test during exposure (SR) and was compared to an exposure only (EO) control group. Contrary to prediction, the threat word manipulation was not associated with lower levels of fear following treatment. Consistent with prediction, the distraction manipulation resulted in less fear reduction at post-treatment. Treatment process analyses revealed that the negative effects of distraction on treatment outcome manifested early as slower between-trial habituation. These results and their relevance to emotional processing theory are discussed.     

Changes in anxiety sensitivity with pharmacotherapy for panic disorder

Fear of anxiety symptoms (anxiety sensitivity) has been implicated in the etiology and maintenance of panic disorder, and has been shown to improve with cognitive-behavioral treatment. The impact of pharmacotherapy on anxiety sensitivity is less clear. We administered the Anxiety Sensitivity Index (ASI) during a 12-week randomized controlled trial investigating the relative efficacy of paroxetine, paroxetine plus sustained clonazepam, and paroxetine plus brief clonazepam for patients with panic disorder. We found a mean reduction in ASI scores of 9.6 points, which correlated with symptomatic improvement, and did not differ significantly between groups. Our data provides further evidence that pharmacotherapy leads to significant acute reductions in fears of anxiety symptoms in patients with panic disorder, albeit at levels that may be somewhat less than the changes associated with CBT. Implications of these findings are discussed relative to optimizing pharmacologic treatment of panic disorder.     

Valuing prevention through economic evaluation: some considerations regarding the choice of discount model for health effects with focus on infectious diseases

In cost-effectiveness analysis, the valuing of costs and health effects over time remains a controversial issue. The debate mostly focuses on whether the discount rates for health and money should be equal and which discounting model and time preferences are most appropriate. In this paper we add to the debate by arguing that the assessment of effectiveness of a preventive intervention may influence the choice of the discounting procedure for health. Health effects in cost-effectiveness analysis are commonly expressed in life-years gained, QALYs gained or lives saved. These denominators are only indirect and partial measures of the effects of a preventive intervention. The actual effect of the intervention is a reduction of the risk of mortality and morbidity in a given period of time. This risk reduction will not always coincide with the moment at which the impact on (quality-adjusted) life-years gained is made (i.e. at risk exposure), for example when preventing chronic disease with an asymptomatic stage. In this paper we show that truly acknowledging the origin of health benefits could have implications for the discounting procedure. We present a discounting model that adequately focuses on the reduction of risk. This model recognises the potential interpretation of risk reduction for infection as an economic good to be acquired with associated mortality reductions as later indirect effects. This implies that our suggested discounting model focuses on the moment(s) of risk reduction. A numerical example illustrates our approach. We discuss the associated potential implications for public health policy and discuss how the effects of the intervention can be additionally corrected for societal preferences.     

Epigenetic regulation of protein phosphatase 2A (PP2A), lymphotactin (XCL1) and estrogen receptor alpha (ER) expression in human breast cancer cells

Absence of the estrogen receptor alpha (ER) in human breast cancer cells is an indicator of poor prognosis, and predictive of lack of response to hormonal therapy. Previous studies in our laboratory and others have shown that epigenetic regulation, including DNA methylation and histone deacetylation, are common mechanisms leading to ER gene silencing. Through the use of pharmacologic inhibitors, 5-aza 2'deoxycytidine (AZA) and Trichostatin A (TSA), we have shown that alterations in both of these mechanisms results in synergistic reexpression of ER mRNA and functional protein. These alterations may play a larger role in stimulation of cell signaling pathways leading to ER expression. We have utilized newly developed genome wide screening microarray techniques to identify gene(s) contributing to the hormone independent phenotype and AZA/TSA mediated ER expression. From this screen, we identified and confirmed expression of 4 candidate genes (PP2A, XCL1, THY1 and NBC4) as potential regulators of the hormone independent phenotype. Expression of two genes, XCL1 and PP2A, appeared to be correlated with ER expression. PP2A expression was not changed with ER degradation using ICI 182,780 whereas XCL1 expression decreased in the presence of AZA/TSA and ICI 182,780. This suggests that PP2A may be a determinant of ER expression while XCL1 appears to be ER responsive and downstream of ER expression. These gene products may be novel targets to be further explored in the development of new therapeutics for ER negative breast cancer.     

Decreased venous return is neither sufficient nor necessary to elicit ultrasonic vocalizations of infant rat pups

It has been proposed that all ultrasonic vocalizations (USVs) in young rats are by-products of a cardiovascular response to decreased venous return, the abdominal compression reaction. To test the hypothesis, venous return was decreased in infant rats while USV and cardiovascular measures were monitored. Neither injection of the vasodilator sodium nitroprusside nor blood withdrawal from the superior vena cava or carotid artery elicited USV from pups in their home cage. Thus, decreased venous return by itself is not sufficient to elicit USV. To test whether venous return is a necessary mechanism for USV production, 5% dextrose in water or blood was infused intravenously into isolated pups that were producing USV. This artificial increase of venous return did not affect the rate of USV.     

Whose child is it anyway? Resolving parent-physician conflict in the NICU setting

Much has been written on parental involvement in decision making when dealing with critically ill children, but few articles have touched upon parental refusal of treatment in noncritically ill children. What steps should be taken when a parent refuses what is generally considered "standard of care" medicine for their hospitalized child? Does medical advice outweigh parental views or wishes, and what does one do when our role as physician turns from medical expert into one of medical negotiator? The following case and discussion deal with parental refusal of conventional medical care, and how one may find peaceful resolutions to challenging situations for the ultimate good of the child.     

Three-dimensional display modes for CT colonography: conventional 3D virtual colonoscopy versus unfolded cube projection

The authors compared a conventional two-directional three-dimensional (3D) display for computed tomography (CT) colonography with an alternative method they developed on the basis of time efficiency and surface visibility. With the conventional technique, 3D ante- and retrograde cine loops were obtained (hereafter, conventional 3D). With the alternative method, six projections were obtained at 90 degrees viewing angles (unfolded cube display). Mean evaluation time per patient with the conventional 3D display was significantly longer than that with the unfolded cube display. With the conventional 3D method, 93.8% of the colon surface came into view; with the unfolded cube method, 99.5% of the colon surface came into view. Sensitivity and specificity were not significantly different between the two methods. Agreements between observers were kappa = 0.605 for conventional 3D display and kappa = 0.692 for unfolded cube display. Consequently, the latter method enhances the 3D endoluminal display with improved time efficiency and higher surface visibility.