Cholinergic regulation of mood: from basic and clinical studies to emerging therapeutics.

Mood disorders are highly prevalent and are the leading cause of disability worldwide. The neurobiological mechanisms underlying depression remain poorly understood, although theories regarding dysfunction within various neurotransmitter systems have been postulated. Over 50 years ago, clinical studies suggested that increases in central acetylcholine could lead to depressed mood. Evidence has continued to accumulate suggesting that the cholinergic system has a important role in mood regulation. In particular, the finding that the antimuscarinic agent, scopolamine, exerts fast-onset and sustained antidepressant effects in depressed humans has led to a renewal of interest in the cholinergic system as an important player in the neurochemistry of major depression and bipolar disorder. Here, we synthesize current knowledge regarding the modulation of mood by the central cholinergic system, drawing upon studies from human postmortem brain, neuroimaging, and drug challenge investigations, as well as animal model studies. First, we describe an illustrative series of early discoveries which suggest a role for acetylcholine in the pathophysiology of mood disorders. Then, we discuss more recent studies conducted in humans and/or animals which have identified roles for both acetylcholinergic muscarinic and nicotinic receptors in different mood states, and as targets for novel therapies

Assessing the clinical value of fast onset and sustained duration of action of long-acting bronchodilators for COPD

Date of Aceptance: 12/02/2015 Acknowledgments The authors were assisted in the preparation of the manuscript by Sarah Filcek, a professional medical writer at CircleScience (Tytherington, UK), part of KnowledgePoint360, an Ashfield Company. This assistance was funded by Novartis Pharmaceuticals. Copyright © 2015. Published by Elsevier Ltd.Peer reviewedPublisher PD

Fesoterodine for the treatment of urinary incontinence and overactive bladder

Overactive bladder (OAB) is a highly prevalent condition, affecting males and females. The prevalence increases with age. Behavioral therapy and antimuscarinic therapy remain the first-line therapies for management of OAB. Despite improvements in symptoms, persistence with antimuscarinic therapy has remained low. Multiple factors including patient expectations, adverse effects and cost may affect persistence. Fesoterodine is one of the newest antimuscarinic agent approved for the management of OAB. It is unique in that it shares the same active metabolite as tolterodine, 5-hydoxymethyltolterodine (5-HMT); however, this conversion is established via ubiquitous esterases and not via the cytochrome P450 system, thus providing a faster and more efficient conversion to 5-HMT. Fesoterodine is available in 2 doses, 4 mg and 8 mg. Clinical trials have established a dose response relationship in efficacy parameters as well as improvements in quality of life. As with all antimuscarinics, dry mouth and constipation are the more common side effects. A combination of medical therapy and behavioral therapy improves the overall outcome in management of OAB. Dose flexibility may help improve efficacy outcomes and patient education on the management of common adverse effects may improve tolerability with these agents

Practical points in the medical treatment of overactive bladder and nocturia in the elderly

AbstractThe prevalence of overactive bladder (OAB) increases with age. Degeneration of the central nervous system in the elderly has been proposed as one of the pathogenic factors of OAB. Antimuscarinic therapy is effective in the treatment of OAB; however, intolerable systemic adverse events and cognitive dysfunction during treatment with nonselective antimuscarinic agents is of growing concern in elderly patients. The newly developed beta-3 adrenoceptor agonist mirabegron does not adversely affect flow rate and detrusor pressure, and its therapeutic efficacy and tolerability are similar in patients aged > 65 years and > 75 years, suggesting it might be the therapeutic choice in older patients with OAB. Nocturia can cause sleep deprivation at night and increase daytime sleepiness and loss of energy in the elderly. Desmopressin add-on therapy is effective in improving nocturia and storage symptoms. However, elderly patients with a baseline serum sodium level below the normal range are at high risk of developing significant hyponatremia

Overactive bladder: the importance of tailoring treatment to the individual patient

Harold P DrutzDepartment of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Ontario, CanadaOn behalf of the Specialist Advisory Group on OAB (Lake Como, Italy, June 2009)Introduction: Overactive bladder (OAB) is a prevalent and persistent condition that is often under-diagnosed and under-treated, and which frequently requires tailored treatment for successful management.Methods: This consensus opinion-based review summarizes the discussions of a group of experts in the field of OAB that were assembled to evaluate the importance of correct diagnosis and appropriate pharmacotherapy in patients with OAB.Results: A thorough diagnostic process is crucial for allowing exclusion of underlying medical issues and differentiation from genitourinary conditions other than OAB. In addition, selecting the most appropriate pharmacotherapy needs to be carefully considered in the context of each patient with OAB. In general, patients with OAB tend to be older with various comorbidities and often receiving multiple concomitant medications. Treatment decisions should take into consideration the differing potential for antimuscarinic medications to alter cognitive and cardiovascular functions, both of which may be compromised in this patient population.Conclusion: Tailoring treatment to individual patients by comprehensive patient assessment may lead to more effective management of patients with OAB, especially those receiving polypharmacy for comorbidities.Keywords: overactive bladder, diagnosis, antimuscarinics, cognitive function, cardiovascular&nbsp

The use of mono- and combination drug therapy in men and women with lower urinary tract symptoms (LUTS) in the UK: a retrospective observational study

Background: Combination drug therapy for lower urinary tract symptoms (LUTS) is beneficial to selected patients and recommended by guidelines. Patterns of real-world LUTS drug use, especially combination drug therapy, have not been studied extensively. Moreover, further understanding of the recent landscape is required following the introduction of the beta-3-adrenoceptor agonist mirabegron in the UK in 2013 for overactive bladder (OAB). The objective was to describe mono- and combination drug therapy use for LUTS in patients in UK clinical practice. Methods: This was a retrospective, descriptive, observational database study using UK Clinical Practice Research Datalink GOLD and linked databases. Men and women ≥ 18 years with a first prescription for any LUTS drug from 2014 to 2016 with ≥ 12 months continuous enrollment pre- and post-index date were included. Primary endpoints were mono- or combination drug therapy use for LUTS in male and female cohorts. Secondary endpoints were description of treatment prescribed, treatment persistence and patient demographics. Data were analyzed descriptively. Sub-cohorts were defined by drugs prescribed at index date. Results: 79,472 patients (61.3% male) were included, based on index treatments. Of all men, 82.5% received any benign prostatic obstruction (BPO) drug, 25.4% any OAB drug, and 7.9% any BPO drug plus any OAB drug. As either mono- or combination drug therapy, 77.1% received an alpha-blocker, 18.9% a 5-alpha reductase inhibitor, 23.9% an antimuscarinic agent, and 2.1% mirabegron. Of all women, 94.5% received any OAB drug, 6.0% duloxetine, and 0.5% any OAB drug plus duloxetine. As either mono- or combination drug therapy, 87.7% received an antimuscarinic, and 9.7% mirabegron. In men or women receiving OAB treatment, approximately 2.5% received combination drug therapy with an antimuscarinic agent and mirabegron. For OAB drug monotherapies, mirabegron had the highest persistence in both male and female cohorts. Conclusions: This study provides a better understanding of the recent landscape of LUTS drug use in UK clinical practice. It highlights potential undertreatment of storage symptoms in men with LUTS and the low use of combination OAB treatments