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Overactive Bladder in Frail Older Adults.
Shaw, C, Wagg, A
Drugs & aging. 2020;(8):559-565
Abstract
Overactive bladder (OAB) and frailty are multidimensional syndromes, and the prevalence of both increases with age. Little evidence exists for a direct association between OAB and frailty, but urinary urgency may well be a precursor of frailty in older people. Frail older adults are no less deserving of treatment than fit older adults, and lifestyle, behavioral, and pharmacological interventions remain the primary options for treatment, with some evidence for efficacy. Data on onabotulinumtoxinA therapy or percutaneous tibial nerve stimulation in frail older adults are sparse. Frail older adults are often excluded from drug trials, but evidence is accumulating that antimuscarinics and, to a lesser extent, beta-adrenergic agonists are safe, well-tolerated, and effective in older adults. Cognitive impairment associated with frailty should not be used as justification for avoiding the use of antimuscarinics. More studies are required to better understand the association between OAB and frailty, as both are associated with poor outcomes and may be amenable to intervention. Drug trials for OAB treatments should be encouraged to include frail older adults, as this population is highly affected yet often excluded.
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Advances in Pain-Predominant Functional Gastrointestinal Disorders in the Adolescent.
Rosen, JM, Alioto, A, Saps, M
Adolescent medicine: state of the art reviews. 2016;(1):34-56
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Research and development of bronchodilators for asthma and COPD with a focus on G protein/KCa channel linkage and β2-adrenergic intrinsic efficacy.
Kume, H, Fukunaga, K, Oguma, T
Pharmacology & therapeutics. 2015;:75-89
Abstract
Bronchodilators are used to improve symptoms and lung function in asthma and COPD. Airway smooth muscle tone is regulated by both muscarinic and β2-adrenergic receptor activity. Large-conductance Ca(2+)-activated K(+) (KCa) channels are activated by β2-adrenergic receptor agonists, via Gs, and suppressed by muscarinic receptor antagonists via Gi. This functional antagonism converges on the G protein/KCa channel linkages. Membrane potential regulated by KCa channels contributes to airway smooth muscle tension via Ca(2+) influx passing through voltage-dependent Ca(2+) (VDC) channels. The Gs/KCa/VDC channel linkage is a key process in not only physiological effects, but also in dysfunction of β2-adrenergic receptors and airway remodeling. Moreover, this pathway is involved in the synergistic effects between β2-adrenergic receptor agonists and muscarinic receptor antagonists. Intrinsic efficacy is also an important characteristic for both maintenance and loss of β2-adrenergic action. Allosteric modulators of G protein-coupled receptors contribute not only to this synergistic effect between β2-adrenergic and muscarinic M2 receptors, but also to intrinsic efficacy. The effects of weak partial agonists are suppressed by lowering receptor number, disordering receptor function, and enhancing functional antagonism; in contrast, those of full or strong partial agonists are not suppressed. Excessive exposure to full agonists causes β2-adrenergic desensitization; in contrast, exposure to partial agonists does not cause desensitization. Intrinsic efficacy may provide the rationale for the clinical use of β2-adrenergic receptor agonists in asthma and COPD. In conclusion, the G protein/KCa linkage and intrinsic efficacy (allosteric effects) may be therapeutic targets for research and development of novel agents against both airway obstruction and airway remodeling.
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[The new era in the pharmacological treatment of overactive bladder (OAB): mirabegron--a new selective beta3agonist].
Rechberger, T, Kulik-Rechberger, B, Miotła, P, Wróbel, A
Ginekologia polska. 2014;(3):214-9
Abstract
Overactive bladder is defined by ICS as urgency frequency and nocturia, with or without urgency urinary incontinence in the absence of urinary tract infection, or other obvious causative pathology Lower urinary tract symptoms (LUTS) are highly prevalent, especially in aging populations. Epidemiological studies reported LUTS in 62% of men and 67% of women, rising to 81% and 79%, respectively in adults over 60 years old. However the actual burden of LUTS remains relatively unrecognized. LUTS, mainly due to considerable distress including almost all aspects of social functioning, impact on sleep and mental health, may significantly affect quality of life. Management of LUTS including OAB has undergone dramatic changes since 1972, when the first antimuscarinic drug-oxybutynin, was introduced into clinical practice. In the last two decades, six new antimuscarinic drugs entered OAB field and this was accompanied by introduction of botulinum toxin into clinical practice in patients resistant to or not compliant with antimuscarinics. Nowadays, it is recognized that OAB is progressive, age-related and non sex-specific condition with most patients experiencing a combination of storage, voiding and post-micturition symptoms. In 2013, the next step was taken, with new therapeutic options for OAB, enabling an even more patient-tailored approach. This was possible for both, male and female OAB sufferers with new class of oral 3 adrenoreceptor agonist (mirabegron). This drug, by stimulation of 3-adrenoceptors, couples via Gs proteins to adenylyl cyclase, what results in an increase of intracellular cAMP levels and a subsequent activation of cAMP-dependent protein kinase A, which then phosphorylates myosin light chain kinase responsible for inhibition of calcium-calmodulin dependent interaction of myosin with actin. Moreover the cAMP increase also leads to the reduction of cytoplasmic Ca2+ concentration by removal of calcium ions from cytoplasm. These both actions result in a significant increase in the storage bladder capacity and by this interval between micturitions is prolonged. Mirabegron was evaluated in three 12-week, double blind, randomized, placebo controlled, parallel-group, multicenter clinical trials in OAB patients with symptoms of urge urinary incontinence, urgency and frequency - study 046, 047 and 074. It should be pointed out that efficacy of mirabegron was maintained through the entire 12-month period in phase Ill long-term study Discoveries on the physiology of the normal bladder and on the pathophysiology underlying OAB have led to the development of new treatment options for OAB. Pharmacological management of OAB should be tailored to patient's characteristics. New and recent options of pharmacological treatment have undoubtedly expanded treatment possibilities, what should allow physicians to select the optimal treatment for each patient.
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Management of OAB in those over age 65.
Natalin, R, Lorenzetti, F, Dambros, M
Current urology reports. 2013;(5):379-85
Abstract
The International Continence Society (ICS) defines overactive bladder (OAB) as an association of symptoms including "urgency, with or without urge incontinence, usually with increased frequency and nocturia". This conditon has been associated with a decrease in quality of life and a higher related risk of overall health condition decrease, and is rising since its prevalence increases with age and the forecast for the world population estimates an increase of those over 65 years old. Aging alone can be considered a major risk factor for developing OAB symptoms that are considered multifactorial and due to body tissue and anatomic changes, lifestyle-associated factors, comorbidities and personal characteristics. The high prevalence of this condition and multiple etiology factors makes of its treatment a challenge-especially in the older population. A major concern over OAB treatment of elderly patients is the risk of cognitive side effects due to the pharmacologic treatment with anticholinergic drugs. First-line treatment for OAB symptoms are the use of pharmacologic therapy with antimuscarinic drugs, which has been proved to be effective in controlling urgency, urge incontinence episodes, incontinence episodes, and nocturia. The impact caused by this condition is significant regarding the economic and human costs associated bringing into attention the need of studying and reviewing this specific population. Conservative Management and Lifestyle Modifications: Behavioral therapy's aims are to reduce urinary frequency and urgency to an accepted level and to increase bladder outlet volume. It consists of actions to teach patients to improve and learn bladder control. Lifestyle modifications are a conjunct of daily activities that can be managed to have the lowest interference on the functioning of the urinary tract. Pharmacologic Therapy: There are various medications with antimuscarinic properties available for the treatment of OAB symptoms. The most commonly used are oxybutinin, tolterodine, solifenacin, darifenacin, fesosterodine and trospium. Second-line Therapy: OAB treatment accounts for some refractory to conventional treatment patients who will require alternative therapies to achieve improvement of symptoms as the use of intradetrusor injection of botulinum A toxin by binding to receptors on the membrane of cholinergic nerves causing temporary chemodenervation and consequent muscle relaxation. Neuromodulation is also an effective therapy that aims to achieve inhibition of detrusor activity by continuous neural stimulation through peripheral nerves as the use of the tibial nerve or central as it is performed by direct spine stimulation on sacral roots through the implantation of an automated generator. In conclusion, evidence from the literature has shown that antimuscarinic treatment of OAB in the elderly population is safe and effective in improving symptoms and patient's quality of life. Managing OAB symptoms in this population is a great challenge. An optimal therapeutic approach to treat should involve medical treatment with drug and behavioral therapy in addition to lifestyle advice.
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Cardiac effects of muscarinic receptor antagonists used for voiding dysfunction.
Andersson, KE, Campeau, L, Olshansky, B
British journal of clinical pharmacology. 2011;(2):186-96
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Abstract
Antimuscarinic agents are the main drugs used to treat patients with the overactive bladder (OAB) syndrome, defined as urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia. Since the treatment is not curative and since OAB is a chronic disease, treatment may be life-long. Antimuscarinics are generally considered to be ‘safe’ drugs, but among the more serious concerns related to their use is the risk of cardiac adverse effects, particularly increases in heart rate (HR) and QT prolongation and induction of polymorphic ventricular tachycardia (torsade de pointes). An elevated resting HR has been linked to overall increased morbidity and mortality, particularly in patients with cardiovascular diseases. QT prolongation and its consequences are not related to blockade of muscarinic receptors, but rather linked to inhibition of the hERG potassium channel in the heart. However, experience with terodiline, an antimuscarinic drug causing torsade de pointes in patients, has placed the whole drug class under scrutiny. The potential of the different antimuscarinic agents to increase HR and/or prolong the QT time has not been extensively explored for all agents in clinical use. Differences between drugs cannot be excluded, but risk assessments based on available evidence are not possible.
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Treatment of mixed urinary incontinence in women.
Gomelsky, A, Dmochowski, RR
Current opinion in obstetrics & gynecology. 2011;(5):371-5
Abstract
PURPOSE OF REVIEW Deciding on an optimal therapy for mixed urinary incontinence (MUI) is challenging, as a single-treatment modality may be inadequate for alleviating both the urge and stress component. A MEDLINE search was conducted regarding English-language literature pertaining to the treatment for MUI focusing on literature within the last 18 months. RECENT FINDINGS Behavioral therapy and lifestyle modification, such as moderate weight loss and caffeine reduction, should be considered first-line options for all women with MUI. The addition of pelvic floor muscle therapy may have an additional salutary effect. Treatment of the urge component with antimuscarinics is effective; however, the stress component is likely to persist after therapy. Treatment with vaginal estrogen cream may help in the short-term, but long-term benefits are unknown. Anti-incontinence surgery may have a positive impact on both the stress and urge components of MUI; however, it appears that women with MUI may have lower cure rates compared to women with pure stress urinary incontinence. SUMMARY The optimum treatment of MUI may often require multiple treatment modalities. Although surgery may often have a positive impact on both components, its routine implementation should be approached with caution and patients should be carefully selected and counseled.
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Medicinal chemistry and therapeutic potential of muscarinic M3 antagonists.
Peretto, I, Petrillo, P, Imbimbo, BP
Medicinal research reviews. 2009;(6):867-902
Abstract
Muscarinic acetylcholine receptors belong to the G-protein-coupled receptors family. Currently five different receptor subtypes have been identified and cloned. M3 receptor subtypes are coupled to G(q) family proteins and increase phosphatidyl inositol hydrolysis and calcium release from internal stores. They are widely distributed both in the central nervous system and in the periphery. At the central level, M3 receptor subtypes are involved in modulation of neurotransmitter release, temperature homeostasis, and food intake, while in the periphery they induce smooth muscle contraction, gland secretion, indirect relaxation of vascular smooth muscle, and miosis. The main therapeutic applications of M3 antagonists include overactive bladder (OAB), chronic obstructive pulmonary disease (COPD), and pain-predominant irritable bowel syndrome (IBS). The introduction of selective M3 antagonists has not improved clinical efficacy compared with the old non-selective antimuscarinics but has reduced the rate of adverse events mediated by the blockade of cardiac M2 receptors (tachycardia) and central M1 receptors (cognitive impairment). Improved tolerability has been obtained also with controlled release or with inhaled formulations. However, there is still a need for safer M3 antagonists for the treatment of COPD and better-tolerated and more effective compounds for the therapy of OAB. New selective muscarinic M3 antagonists currently in early discovery and under development have been designed to address these issues. However, as M3 receptors are widely located in various tissues including salivary glands, gut smooth muscles, iris, and ciliary muscles, further clinical improvements may derive from the discovery and the development of new compounds with tissue rather than muscarinic receptor subtype selectivity.
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Emerging drugs for treatment of overactive bladder and detrusor overactivity.
Drake, MJ
Expert opinion on emerging drugs. 2008;(3):431-46
Abstract
BACKGROUND Overactive bladder (OAB) signifies the presence of urinary urgency and can have major effects on quality of life and social functioning. Standard antimuscarinic drugs have good initial response rates but substantial adverse effects and long-term compliance problems. OBJECTIVES To review the complexities of the mechanisms underlying OAB and the current drugs available for treating its symptoms. METHODS The literature was reviewed to define current therapies and drugs in clinical trials. Articles were identified by means of a computerised PubMed and Cochrane Library search (using the following keywords: overactive bladder, detrusor overactivity, urgency and bladder), supported by a search of the PharmaProjects database. CONCLUSIONS New drug classes, such as beta-3 adrenergic agonists, may work by reducing contractility or excitability of bladder muscle. Moderation of afferent activity may allow improved OAB symptoms, with lower risk of affecting voiding function. Agents acting on the CNS could influence OAB favourably, but target selection and adverse effects are an issue. The recognition of the functional contribution of the urothelium and the diversity of nerve transmitters has sparked interest in both peripheral and central modulation of OAB pathophysiology.
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10.
Muscarinic acetylcholine receptors.
Ishii, M, Kurachi, Y
Current pharmaceutical design. 2006;(28):3573-81
Abstract
Muscarinic acetylcholine receptors mediate diverse physiological functions. At present, five receptor subtypes (M(1) - M(5)) have been identified. The odd-numbered receptors (M(1), M(3), and M(5)) are preferentially coupled to G(q/11) and activate phospholipase C, which initiates the phosphatidylinositol trisphosphate cascade leading to intracellular Ca(2+) mobilization and activation of protein kinase C. On the other hand, the even-numbered receptors (M(2) and M(4)) are coupled to G(i/o), and inhibit adenylyl cyclase activity. They also activate G protein-gated potassium channels, which leads to hyperpolarization of the plasma membrane in different excitable cells. Individual members of the family are expressed in an overlapping fashion in various tissues and cell types. Recent gene targeting approaches have unraveled the specific function of these muscarinic receptor subtypes, which were not able to be fully elucidated with pharmacological approaches because of the non-selective effects of the available ligands. Based on these findings, muscarinic receptors have been emerging as an important therapeutic target for various diseases, including dry mouth, incontinence and chronic obstructive pulmonary disease. Here we review the latest advances in the structural and functional characterization of muscarinic acetylcholine receptors and the pharmaceutical development of muscarinic receptor ligands.