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La Revue Du Praticien Nov 2023MALE URINARY INCONTINENCE. Male urinary incontinence is a common condition that tends to increase with age and can significantly impact the quality of life. Beyond the...
MALE URINARY INCONTINENCE. Male urinary incontinence is a common condition that tends to increase with age and can significantly impact the quality of life. Beyond the clinical diagnosis made through patient history and examination, healthcare practitioners must strive to identify the underlying mechanism(s) and assess the degree of discomfort to initiate appropriate treatment. Two main types of urinary incontinence are distinguished: stress urinary incontinence, which can often benefit from pelvic floor muscle training, and urgency urinary incontinence, which typically responds to drug therapies (such as anticholinergics or β3-adrenergic agonists) and posterior tibial nerve stimulation as first-line options. Moreover, a certain number of red flags must be systematically sought to avoid missing, among other things, a urinary retention or an underlying local condition, and to identify as early as possible men requiring specialized urological care. It is also crucial for the general practitioner to discuss with the patient the various palliative approaches when necessary, such as the use of protective pads, penile sheaths, or a clamp, to improve the patient's comfort and quality of life.
Topics: Humans; Male; Quality of Life; Urinary Incontinence; Cholinergic Antagonists; General Practitioners; Urinary Retention
PubMed: 38294456
DOI: No ID Found -
Cleveland Clinic Journal of Medicine Mar 2024Medical management of benign prostatic hyperplasia (BPH) has progressed gradually in recent years and remains the starting point for most symptomatic patients seeking... (Review)
Review
Medical management of benign prostatic hyperplasia (BPH) has progressed gradually in recent years and remains the starting point for most symptomatic patients seeking treatment. Beyond well-known alpha-blockers and 5-alpha reductase inhibitors, there is growing evidence for the use of phosphodiesterase-5 inhibitors and beta-3 agonists in managing the condition, which may afford additional relief of "bothersome" symptoms in some patients. This review details contemporary medical management of BPH with an emphasis on the indications for certain classes of pharmacotherapy and their relative benefits and side effects. Surgical and procedural treatment of BPH is covered in a separate review.
Topics: Male; Humans; Prostatic Hyperplasia; 5-alpha Reductase Inhibitors; Adrenergic alpha-Antagonists
PubMed: 38429006
DOI: 10.3949/ccjm.91a.23027 -
Journal of Clinical Medicine Nov 2023Obesity is becoming a global health epidemic. Brown and "beige" adipose tissue may produce heat, leading to energy expenditure enhancement and weight loss. Mirabegron, a... (Review)
Review
Obesity is becoming a global health epidemic. Brown and "beige" adipose tissue may produce heat, leading to energy expenditure enhancement and weight loss. Mirabegron, a selective β3-adrenergic receptor agonist, has been found to be effective as a brown adipose tissue activator, a "beige" cells stimulator and a metabolic homeostasis controller in animal and human studies. Although in animal studies, administration of mirabegron led to obesity improvement, significant weight loss in obese patients after mirabegron treatment has not been demonstrated so far, which may be associated with the too-short duration of the trials and the small number of participants in the studies. In humans, the most effective treatment for adipose tissue stimulation was high doses of mirabegron; however, cardiovascular side effects may limit the use of such doses, so the long-term safety must be evaluated. In cases of tachycardia or blood pressure elevation, the co-administration of a β1-adrenergic receptor blocker may be useful. It should be checked whether smaller doses of mirabegron, taken for a longer time, will be sufficient to stimulate brown and "beige" adipose tissue, leading to weight loss. The introduction of mirabegron into obesity treatment in the future will require long-term trials with larger numbers of subjects, to assess mirabegron efficacy, tolerability, and safety.
PubMed: 37959362
DOI: 10.3390/jcm12216897 -
Trends in Endocrinology and Metabolism:... Nov 2023White adipose tissue (WAT) plays an important role in the integration of whole-body metabolism by storing fat and mobilizing triacylglycerol when needed. The released... (Review)
Review
White adipose tissue (WAT) plays an important role in the integration of whole-body metabolism by storing fat and mobilizing triacylglycerol when needed. The released free fatty acids can then be oxidized by other tissues to provide ATP. AMP-activated protein kinase (AMPK) is a key regulator of metabolic pathways, and can be targeted by a new generation of direct, small-molecule activators. AMPK activation in WAT inhibits insulin-stimulated lipogenesis and in some situations also inhibits insulin-stimulated glucose uptake, but AMPK-induced inhibition of β-adrenergic agonist-stimulated lipolysis might need to be re-evaluated in vivo. The lack of dramatic effects of AMPK activation on basal metabolism in WAT could be advantageous when treating type 2 diabetes with pharmacological pan-AMPK activators.
PubMed: 37673765
DOI: 10.1016/j.tem.2023.08.011 -
Nature Communications Aug 2023α-adrenergic receptors (α-ARs) play critical roles in the cardiovascular and nervous systems where they regulate blood pressure, cognition, and metabolism. However,...
α-adrenergic receptors (α-ARs) play critical roles in the cardiovascular and nervous systems where they regulate blood pressure, cognition, and metabolism. However, the lack of specific agonists for all α subtypes has limited our understanding of the physiological roles of different α-AR subtypes, and led to the stagnancy in agonist-based drug development for these receptors. Here we report cryo-EM structures of α-AR in complex with heterotrimeric G-proteins and either the endogenous common agonist epinephrine or the α-AR-specific synthetic agonist A61603. These structures provide molecular insights into the mechanisms underlying the discrimination between α-AR and α-AR by A61603. Guided by the structures and corresponding molecular dynamics simulations, we engineer α-AR mutants that are not responsive to A61603, and α-AR mutants that can be potently activated by A61603. Together, these findings advance our understanding of the agonist specificity for α-ARs at the molecular level, opening the possibility of rational design of subtype-specific agonists.
Topics: Receptors, Adrenergic, alpha-1; Epinephrine; Signal Transduction
PubMed: 37563160
DOI: 10.1038/s41467-023-40524-2 -
PloS One 2023β3-Adrenoceptor (AR) agonists are used to treat patients with an overactive bladder (OAB). Clinical proof-of-concept data have been obtained for the β3-AR agonists...
β3-Adrenoceptor (AR) agonists are used to treat patients with an overactive bladder (OAB). Clinical proof-of-concept data have been obtained for the β3-AR agonists vibegron, mirabegron, solabegron, and ritobegron; however, the selectivities of these agents have not been compared directly under the same experimental conditions. Moreover, the bladders of some patients express lower β3-AR densities than those of healthy individuals, and the β3-AR density might be expected to affect agonist activity. This study assessed the β3-AR selectivities of four β3-AR agonists and examined the effects of β-AR density on their pharmacological profiles. Functional cellular assays were performed using Chinese hamster ovary-K1 cells expressing three human β-AR subtypes transfected with different amounts of plasmid DNA (0.1, 0.05, 0.025 μg/well). The half-maximal effective concentration values, intrinsic activities (IAs), and β3-AR selectivities of vibegron, mirabegron, solabegron, and ritobegron were calculated to assess their pharmacological profiles. The β3-AR selectivities of vibegron, mirabegron, solabegron, and ritobegron were >7937-, 517-, 21.3-, and >124-fold higher than for β1-ARs, and >7937-, 496-, >362- and 28.1-fold higher than for β2-ARs, respectively, under the same experimental conditions. The IAs of mirabegron, solabegron, and ritobegron decreased in line with decreasing receptor density, while the IA of vibegron was maintained at the same level as that of the full agonist isoproterenol at various β3-AR densities. Vibegron has high β3-AR selectivity and exhibits full agonist activity, regardless of the β3-AR density. These results suggest that vibegron is a highly effective and safe drug for treating OAB.
Topics: Animals; Cricetinae; Humans; CHO Cells; Cricetulus; Receptors, Adrenergic, beta-3
PubMed: 37656760
DOI: 10.1371/journal.pone.0290685 -
Expert Opinion on Pharmacotherapy 2023Overactive bladder (OAB) is a common syndrome in adults. Current pharmacologic treatment includes antimuscarinic agents and β-3 adrenoceptor agonists. For... (Review)
Review
INTRODUCTION
Overactive bladder (OAB) is a common syndrome in adults. Current pharmacologic treatment includes antimuscarinic agents and β-3 adrenoceptor agonists. For non-responders to oral medication, intravesical injection of botulinum toxin A (BoNT-A) is an effective option. However, these treatments have potential adverse events and should be cautiously selected for appropriate patients. This review presents the recently published results of clinical trials and studies for patients with OAB and the underlying pathophysiology of OAB. Appropriate medical therapy based on pathophysiology of OAB is also presented.
AREAS COVERED
Literature search from Pubmed from 2001 to 2023 including clinical background, pharmacology, and clinical studies for OAB medications.
EXPERT OPINION
Treatment of OAB syndrome with any antimuscarinic or β-3 adrenoceptor agonist is feasible as a first-line approach. For patients with suboptimal therapeutic effect to full-dose antimuscarinics or mirabegron, combination with both drugs can improve efficacy. Intravesical BoNT-A 100-U injection provides therapeutic effects for refractory OAB. Patients who are refractory to initial pharmacotherapies should be investigated for the underlying pathophysiology; then an appropriate medication can be added, such as an α1-blocker or anti-inflammatory agents. Patient education about behavioral modification and therapies should always be provided with oral medication or BoNT-A injection for OAB patients.
Topics: Adult; Humans; Urinary Bladder, Overactive; Muscarinic Antagonists; Botulinum Toxins, Type A; Administration, Intravesical; Adrenergic beta-3 Receptor Agonists; Acetanilides; Receptors, Adrenergic
PubMed: 37752121
DOI: 10.1080/14656566.2023.2264183 -
Journal of Aerosol Medicine and... Aug 2023The journey of using anticholinergics in the treatment of asthma started with anticholinergic-containing plants such as Datura stramonium and Atropa belladonna, followed... (Review)
Review
The journey of using anticholinergics in the treatment of asthma started with anticholinergic-containing plants such as Datura stramonium and Atropa belladonna, followed by ipratropium bromide and continued with tiotropium, glycopyrronium, and umeclidinium. Although antimuscarinics were used in the maintenance treatment of asthma over a century ago, after a long time (since 2014), it has been recommended to be used as an add-on long-acting antimuscarinic agent (LAMA) therapy in the maintenance treatment of asthma. The airway tone controlled by the vagus nerve is increased in asthma. Allergens, toxins, or viruses cause airway inflammation and inflammation-related epithelial damage, increased sensory nerve stimulation, ganglionic and postganglionic acetylcholine (ACh) release by inflammatory mediators, intensification of ACh signaling at M1 and M3 muscarinic ACh receptors (mAChRs), and dysfunction of M2 mAChR. Optimal anticholinergic drug for asthma should effectively block M3 and M1 receptors, but have minimal effect on M2 receptors. Tiotropium, umeclidinium, and glycopyrronium are anticholinergic agents with this feature. Tiotropium has been used in a separate inhaler as an add-on treatment to inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA), and glycopyrronium and umeclidinium have been used in a single inhaler as a combination of ICS/LABA/LAMA in asthma in recent years. Guidelines recommend this regimen as an optimization step for patients with severe asthma before initiating any biologic or systemic corticosteroid therapy. In this review, the history of antimuscarinic agents, their effectiveness and safety in line with randomized controlled trials, and real-life studies in asthma treatment will be discussed according to the current data.
Topics: Humans; Muscarinic Antagonists; Tiotropium Bromide; Glycopyrrolate; Administration, Inhalation; Asthma; Cholinergic Antagonists; Adrenal Cortex Hormones; Inflammation; Bronchodilator Agents; Adrenergic beta-2 Receptor Agonists; Pulmonary Disease, Chronic Obstructive
PubMed: 37428619
DOI: 10.1089/jamp.2022.0059 -
Journal of Neuroinflammation Nov 2023Enteric glia contribute to the pathophysiology of various intestinal immune-driven diseases, such as postoperative ileus (POI), a motility disorder and common...
BACKGROUND
Enteric glia contribute to the pathophysiology of various intestinal immune-driven diseases, such as postoperative ileus (POI), a motility disorder and common complication after abdominal surgery. Enteric gliosis of the intestinal muscularis externa (ME) has been identified as part of POI development. However, the glia-restricted responses and activation mechanisms are poorly understood. The sympathetic nervous system becomes rapidly activated by abdominal surgery. It modulates intestinal immunity, innervates all intestinal layers, and directly interfaces with enteric glia. We hypothesized that sympathetic innervation controls enteric glia reactivity in response to surgical trauma.
METHODS
Sox10/Rpl22 mice were subjected to a mouse model of laparotomy or intestinal manipulation to induce POI. Histological, protein, and transcriptomic analyses were performed to analyze glia-specific responses. Interactions between the sympathetic nervous system and enteric glia were studied in mice chemically depleted of TH sympathetic neurons and glial-restricted Sox10/JellyOP/Rpl22 mice, allowing optogenetic stimulation of β-adrenergic downstream signaling and glial-specific transcriptome analyses. A laparotomy model was used to study the effect of sympathetic signaling on enteric glia in the absence of intestinal manipulation. Mechanistic studies included adrenergic receptor expression profiling in vivo and in vitro and adrenergic agonism treatments of primary enteric glial cell cultures to elucidate the role of sympathetic signaling in acute enteric gliosis and POI.
RESULTS
With ~ 4000 differentially expressed genes, the most substantial enteric glia response occurs early after intestinal manipulation. During POI, enteric glia switch into a reactive state and continuously shape their microenvironment by releasing inflammatory and migratory factors. Sympathetic denervation reduced the inflammatory response of enteric glia in the early postoperative phase. Optogenetic and pharmacological stimulation of β-adrenergic downstream signaling triggered enteric glial reactivity. Finally, distinct adrenergic agonists revealed β-1/2 adrenoceptors as the molecular targets of sympathetic-driven enteric glial reactivity.
CONCLUSIONS
Enteric glia act as early responders during post-traumatic intestinal injury and inflammation. Intact sympathetic innervation and active β-adrenergic receptor signaling in enteric glia is a trigger of the immediate glial postoperative inflammatory response. With immune-activating cues originating from the sympathetic nervous system as early as the initial surgical incision, adrenergic signaling in enteric glia presents a promising target for preventing POI development.
Topics: Animals; Mice; Gliosis; Adrenergic Agents; Neuroglia; Signal Transduction; Sympathetic Nervous System; Enteric Nervous System
PubMed: 37941007
DOI: 10.1186/s12974-023-02937-0