Phosphodiesterase (PDE) inhibitors in the treatment of lower urinary tract dysfunction
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TLDR
The strategy of modulating the activity of PDE isoenzymes might represent a novel approach in patients with lower urinary tract dysfunction (LUTD), which is regarded as efficacious, have a rapid onset of action and favourable effect-to-side-effect ratio.Abstract:
Several disorders of the human upper and lower urinary tract, such as urinary stone disease, lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) and detrusor overactivity, can be therapeutically addressed by influencing the function of the smooth musculature of the ureter, prostate or urinary bladder, respectively. In order to ensure a drug effect without significant adverse events, a certain degree of tissue selectivity is mandatory. The treatment of said conditions aims to focus on orally available drugs acting via intracellular signalling pathways. Specifically, the cyclic nucleotide monophosphate cyclic GMP represents an important mediator in the control of the outflow region (bladder, urethra). The use of phosphodiesterase (PDE) inhibitors, such as sildenafil, tadalafil, vardenafil, avanafil or udenafil, known to restrain the degradation of the second messenger cyclic GMP, offers great opportunities in the treatment of lower urinary tract dysfunction. PDE inhibitors are regarded as efficacious, have a rapid onset of action and favourable effect-to-side-effect ratio. The role of PDE5 inhibitors in the treatment of BPH/LUTS and the overactive bladder has already been addressed in randomized, double-blind, placebo-controlled trials, as well as preliminary open-label studies enrolling either several hundreds or only 20 patients. The purpose of this review is to focus on the potential use and clinical significance of PDE inhibitors in the treatment of storage and voiding dysfunctions of the lower urinary tract. The strategy of modulating the activity of PDE isoenzymes might represent a novel approach in patients with lower urinary tract dysfunction (LUTD).read more
Citations
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Journal ArticleDOI
Clinical and molecular genetics of the phosphodiesterases (PDEs).
Monalisa F. Azevedo,Monalisa F. Azevedo,Fabio R. Faucz,Fabio R. Faucz,Eirini I. Bimpaki,Anelia Horvath,Isaac Levy,Rodrigo Bertollo de Alexandre,Rodrigo Bertollo de Alexandre,Faiyaz Ahmad,Vincent C. Manganiello,Constantine A. Stratakis +11 more
TL;DR: How PDEs affect cAMP and cGMP signaling in health and disease, and what pharmacological exploitations of Pdes may be useful in modulating cyclic nucleotide signaling in a way that prevents or treats certain human diseases are reviewed.
Journal ArticleDOI
Cyclic Nucleotide Phosphodiesterases: important signaling modulators and therapeutic targets
TL;DR: Future paths to novel drug discovery include the crystal structure-based design approach, which has resulted in generation of more effective family-selective inhibitors, as well as burgeoning development of strategies to alter compartmentalized cyclic nucleotide signaling pathways by selectively targeting individual PDEs and their signalosome partners.
Journal ArticleDOI
Sildenafil Effect on the Human Bladder Involves the L-cysteine/Hydrogen Sulfide Pathway: A Novel Mechanism of Action of Phosphodiesterase Type 5 Inhibitors
Ferdinando Fusco,Roberta d'Emmanuele di Villa Bianca,Emma Mitidieri,Giuseppe Cirino,Raffaella Sorrentino,Vincenzo Mirone +5 more
TL;DR: The sildenafil relaxant effect on the human bladder involves the H(2)S signaling pathway and may account in part for the efficacy of PDE5-Is in LUTS.
Journal ArticleDOI
Control of Urinary Drainage and Voiding
TL;DR: Provocative new findings suggest that in some cases, lower urinary tract symptoms, such as incontinence, urgency, frequency, overactivity, and pain may be viewed as a consequence of urothelial defects (either urothalial barrier breakdown or inappropriate signaling from uroclinical cells to underlying sensory afferents and potentially interstitial cells).
Journal ArticleDOI
Sexual Dysfunction Related to Drugs: a Critical Review. Part V: α-Blocker and 5-ARI Drugs.
TL;DR: A critical review of the current literature to identify possible intervention strategies for sexual dysfunction related to α-blocker and 5-ARI drugs and the use of phosphodiesterase type 5 (PDE5) inhibitors in combination with these drugs.
References
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Journal ArticleDOI
The Effects of Antimuscarinic Treatments in Overactive Bladder: An Update of a Systematic Review and Meta-Analysis
Christopher R. Chapple,Vik Khullar,Zahava Gabriel,Dominic Muston,Caty Ebel Bitoun,David Weinstein +5 more
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Cyclic nucleotide phosphodiesterases.
TL;DR: The available in vitro, preclinical, and clinical data supporting the potential for selective PDE inhibitors as immunomodulatory agents are reviewed.
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Cyclic GMP Phosphodiesterases and Regulation of Smooth Muscle Function
TL;DR: Cyclic GMP made in response to atrial natriuretic peptide (ANP) or nitric oxide (NO) is an important regulator of short-term changes in smooth muscle tone and longer-term responses to chronic drug treatment or proliferative signals.
Book ChapterDOI
The molecular biology of cyclic nucleotide phosphodiesterases.
Marco Conti,S.-L. C. Jin +1 more
TL;DR: The use of different transcriptional units and exon splicing of a single PDE gene generates proteins with different regulatory domains joined to a common catalytic domain, therefore expanding the array of isoforms with subtle differences in properties and sensitivities to different signals.
Journal ArticleDOI
Antimuscarinics for treatment of overactive bladder
TL;DR: These drugs are the only treatment with undisputed effectiveness in the treatment of overactive bladder and may not be the perfect treatment for all patients with this disorder, but their value for individual patients should not be underestimated.
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