The Forefront for Novel Therapeutic Agents Based on the Pathophysiology of Lower Urinary Tract Dysfunction: Pathophysiology of Voiding Dysfunction and Pharmacological Therapy

Takeda, Masayuki; Araki, Isao; Mochizuki, Takashi; Nakagomi, Hiroshi; Kobayashi, Hideki; Sawada, Norifumi; Zakohji, Hidenori

doi:10.1254/jphs.09r17fm

Cited by 18 publications

(11 citation statements)

References 43 publications

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“…Potential mechanism of action may involve effects on the bladder detrusor contraction and relaxation (through muscarinic receptor agonist or α-blockers) or on dynamic and static prostatic components of voiding (through α-blockers, 5α-reductase inhibition, or phosphodiesterase-5 inhibition), modulation of micturition reflex, or reduction in inflammation [2,[20][21][22][23][24].…”

Section: Discussionmentioning

confidence: 99%

Cranberry fruit powder (Flowens™) improves lower urinary tract symptoms in men: a double-blind, randomized, placebo-controlled study

Vidlář

Vostalová

Fromentin³

et al. 2015

World J Urol

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Section: Discussionmentioning

confidence: 99%

Cranberry fruit powder (Flowens™) improves lower urinary tract symptoms in men: a double-blind, randomized, placebo-controlled study

Vidlář

Vostalová

Fromentin³

et al. 2015

World J Urol

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“…[22,45] In this light, using ac onsolidated experience in the synthesis of polycyclic pyridazinones, we designed,p repared and tested al arge series of molecules for their activity towardselected GPCRs(i.e., a 1A ,5-HT 1A ,and D 2 receptors) and for their inhibition of AChEa nd BChE. To gether,o ur data suggestauseful potential for most compounds as multitarget agents, but especially as AChE-a 1A dual binders, particularly compounds 29K and 30K,w hile 4Fa resultedi nB ChE-a 1A dual activity.T hese peculiar features suggest their possible development as peripherally acting drugs in pathologies of the lower urinaryt ract [32] andi ng laucoma, [46] provided that in both cases ah igher water solubility and al ower log P value could be reached to minimize central effects. These lead compounds should feature the combination of ACh restoration deriving from AChE and/or BChE inhibition andt he modulation of 5-HT 1A activities in extrapyramidals ymptoms and neurologic disorders associated with AD.…”

Section: Discussionmentioning

confidence: 99%

Multitarget‐Directed Tricyclic Pyridazinones as G Protein‐Coupled Receptor Ligands and Cholinesterase Inhibitors

et al. 2015

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By following a multitarget ligand design approach, a library of 47 compounds was prepared, and they were tested as binders of selected G protein-coupled receptors (GPCRs) and inhibitors of acetyl and/or butyryl cholinesterase. The newly designed ligands feature pyridazinone-based tricyclic scaffolds connected through alkyl chains of variable length to proper amine moieties (e.g., substituted piperazines or piperidines) for GPCR and cholinesterase (ChE) molecular recognition. The compounds were tested at three different GPCRs, namely serotoninergic 5-HT1A, adrenergic α1A, and dopaminergic D2 receptors. Our main goal was the discovery of compounds that exhibit, in addition to ChE inhibition, antagonist activity at 5-HT1A because of its involvement in neuronal deficits typical of Alzheimer's and other neurodegenerative diseases. Ligands with nanomolar affinity for the tested GPCRs were discovered, but most of them behaved as dual antagonists of α1A and 5-HT1A receptors. Nevertheless, several compounds displaying this GPCR affinity profile also showed moderate to good inhibition of AChE and BChE, thus deserving further investigations to exploit the therapeutic potential of such unusual biological profiles.

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“…One of the potential targets of LUTS therapy described in recent studies is the NO/cGMP pathway [3,9,10,11]. The first approach targeting the NO/cGMP pathway is systemic administration of NO donors [18].…”

Section: Discussionmentioning

confidence: 99%

“…There is some evidence that drugs acting on the NO/cGMP pathway might have a potential role in treating infravesical obstruction caused by BPH [3,9,10,11]. Phosphodiesterase-5 inhibitors, which increase cGMP levels in the lower urinary tract, have already been shown to have a beneficial influence on LUTS [12,13,14].…”

Section: Introductionmentioning

confidence: 99%

Comparison of the Efficacy of Isosorbide Mononitrate and Doxazosin in the Treatment of Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia: A Randomized Clinical Trial

Tarhan¹,

Çelik

Tosun

et al. 2014

Urol Int

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Objective: We aimed to compare the efficacy of isosorbide mononitrate and doxazosin in the treatment of lower urinary tract symptoms (LUTS). Patients and Methods: 80 patients with LUTS were included in this randomized clinical study. All patients were evaluated with uroflowmetry, post-void residual (PVR) urine, prostate volume, International Prostate Symptom Score (IPSS), serum PSA, urinalysis and culture. 40 patients were prescribed doxazosin for 4 weeks, another 40 were prescribed isosorbide mononitrate for 4 weeks. Urologic re-evaluation was done at the end of the study. Results: 74 patients completed the study. The mean age of patients was 59.6 ± 0.7 years, the mean PSA value was 1.7 ± 0.1 ng/ml and the mean prostate volume was 41.9 ± 1.7 ml. Doxazosin markedly improved IPSS (from 16.2 ± 0.7 to 9.5 ± 0.5), maximum urinary flow rate (from 10.9 ± 0.7 to 12.8 ± 0.6 ml/s) and PVR urine (from 68.1 ± 9.4 to 39.0 ± 4.4 ml) (p < 0.0001, p < 0.0001, p = 0.0004, respectively). Isosorbide only improved IPSS (from 16.5 ± 0.9 to 14.6 ± 0.8) (p = 0.032). Conclusions: Daily administration of isosorbide does not seem to be an alternative to α-blocker therapy. Controlled, randomized novel studies are required to establish that whether nitric oxide donors are an effective alternative in LUTS treatment.

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The Forefront for Novel Therapeutic Agents Based on the Pathophysiology of Lower Urinary Tract Dysfunction: Pathophysiology of Voiding Dysfunction and Pharmacological Therapy

Cited by 18 publications

References 43 publications

Cranberry fruit powder (Flowens™) improves lower urinary tract symptoms in men: a double-blind, randomized, placebo-controlled study

Cranberry fruit powder (Flowens™) improves lower urinary tract symptoms in men: a double-blind, randomized, placebo-controlled study

Multitarget‐Directed Tricyclic Pyridazinones as G Protein‐Coupled Receptor Ligands and Cholinesterase Inhibitors

Comparison of the Efficacy of Isosorbide Mononitrate and Doxazosin in the Treatment of Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia: A Randomized Clinical Trial

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