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Pharmacological methods for the preclinical assessment of therapeutics for OAB: an up-to-date review

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Abstract

Introduction

Licenced oral pharmacotherapies for overactive bladder (OAB) act on muscarinic receptors or β3-adrenoceptors. The search for new drugs to treat OAB that have novel mechanisms of action is very active, with the aim of discovering more effective and/or better tolerated agents.

Methods

A literature review of the most frequently used pharmacological methods for the preclinical assessment of new agents aimed at treating OAB, such as isolated organ technique, electrophysiological techniques, radioligand binding assay, and animal models, was carried out. Novel potential developments based on recent knowledge of urothelial and neural mechanisms are also discussed.

Results

The isolated organ technique, electrophysiological techniques, and the radioligand binding assay are very effective methods for the demonstration that a novel pharmacological target with a specific and high affinity binding site for a new drug is present in the bladder and its modulation regulates functions critical for the pathophysiology of OAB. Afterward, the new drug should be shown to be effective in animal models of OAB, although the translational value of these models is limited by a poor pathophysiological relationship with human OAB. Exciting novel perspectives focusing in particular on the theory of the mucosal–bladder network have recently opened new paths in the discovery and assessment of new therapeutics in this field.

Conclusions

Available experimental models still play a central role in the appraisal of OAB therapeutics; however, their shortcomings and the paucity of very effective drugs indicate the need for new models that better reproduce the pathophysiological features of OAB. Some emerging lines of research show promise. A change of perspective in the future evaluation of putative drugs is required, especially in the light of the latest knowledge on the key role of the mucosal–bladder network and the brain–bladder neural pathways.

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Abbreviations

BOO:

Bladder outlet obstruction

CNS:

Central nervous system

DO:

Detrusor overactivity

EAE:

Experimental autoimmune encephalomyelitis

DM:

Diabetes mellitus

EFS:

Electrical field stimulation

ICs:

Interstitial cells

KV7 channels:

Voltage-dependent type 7 K+ channels

LUT:

Lower urinary tract

MPTP:

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

NGF:

Nerve growth factor

nNOS:

Neuronal nitric oxide synthase

NO:

Nitric oxide

NVC:

Non-voiding contractions

OAB:

Overactive bladder

SHR:

Spontaneous hypertensive rat

TTX:

Tetrodotoxin

WKY:

Wistar–Kyoto rats

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Acknowledgements

The significant contribution of Dr Lucia Lisi (Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy) for the preparation of the figures is gratefully acknowledged. The authors thank her warmly.

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Authors and Affiliations

  1. Department of Urology, “Agostino Gemelli” Hospital, Catholic University Medical School, Rome, Italy

    Emilio Sacco, Riccardo Bientinesi & Pierfrancesco Bassi

  2. Institute of Pharmacology, Catholic University Medical School, Largo Vito 1, 00168, Rome, Italy

    Diego Currò

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  1. Emilio Sacco
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Sacco, E., Bientinesi, R., Bassi, P. et al. Pharmacological methods for the preclinical assessment of therapeutics for OAB: an up-to-date review. Int Urogynecol J 27, 1633–1644 (2016). https://doi.org/10.1007/s00192-016-2977-9

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