Christopher Henry Fry1, Basu Chakrabarty1, Hikaru Hashitani2, Karl-Erik Andersson3,4, Karen McCloskey5, Rita I Jabr6, Marcus J Drake7. 1. School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK. 2. Department of Cell Physiology, Nagoya City University, Nagoya, Japan. 3. Institute of Laboratory Medicine, Lund University, Lund, Sweden. 4. Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina. 5. School of Medicine, Dentistry and Biomedical Sciences, Queens University Belfast, Belfast, UK. 6. Division of Biochemical Sciences, Faculty of Health and Biomedical Sciences, University of Surrey, Guildford, UK. 7. Bristol Medical School, University of Bristol, Bristol, UK.
Abstract
AIM: To review evidence for novel drug targets that can manage overactive bladder (OAB) symptoms. METHODS: A think tank considered evidence from the literature and their own research experience to propose new drug targets in the urinary bladder to characterize their use to treat OAB. RESULTS: Five classes of agents or cellular pathways were considered. (a) Cyclic nucleotide-dependent (cyclic adenosine monophosphate and cyclic guanosine monophosphate) pathways that modulate adenosine triphosphate release from motor nerves and urothelium. (b) Novel targets for β3 agonists, including the bladder wall vasculature and muscularis mucosa. (c) Several TRP channels (TRPV1 , TRPV4 , TRPA1 , and TRPM4 ) and their modulators in affecting detrusor overactivity. (d) Small conductance Ca2+ -activated K+ channels and their influence on spontaneous contractions. (e) Antifibrosis agents that act to modulate directly or indirectly the TGF-β pathway-the canonical fibrosis pathway. CONCLUSIONS: The specificity of action remains a consideration if particular classes of agents can be considered for future development as receptors or pathways that mediate actions of the above mentioned potential agents are distributed among most organ systems. The tasks are to determine more detail of the pathological changes that occur in the OAB and how the specificity of potential drugs may be directed to bladder pathological changes. An important conclusion was that the storage, not the voiding, phase in the micturition cycle should be investigated and potential targets lie in the whole range of tissue in the bladder wall and not just detrusor.
AIM: To review evidence for novel drug targets that can manage overactive bladder (OAB) symptoms. METHODS: A think tank considered evidence from the literature and their own research experience to propose new drug targets in the urinary bladder to characterize their use to treat OAB. RESULTS: Five classes of agents or cellular pathways were considered. (a) Cyclic nucleotide-dependent (cyclic adenosine monophosphate and cyclic guanosine monophosphate) pathways that modulate adenosine triphosphate release from motor nerves and urothelium. (b) Novel targets for β3 agonists, including the bladder wall vasculature and muscularis mucosa. (c) Several TRPchannels (TRPV1 , TRPV4 , TRPA1 , and TRPM4 ) and their modulators in affecting detrusor overactivity. (d) Small conductance Ca2+ -activated K+ channels and their influence on spontaneous contractions. (e) Antifibrosis agents that act to modulate directly or indirectly the TGF-β pathway-the canonical fibrosis pathway. CONCLUSIONS: The specificity of action remains a consideration if particular classes of agents can be considered for future development as receptors or pathways that mediate actions of the above mentioned potential agents are distributed among most organ systems. The tasks are to determine more detail of the pathological changes that occur in the OAB and how the specificity of potential drugs may be directed to bladder pathological changes. An important conclusion was that the storage, not the voiding, phase in the micturition cycle should be investigated and potential targets lie in the whole range of tissue in the bladder wall and not just detrusor.
Authors: Karl-Erik Andersson; Lori Birder; Christopher Chermansky; Russell Chess-Williams; Christopher Fry Journal: Neurourol Urodyn Date: 2020-07 Impact factor: 2.696
Authors: Csaba Dienes; Zsigmond Máté Kovács; Tamás Hézső; János Almássy; János Magyar; Tamás Bányász; Péter P Nánási; Balázs Horváth; Norbert Szentandrássy Journal: Pharmaceuticals (Basel) Date: 2021-12-28