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June, 2008
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Human tissue based pharmacology
models for urology research
The last decade has seen a vast change in the clinical management of urological problems, with a switch from the majority of patients undergoing surgery to being treated through the introduction of effective drugs. Commitment and research into urological disorders is still a key focus area for several pharmaceutical and biotechnology companies, with overactive bladder (OAB) syndrome and stress urinary incontinence (SUI) being the primary areas of interest. OAB has been estimated to occur in 16% of the population over 40 years of age
1
, whereas SUI affects an average of ~50% of incontinent women between the ages of 18-90 years, with no globally accepted pharmacotherapy
2
. Despite considerable progress in this field over the last few years there is still significant investment from pharmaceutical companies to discover new drugs.
There are currently three key therapeutic approaches for OAB, each of which can be investigated using human tissue-based approaches.
Muscarinic receptor antagonists
Over the last three decades there has been widespread use of anti-muscarinic compounds, both subtype-selective (e.g. darifenacin) and non-selective (e.g. oxybutinin), for the management of OAB. Anti-muscarinic compounds have been associated with poor tolerance due to the side effects arising from actions on both the salivary glands, causing dry-mouth, and on the GI-tract, causing constipation, through the activation of muscarinic M
3
- receptors. A recent study showed that <20% of patients are still on their prescribed therapy at the end of 12 months
3
. Therefore, there is still a drive both to find both novel targets for the management of OAB and to design better anti-muscarinic compounds with better patient tolerability.
β-adrenoceptor agonists
There is evidence for β
3
-adrenoceptors mediating relaxation in human detrusor smooth muscle
4
, although their functional importance remains to be established. There is speculation that in detrusor overactivity there is a lack of β-adrenoceptor mediated inhibitory responses. Therefore, an alternative approach to anti-muscarinics for treating OAB could be to enhance the relaxation (via the stimulation of β-adrenoceptors) of the bladder during the filling phase.
Effects of novel β
3
-adrenoceptor agonists can be compared to that of isoprenaline, which causes reproducible relaxation in human detrusor smooth muscle.
Role of the urothelium
The third key area of interest as a potential target for the management of OAB is the role of the lining of the bladder. Classically, the urothelium was thought to be only a passive barrier to ions and solutes, but a number of novel properties have recently been attributed to urothelial cells
5
. Further discovery of mechanisms that influence urothelial function might provide insights into the pathology in bladder dysfunction.
Muscarinic receptors are found on the urothelium in humans, where their activation results in the release of an unidentified inhibitory factor (which inhibits contraction of the underlying detrusor smooth muscle tone
6
). Understandably, this is another exciting area of current urology research, which could potentially have a significant impact on the clinical management of OAB. Species differences are known to exist; in the rat bladder this inhibitory factor is released from the detrusor smooth muscle cells and not the urothelial cells.
Conclusions
Historically, normal urological function and associated pathologies have been hard to characterise in human tissue
in vitro
due to poor availability and quality of tissue. Over the last 11 years, Asterand has established access to a wide range of high quality human tissues, ethically consented for research. Our human tissue network provides us with regular access to a comprehensive range of fresh urology tissues including bladder, urethra, from both male and female donors, and prostate. Using these tissues, with our PhaseZERO
®
human tissue-based services platform, we are able to generate data for the pharmaceutical industry to support progression of their urology R&D programs.
The attrition rate for compounds entering clinical development remains high and is largely due to lack of clinical efficacy
7,8
. Therefore, a clear understanding of species differences in target expression and function in urological tissues may help to achieve the desired clinical effect in urinary disorders with novel compounds.
To date the physiology and pharmacology of the lower urinary tract has been advanced, in part, due to
in vitro
assays that have facilitated this exploration. We believe that confidence for clinical success can be greatly enhanced by not going with the flow of only using animal models or human recombinant assays but by also generating human tissue-based data prior to compounds entering clinical development. Asterand’s regular supply of high quality, fresh urological tissues from both men and women allows our customers to use our PhaseZERO
®
pharmacology research services for the discovery and testing of new therapies for a range of urological pathologies.
References
1
Milsom I, Abrams P, Cardozo L, Roberts RG, Thüroff J and Wein AJ (2001). BJU Int. 87: 760-766
2
Schuessler B and Baessler K (2003). Urology 62: 31-38
3
Chui MA, Wiliamson T, Arciniega J, Thompson C, Benecke H (2004). Value Health 7:366
4
Igawa Y, Yamazaki Y, Takeda H, Hayakawa K, Akahane M, Ajisawa Y, Yoneyama T, Nishizawa O, Andersson KE (1999) Br J Pharmacol 126:819-825
5
deGroat WC (2004) Urology 64:7-11
6
Hawthorn MH, Chapple CR, Cock M, Chess-Williams R. (2000) Br J Pharmacol. 129:416-41
7
Kennedy T. (1997). Drug Discovery Today 2: 436-444
8
Kola I and Landis J. (2004). Nature Reviews Drug Discovery 3: 711-715
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