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Doug ArbesfeldManning Selvage and Lee212-213-7224
New Study Discovers Key Mechanism Involved in Bladder Control-- May Lead to New Treatments for Overactive Bladder --
Palo Alto, Calif. October 26, 2000 -- Researchers from California and London have identified a previously unknown mechanism that controls the storage capacity of the bladder and the frequency of elimination (urination). The research, published today in the journal Nature, could lead to the discovery of new medicines for overactive bladder (urge incontinence), a condition that affects 35 million people worldwide, including one in 11 American adults, mostly middle-aged women and elderly adults.
The study, conducted in mice, found that as the bladder fills and releases ATP (adenosine tri-phosphate, the energy source for most chemical reactions in each human cell), it activates nerve endings via specific receptor proteins, called P2X3. The researchers believe that if a molecule could be developed to effectively block the P2X3 receptor, increased bladder capacity and reduced frequency of urination would result, just the relief needed by people with overactive bladders.
"By utilizing our expertise in mouse genomics, we were able to create knockout mice that lack the gene for a sensory neuron receptor -- the P2X3 receptor," said Dr. Anthony Ford, head of Genitourinary Research at Roche Bioscience, and an author of the Nature study. "What we discovered is that the absence of the receptor alters the control of urine storage and elimination leading us to conclude that the protein P2X3 plays a pivotal role, receiving signals from the filling bladder."
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Drs. Ford and Debra Cockayne, principal scientist and expert in mouse genetics, Roche Bioscience, collaborated on the research with world-renowned ATP expert Professor Geoff Burnstock and his colleagues, from the Autonomic Neuroscience Institute at The Royal Free and University College Medical School and the Centre for Neuroscience Research at Kings College, both in London. The paper is titled Urinary Bladder hyporeflexia and reduced pain behaviour in P2X3 receptor-deficient mice. (1)
P2X3 Knockout Mice Studied
Mice lacking the P2X3 receptor, known as knockout mice, were compared to regular, so-called wild-type mice for their ability to respond to specific stimuli. The scientists found that the P2X3 knockout mice had a weaker response to external stimuli and that their bladders were less responsive when filled with saline. Compared to the wild-type mice, the bladders of the knockout mice appeared unusually large, storing twice as much urine and thus urinating half as frequently.
"People with overactive bladders cannot tolerate large volumes of urine and therefore, urinate frequently, and often suffer embarrassing accidents" said Dr. Ford. "Our research suggests that blocking the P2X3 receptor may provide a more normal return to urinary control than current treatment methods, which weaken the muscle responses of the bladder, as well as impairing a broad range of bodily functions."
Improvement over Current Therapies
Targeting P2X3 antagonism may offer an improved side effect profile over current drug therapies because the P2X3 receptor is found in only a few areas of the body, besides the bladder. Current approaches to managing overactive bladder typically involve medications (anticholinergics) that block acetylcholine receptors throughout the body, and can cause a wide variety of side effects including dry mouth, dry skin, and dry eyes.
Genitourinary Research at Roche
The field of genitourinary research was added to the Roche portfolio in 1995 and encompasses several significant disease areas including, stress incontinence, overactive bladder, benign prostatic hyperplasia and pelvic hypersensitivity. Worldwide, these diseases collectively affect more than 110 million individuals; therefore, understanding these diseases has been a goal for the medical community for some time. This has resulted in a focus by scientists on pharmacological approaches and the development of novel therapies. Roche is conducting research on a wide range of mechanisms involved in triggering these diseases with the aim of finding new and more effective compounds to treat these quality of life disorders. Understanding these mechanisms has allowed for the evolving perception that genitourinary disorders have origins in "wiring" (neurophysiology) rather than simply "plumbing" (anatomy)."
About Roche Bioscience
Roche Bioscience is involved in the discovery and early clinical development of innovative new medicines to treat diseases including arthritis, asthma and other respiratory diseases; anxiety, depression, schizophrenia and other neuropsychiatric diseases; genitourinary diseases and osteoporosis. Roche Bioscience is one of six pharmaceutical research locations for Roche Holding Ltd. Headquartered in Basel, Switzerland, Roche is one of the world's leading research-oriented healthcare groups in the fields of pharmaceuticals, diagnostics and vitamins. Roche's innovative services address the prevention, diagnosis and treatment of diseases, thus enhancing people's well being and quality of life.
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(1) Nature, October 26, 2000 -- Urinary Bladder hyporeflexia and reduced pain behaviour in P2X3 receptor-deficient mice. Authors: Debra A. Cockayne*, Sara G. Hamilton** , Quan-Ming Zhu*, Philip M. Dunn*** , Yu Zhong Sanja Novakovic*, Annika B. Malmberg*, Gary Canin*, Amy Berson*, Laura Kassotakis*, Linda Hedley*, Wilhelm G. Lachnit*, Geoffrey Burnstock*** , Stephen B. McMahon** , and Anthony P.D.W. Ford*
From *The Neurobiology Unit, Roche Bioscience, 3401 Hillview Avenue, Palo Alto, CA 94304, USA, **Centre for Neuroscience Research, Kings College London, SE1 9RT, UK, and ***Autonomic Neuroscience Institute, Royal Free and University College medical School, Rowland Hill Street, London, NW3 2PF, UK
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