Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-08
2002-08-27
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S292000
Reexamination Certificate
active
06440988
ABSTRACT:
BACKGROUND OF THE INVENTION
Throughout this application, various publications are referenced in parentheses by author and year. Full citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application to describe more fully the art to which this invention pertains.
Normal bladder function requires coordinated bladder contraction and urethral sphincter relaxation during the emptying phase and the opposite, bladder relaxation and urethral sphincter contraction, during the filling/storage phase. The occurrence of irregularities in these processes increases with age in males and females and can lead to a variety of disorders of lower urinary tract function, including incontinence and urinary retention.
Incontinence and Urinary Retention
Incontinence is characterized by the involuntary loss of urine. It can be divided generally into two types, stress and urge incontinence. Stress incontinence is characterized by an inability to generate or maintain normal closing pressure at the bladder outlet and urethra. Involuntary urine loss can be provoked whenever the physical stress of everyday activities causes abdominal pressure to rise above the level of the bladder closing pressure; hence the name. The underlying pathology may involve (1) damage to the nerves which send contractile signals to these structures (such as may occur during childbirth), or (2) loss of mass of the urothelium after menopause, or (3) other processes which result in primary muscle weakness or loss of tone to these structures (Wein, 1987; Andersson, 1988).
Urge incontinence, in contrast, involves primarily changes in the function of the main body (detrusor) of the bladder. These changes disrupt the normal manner in which bladder volume/distention is sensed and translated into, first, the desire to void and, ultimately, the neuronal impulses signaling detrusor contraction. Rather than a graded response to bladder distention, patients with urge incontinence experience involuntary leakage preceded by a sensation of urgency and impending urinary loss. A large portion of patients with urge incontinence are shown by urodynamic evaluation to have detrusor instability, characterized by spontaneous, involuntary contractions (Swami and Abrams, 1996). The underlying pathology may involve either the sensory or motor nervous systems innervating the detrusor, or may be associated with inflammation and irritative processes in the bladder muscle, or may be idiopathic (Andersson, 1988).
As the name implies, urinary retention describes a condition in which there is difficulty in voiding. In some instances this may occur as a result of bladder outlet obstruction, as is seen in patients with benign prostatic hyperplasia (BPH). Indeed, chronic bladder outlet obstruction may lead to secondary bladder hyper-reflexia which may persist after correction of the obstruction and may involve remodeling of the neuronal circuitry of the bladder (Swami and Abrams, 1996). Urinary retention in the absence of bladder outlet obstruction may arise from deficits in the same systems as urge incontinence: the neurons or smooth muscle of the detrusor.
Neural Control of the Urinary Bladder
The contractile activity of the lower urinary tract structures is controlled primarily by two neurotransmitter systems (Wein, 1987). Neurons of the sympathetic nervous system innervate the urethra and bladder base, and to a lesser extent the detrusor, releasing the neurotransmitter norepinephrine (NE). The smooth muscle of the urethra and bladder base are endowed with alpha-adrenergic receptors where NE acts to cause contractions. In contrast, adrenergic receptors of the detrusor are of the beta-adrenergic subtype, the activation of which causes relaxation. Thus, activation of the sympathetic nervous system in the bladder promotes urine storage. Parasympathetic neurons innervate the detrusor, but not the bladder base or urethra. Parasympathetic neurons release the neurotransmitters acetylcholine (ACh) and adenosine-5′-triphosphate (ATP) which act, respectively, at M
3
-muscarinic and P
2X
-purinergic receptors to elicit contractions. Activation of the parasympathetic nervous system, therefore, promotes bladder emptying.
Although these neuronal systems play a key role in the motor activity of the lower urinary tract, other neurotransmitters are involved to varying degrees in different species, and possibly to varying degrees during different pathological states within a given species (e.g. humans). Indeed, Ferguson and Christopher (1996) state that “up to 50% of contractile activity in patients with bladder instability is sensitive to tetrodotoxin (i.e., is of neuronal origin) but resistant to atropine, suggesting that purinergic (i.e., involving the neurotransmitter ATP) or other NANC (non-adrenergic, non-cholinergic) neurotransmission plays a greater role in pathological conditions.”
In addition to transmitters stored in and released from terminals of efferent nerves, transmitters of afferent nerves and their receptors are also involved in the control of lower urinary tract function. Tachykinins, such as substance P, neurokinins A and B, and other neuropeptides have been demonstrated in nerves of the lower urinary tract and shown to be able to influence bladder function (Andersson, 1996). Among the ‘non-classical’ transmitters which have been studied is nitric oxide, which plays a role in the relaxation of the bladder base and urethra during micturition (Werkstrom et al., 1997). One of the more extensively studied classical neurotransmitters in the bladder is 5-hydroxytryptamine (5-HT). In the human detrusor 5-HT has been shown to have multiple effects on bladder contractility. One of the ways in which 5-HT has been shown to affect contractions is by modifying the neuronal release of the primary parasympathetic neurotransmitters, ACh and ATP (see below).
Current Treatments for Micturition Disorders
A variety of pharmaceutical agents have been employed to treat micturition disorders. Drugs used to reduce bladder contractility associated with urge incontinence include muscarinic receptor antagonists, calcium channel blockers, direct smooth muscle relaxants, and beta-adrenergic receptor agonists (Andersson, 1988). In addition, prostaglandin synthesis inhibitors and tricylic antidepressants have been investigated for this purpose (Andersson, 1988). More recently, there has been an interest in developing potassium channel openers, aimed at reducing contractility by hyperpolarizing detrusor smooth muscle cells (Ohnmacht et al., 1996). The most commonly employed therapeutic agents for increasing bladder outlet resistance are the alpha-adrenergic receptor agonists and estrogen (Wein, 1987). The only agents which are effective at increasing detrusor contractions and improving bladder emptying are the muscarinic receptor agonists (Andersson, 1988). Each of these therapies is associated with limited efficacy and unwanted side effects (Andersson, 1988; Wein, 1987).
5-HT in Bladder Function
The physiological role of 5-hydroxytryptamine (5-HT) in bladder detrusor varies widely among different species, with respect to both the nature of response and the receptor subtype involved. For example, 5-HT produces marked contractions mediated by postjunctional 5-HT
2
receptors in isolated detrusor from cat (Saxena et al., 1985) and dog (Cohen, 1990). Potent direct 5-HT-evoked contractions have also been described for human detrusor strips (Klarskov and Hørby-Petersen, 1986). Although the responses were found to be relatively insensitive to 0.1 &mgr;M ketanserin, and therefore not associated with 5-HT
2A
receptor activation, the identity of the subtype involved remains to be determined. In contrast, direct contractile effects of 5-HT are absent in the bladder body of rat and guinea pig (Cohen and Drey, 1989) and monkey (Waikar et al., 1994). Unlike other species, the monkey bladder expresses postjunctional 5-HT
4
receptors, acti
Cooper & Dunham LLP
Synaptic Pharmaceutical Corporation
Weddington Kevin E.
White John P.
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