Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-01
2002-08-27
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S247000, C514S368000, C514S406000, C514S407000, C514S600000
Reexamination Certificate
active
06440963
ABSTRACT:
The present application claims priority under 35 U.S.C.§ 119 (a)-(d) of Italian patent application no. MI 2001 A 000733, which is hereby incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
The invention relates to compositions and methods for treating neuromuscular dysfunction of the lower urinary tract in mammals, including humans, using selective inhibitors of the cyclooxygenase-2 isozyme (COX-2).
BACKGROUND OF THE INVENTION
In mammals, micturition is a complex process that requires the integrated actions of the bladder, its internal and external sphincters, and the musculature of the pelvic floor. Neurological control over these muscles occurs at three levels—in the bladder wall or sphincters, in the autonomic ganglia of the spinal cord, and in the central nervous system in the pontine micturition center of the brainstem (pons), under the control of the cerebral cortex.
Micturition results from contraction of the bladder detrusor muscle, which consists of interlacing smooth muscle fibers that are under parasympathetic autonomic control from the sacral spinal cord. A simple voiding reflex is formed by sensory nerves for pain, temperature, and distension that run from the bladder to the sacral cord. However, sensory tracts from the bladder also reach the pontine micturition center, resulting in the generation of nerve impulses that normally act at the spinal cord to suppress the sacral spinal reflex arc controlling bladder emptying. As a result, normal micturition is initiated by voluntary suppression of the cortical inhibition of the reflex arc and by relaxation of the muscles of the pelvic floor and the external sphincter. These events are followed by contraction of the detrusor muscle and voiding.
Functional abnormalities of the lower urinary tract, e.g., dysuria, incontinence, and enuresis, are common in the general population. Dysuria includes urinary frequency, nocturia, and urgency, and may be caused by cystitis, prostatitis or benign prostatic hypertrophy, which affects about 70% of elderly males, or by neurological disorders. Incontinence syndromes include stress incontinence, urgency incontinence, and overflow incontinence. Enuresis refers to the involuntary passage of urine at night or during sleep.
Prior to the present invention, treatment of neuromuscular disorders of the lower urinary tract has involved administration of compounds that act directly on the bladder muscles, such as flavoxate, a spasmolytic drug that is also active on the pontine micturition center, or anticholinergic compounds such as oxybutynin. The use of &agr;1-adrenergic receptor antagonists for the treatment of benign prostatic hypertrophy is also common. However, treatments that involve direct inhibition of the pelvic musculature or detrusor muscle may have undesirable side effects, such as incomplete voiding, accommodation reflex paralysis, tachycardia and dry mouth. Thus, it would be preferable to treat neuromuscular disorders of the lower urinary tract with compounds that act via the peripheral or central nervous system, to affect, for example, the sacral spinal reflex arc and/or the inhibitory impulses of the pontine micturition center in a manner that restores normal functioning of the micturition mechanism.
Available evidence indicates that arachidonic acid metabolites produced via the cyclooxygenase (COX) pathway are involved in the physiological regulation of the micturition reflex. Prostaglandin E
1
(PGE
1
), PGE
2
, PGD
2
, PGF
2&agr;
as well as tromboxane A
2
(TXA
2
) have been shown to induce contractile activity of animal and human bladder detrusor, in vitro (Andersson et al., Acta Physiol. Scand. 100:165-171, 1977; Borda et al., J. Urol. 129:1250-1253, 1983; Maggi et al., J. Pharmacol. Exp. Ther. 230:500-513, 1984; Gotoh et al., J. Urol. 135:431-437, 1986; and Palea et al., Br. J. Pharmacol. 124:865-872, 1998). PGE
2
and PGF
2&agr;
also play a role in modulating cholinergic and purinergic contractions generated by electrical stimulation, as demonstrated in isolated rabbit urinary bladder (Downie et al., J. Pharmacol. Exp. Ther. 230:445-449, 1984 and Husted et al, Arch. Intl. Pharmacodyn. 246:84-97, 1980). Furthermore, distension of the bladder wall leads to local production of endogenous prostanoids that modulate the afferent branch of the micturition reflex by lowering the threshold for eliciting voiding contractions (Ghoneim et al., J. Urol. 116:739-743, 1976), thus representing the link between stretching of the detrusor muscle due to bladder filling and activation of capsaicin-sensitive afferents.
Accordingly, indomethacin and flurbiprofen, well known inhibitors of cyclooxygenase, showed favorable effects in double-blind controlled studies in patients with detrusor instability, although they did not completely abolish detrusor overactivity and showed a high incidence of gastrointestinal side effects (Andersson, Drugs 35:477-494, 1988).
Prostaglandins are produced from free arachidonic acid through the catalytic activity of two COX enzymes. COX-1 is considered the constitutive isoform, being expressed in almost all tissues, whereas COX-2 is considered inducible, since its expression can be triggered typically by inflammatory insults. Several groups, however, have reported constitutive expression of COX-2 in different tissues, including the central nervous system (Yasojima et al., Brain Res. 830:226-236, 1999).
In the brainstem, COX-2-containing neurons were observed in the dorsal raphe nucleus, the nucleus of the brachium of the inferior colliculus, and in the region of the subcoeruleus, suggesting that COX-2 may be involved in the processing and integration of visceral sensory input and in the modulation of autonomic responses (Breder et al., J. Comp. Neurol. 355:296-315, 1995). Furthermore, it has been demonstrated (Yamamoto et al., Brain Res. 739:104-110, 1996) that COX-2 is constitutively expressed in the spinal cord, where it plays an important role in the spinal nociceptive information transmission.
Previous attempts did not establish a role for COX-2 specific antagonists in the treatment of non-inflammatory based neuromuscular dysfunction of the lower urinary tract. Lecci et al. (Br. J. Pharm. 130:331-338, 2000) compared the effects of a non-selective COX-1/COX-2 inhibitor, dexketoprofen, and a COX-2 selective inhibitor, NS-398, on urodynamic function, in both inflammation-based and non-inflammation based rat models. Bladder contractions elicited by application of arachidonic acid onto the serosal surface of the urinary bladder were blocked by dexketoprofen, but not by NS-398. Furthermore, although both dexketoprofen and NS-398 normalized bladder reflexes following either surgery or experimentally-induced inflammation of the lower urinary tract, there was no enhanced effect evidenced by the COX-2-specific inhibitor.
Lecci et al., therefore, failed to show any effect of NS-398 in a non-inflammation-based model of bladder function. Nor did Lecci et al. demonstrate a selective effect of a COX-2 inhibitor in inflammation-based models of urodynamic function. Nor did Lecci et al. demonstrate that selective COX-2 inhibitors are more potent than non-selective COX-1/COX-2 inhibitors at inhibiting the central part of the micturition reflex. Given these results, Lecci et al. speculated that, under non-inflammatory conditions, only the blockade of both COX-1 and COX-2 leads to urodynamic changes.
PCT application WO 98/09948 measured the effect in vitro of the COX-2 specific inhibitor, nimesulide, on contractility of isolated rat bladder strips stimulated with 40 mM potassium. Nimesulide was ineffective at inhibiting contractility, in that a high concentration (1×10
−4
M) of nimesulide achieved only a 42% inhibition. The requirement for such a high concentration suggests that the observed effect was not to due neuronal control of micturition, but rather was due to local effect of nimesulide on the bladder dome tissue.
Thus, there remains a need in the art for potent COX-2 specific inhibitors that are effective in treating neuromuscular dysfun
Guarneri Luciano
Leonardi Amedeo
Testa Rodolfo
Darby & Darby
Henley III Raymond
Recordati S.A. Chemical and Pharmaceutical Company
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