Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-12-08
2002-11-05
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
Reexamination Certificate
active
06476007
ABSTRACT:
BACKGROUND OF THE INVENTION
Nitric oxide (NO), which serves as an intracellular messenger, is implicated in a number of processes in the central nervous system. In the spinal cord, considerable evidence has demonstrated that NO contributes to the development of hyperalgesia in models of acute and chronic pain (Meller and Gebhart, 1993). Noxious stimulation increased NO synthase (NOS) expression (Lam et al., 1996) and cyclic guanosine 3′, 5-monophosphate (cGMP) content (Garry et al., 1994b) in the spinal cord. Administration of inhibitors of NOS and soluble guanylate cyclase caused analgesic effects (Malmberg and Yaksh, 1993; Meller et al., 1992a, b; Moore et al., 1990). Moreover, NO donors and cGMP analogues applied intrathecally caused a reduction in tail flick or paw withdrawal latency (Garry et al., 1994a; Inoue et al., 1997). Recently, sodium nitroprusside (an NO donor) was shown to evoke the release of immunoreactive cGMP from dorsal horn slices, which was suppressed by the application of methylene blue (a soluble guanylate cyclase inhibitor) (Garry et al., 1994c). These data indicate that the NO/cGMP signaling pathway contributes to spinal hyperalgesia via a cGMP-dependent mechanism.
It has been demonstrated that the N-methyl-D-aspartate (NMDA) receptors play a key role in multisynaptic nociceptive transmission and plasticity within the spinal cord (Aanonsen et al., 1990; Dickenson and Aydar, 1991). The NMDA receptors may be involved in changes such as central sensitization, wind-up, facilitation, hyperalgesia and allodynia, all of which may be manifestations of the same mechanisms. It is found that many of the effects of NMDA receptor activation appear to be ultimately mediated through the production of NO and cGMP (Meller and Gebhart, 1993). In the cerebellum, NMDA receptor activation results in a Ca
2+
-dependent increase in cGMP through the production of NO (Garthwaite et al., 1988). In the spinal cord, NMDA-produced facilitation of the tail flick reflex was completely abolished by pretreatment with either an NOS inhibitor (N
G
-nitro-L-arginine methyl ester) or a soluble guanylate cyclase inhibitor (methylene blue) (Meller et al., 1992a). Moreover, NMDA has been demonstrated to directly produce the release of NO in vivo at the spinal cord level (Rivot et al., 1999). These results indicate that NMDA may produce thermal hyperalgesia through the activation of the NO/cGMP signaling system in the spinal cord.
The NO/cGMP signaling pathway modifies several intracellular processes including activation of protein kinase, ion channels and phosphodiesterases. cGMP-dependent protein kinases are serine/threonine protein kinases and belong to the large family of protein kinases. cGMP-dependent protein kinases have been found to serve as major effectors for the NO/cGMP signaling pathway in the vascular and nervous system (Meller and Gebhart, 1993). Two isoenzymes of cGMP-dependent protein kinase have been recognized in mammals: cytosolic cGMP-dependent protein kinase I and membrane-bound cGMP-dependent protein kinase II. Furthermore, cGMP-dependent protein kinase I has been shown to exist in two isoforms, designated I&agr; and I&bgr;.
Sluka and Willis (1997) reported that the mechanical allodynia induced by capsaicin could be reversed by KT5823, a selective cGMP-dependent protein kinase but not selective cGMP-dependent protein kinase isoform inhibitor. There is a need in the art for drugs which will treat pain without having undesirable side effects.
The nitric oxide/cyclic guanosine monophosphate (NO/cGMP) signaling pathway has become increasingly important as our understanding of its diverse biological actions has expanded, especially within the central nervous system (1, 2). The best understood trigger for the NO/cGMP signaling pathway in the central nervous system is the opening of N-methyl-D-aspartate (NMDA) receptor channels and the activation of NO synthase (NOS) in a Ca
2+
-dependent manner. NO then results in cGMP formation in adjacent neurons through the activation of soluble guanylate cyclase (sGC) (3, 4). Considerable evidence has demonstrated that the NO/cGMP signaling pathway is present in the neurons of the spinal cord and contributes to the development of hyperalgesia in models of acute and chronic pain (4, 5).
SUMMARY OF THE INVENTION
It is an object of the invention to provide a method of affecting nociception.
It is an object of the invention to provide a catheter for treating pain.
It is an object of the invention to provide a pharmaceutical composition for treating pain.
It is an object of the invention to provide a method for screening for drugs useful in the treatment of pain.
These and other objects of the invention are provided by one or more of the embodiments described below. In one embodiment of the invention a method of affecting nociception is provided. An analgesic amount of an inhibitor of cyclic guanosine monophosphate (cGMP)-dependent protein kinase I&agr; (PKGI&agr;) is administered to a patient in need thereof. Desirably, the inhibitor preferentially inhibits isoenzyme I relative to isoenzyme II and inhibits isoform I&agr; relative to isoform I&bgr;.
According to another embodiment of the invention another method of affecting nociception is provided. An analgesic amount of Rp-8-[(4-Chlorophenyl)thio]-cGMPS triethylamine (Rp-8-CPT-cGMPS) or other inhibitor of cyclic guanosine monophosphate (cGMP)-dependent protein kinase I&agr; (PKGI&agr; )is administered intrathecally to a patient in need thereof.
Another aspect of the invention is a catheter. The catheter comprises an analgesic amount of an inhibitor of cyclic guanosine monophosphate (cGMP)dependent protein kinase I&agr; (PKGI&agr;). Desirably, the inhibitor preferentially inhibits isoenzyme I relative to isoenzyme II and preferentially inhibits isoform &agr; relative to isoform &bgr;.
According to another embodiment of the invention a pharmaceutical composition for treating pain is provided. The composition comprises Rp-8-CPT-cGMPS or another inhibitor of cyclic guanosine monophosphate (cGMP)-dependent protein kinase I&agr; (PKGI&agr;) in a sterile, pyrogen-free, aqueous vehicle.
In yet another aspect of the invention a method of screening for drugs useful in the treatment of pain is provided. A compound is tested for the ability to inhibit PKG I&agr;. The compound is also tested for the ability to inhibit PKG I&bgr;. A compound is identified as a candidate drug useful in the treatment of pain if it selectively inhibits PKG I&agr; relative to PKG I&bgr;.
Another embodiment of the invention is another method for screening for drugs useful in the treatment of pain. Cells are contacted with a test compound. Transcription , activity, or translation of PKG I&agr; is monitored in the cells. A compound is identified as a candidate drug if it inhibits transcription, activity, or translation of PKG I&agr;.
The present invention thus provides the art with new targets, new drugs, and new methods for treating pain.
REFERENCES:
patent: 5625056 (1997-04-01), Genieser et al.
E. Butt et al., “(Rp)-8-pCPT-cGMPS, a Novel cGMP-Dependent Protein Kinase Inhibitor”, European Jour. Of Pharmacology, No. 269, 1994, pp. 265-268.
Y. Tao et al., “Activation of cGMP-Dependent Protein Kinase I&agr; Is Required For N-Methyl-D-Aspartate-Or Nitric Oxide-Produced Spinal Thermal”, European Jour. Of Pharmacology, No. 392, 2000, pp. 141-145.
Y. Tao et al., “Expression And Action Of Cyclic GMP-Dependent Protein Kinase I&agr; In Inflammatory Hyperalgesia In Rat Spinal Cord”, Neuroscience, vol. 95, No. 2, 2000, pp. 525-533.
Butt, Elke, et al., (Rp)-8-pCPT-cGMPS, a novel cGMP-dependent protein kinase inhibitor, European Journal of Pharmacology Molecular Pharmacology Section 269, 1994, pp. 265-268, vol. 17, No. 2, Elsevier Science.
Lewin, Matthew R., et al., “Cyclic GMP pathway is critical for inducing long-term sensitization of nociceptive sensory neurons,” NatureNeuroscience, Jan. 1999, pp. 18-23, vol. 2, No. 1.
Sluka, K.A., et al., “The effects of G-protein and protein kinase inhibitors on the behaviou
Johns Roger A.
Tao Yuanxiang
Banner & Witcoff , Ltd.
Jarvis William R. A.
The Johns Hopkins University
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