Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-02-09
2002-06-18
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S455000, C424S457000, C424S464000
Reexamination Certificate
active
06406716
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to a composition and method for alleviating neuropathic pain. More particularly, this invention is directed to a composition and method for alleviating neuropathic pain in which a neuropathic pain-alleviating amount of an anticonvulsant is combined with an anticonvulsant-potentiating amount of a nontoxic antagonist, or blocker, for the N-methyl-D-aspartate (NMDA) receptor or nontoxic substance that blocks a major intracellular consequence of NMDA receptor activation.
Neuropathic pain is pain that is due to functional abnormalities of the nervous system. Fields, “Pain”, McGraw-Hill, Inc. (1987), pp. 133 et seq. There are a variety of possible mechanisms by which nerve dysfunction can cause neuropathic pain: hyperactivity in primary afferent or central nervous system (CNS) nociceptive neurons, loss of central inhibitory connections, and increased activity in sympathetic efferents. Neuropathic pain typically occurs following injury to elements of the nervous system involved in nociception, such as peripheral nerve injury, in which the lesions deafferent the nociceptive pathway, the resultant pain sometimes being referred to deafferentation pain. Neuropathic pain is much more likely to occur with peripheral than with central nervous system damage. Examples of causes of painful nerve injury are: accidental trauma, tumors, cerval or lumbar spine disease, and surgical procedures. These injuries usually involve one or two peripheral nerves or nerve roots, and the pain is felt in the body region normally innervated by the damaged nerves. Additionally, there are also toxic, metabolic, and hereditary causes of painful polyneuropathies, e.g., alcohol abuse, diabetes mellitus. These tend to be symmetrical and are most severe on the distal limbs.
SUMMARY OF THE INVENTION
In accordance with the present invention, a drug composition is provided which comprises a neuropathic pain-alleviating amount of at least one anticonvulsant in combination with an anticonvulsant-potentiating amount of at least one nontoxic antagonist for the NMDA receptor or nontoxic substance that blocks a major intracellular consequence of NMDA receptor activation.
Further in accordance with the present invention, a method of alleviating neuropathic pain is provided which comprises administering to a mammal exhibiting neuropathic pain (a) a neuropathic pain-alleviating amount of at least one anticonvulsant and (b) an anticonvulsant-potentiating amount of at least one nontoxic antagonist for the NMDA receptor or nontoxic substance that blocks a major intracellular consequence of NMDA receptor activation with (a) being administered prior to, with or following the administration of (b).
The expression “N-methyl-D-aspartate receptor” shall be understood to include all of the binding site subcategories associated with the NMDA receptor, e.g., the glycine-binding site, the phenylcyclidine (PCP)-binding site, etc., as well as the NMDA channel. Thus, the invention herein contemplates the use of nontoxic substances that block an NMDA receptor binding site, e.g., dextrorphan, or the NMDA channel, e.g., a source of magnesium such as magnesium sulfate.
The term “nontoxic” as used herein shall be understood in a relative sense and is intended to designate any substance that has been approved by the United States Food and Drug Administration (“FDA”) for administration to humans or, in keeping with established regulatory criteria and practice, is susceptible to approval by the FDA for administration to humans. The term “nontoxic” is also used herein to distinguish the NMDA receptor antagonists, or blockers, that are useful in the practice of the present invention from NMDA receptor antagonists such as MK 801 (the compound 5-methyl-10,11-dihydro-SH-dibenze[a,d]cyclohepten-5,10-imine), CPP (the compound 3-[2-carboxypiperazin-4-yl]propyl-1-phosphonic acid) and PCP (the compound 1-(1-phenylcyclohexyl)piperidine) whose toxicities effectively preclude their therapeutic use.
The expression “neuropathic pain-alleviating” shall be understood herein to include the expressions “neuropathic pain-suppressing” and “neuropathic pain-inhibiting” as the invention is applicable to the alleviation of existing neuropathic pain as well as the suppression or inhibition of neuropathic pain which would otherwise ensue from an imminent neuropathic pain-causing event.
REFERENCES:
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patent: 6187338 (2001-02-01), Caruso et al.
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International Search Report for PCT/US 97/14680; International filing date Aug. 21, 1997.
Caruso Frank S.
Lyle John W.
Minn Fredrick L.
Dilworth & Barese, LLP
Endo Pharmaceuticals Inc.
Spear James M.
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