Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-15
2003-12-16
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S396000, C514S394000, C514S393000, C514S385000, C514S438000, C514S439000, C514S443000, C514S444000, C548S151000, C548S303100, C548S150000, C548S302100, C548S302400, C548S302700, C548S301700
Reexamination Certificate
active
06664283
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel medical uses as pharmaceuticals for neuropathic pain by systemically administrating a compound having an mGluR1 receptor antagonistic activity.
BACKGROUND OF THE INVENTION
Neuropathic pain is intractable pain caused as a result of a functional abnormality of the peripheral or central nervous system. Neuropathic pain manifests itself due to neurological disorders accompanying various causes such as wound, infection, cancer, ischemia and metabolic disorders including diabetes mellitus. Though there are many unclear points on the mechanism of neuropathic pain, it is considered that abnormal continuous firing of sensory nerve and the like are the cause. Typical symptoms of neuropathic pain include allodinia, hyperalgesia, hyperesthesia and the like. Their symptoms include characteristic pains expressed as “like burning”, “like stinging”, “like electrical shock” and the like. It is known that analgesics, particularly narcotic analgesics and the like, which are effective for general nociceptive pains are hardly effective for neuropathic pain (
The Lancet
, 353, 1959-1966, 1999). For example, it is known that morphine has a strong analgesic effect on nociceptive pains but does not show a sufficient effect on neuropathic pain. Consequently, this resistance to morphine is used in diagnoses as a main characteristic of neuropathic pain (
Advances in Medical Science
, 189(10), 751-755, 1999). It is considered that the ineffectiveness of morphine for neuropathic pain is due to degeneration of inhibitory neurons and reduction of opiate receptors caused by neurological changes of nerves (Recent Brain and Neuroscience Series vol. 6, Neuroscience of Pains, published by Medical View, p. 97, 1997).
Accordingly, it is considered that various factors are complicatedly involved in the generation and maintenance of neuropathic pain. As the therapeutic methods, neurosurgery treatments such as nerve block and epidural spinal cord electric stimulus (
Advances in Medical Science
, 189 (10), 757-762, 1999), tricyclic antidepressants (
Clinical and Drug therapies
, 18 (7), 643-646, 1999), intrathecal administration of baclofen (
Functional Cerebral Nerve Surgery
, 33, 45-49, 1994) and the like have so far been used. However, since a safe and effective therapeutic method has not been established, concern has been directed toward the development of a therapy effective for neuropathic pain.
Glutamate is a main excitatory transmitter that is present in sensory nerve fibers and mediates sensory information to the spinal cord. Peripherally evoked nociceptive signals are sent to supraspinal regions through non-NMDA, NMDA and mGluRs in the spinal cord. Also, it has been reported that NMDA receptor antagonists and AMPA receptor antagonists improve reduced pain thresholds in a neuropathic pain model (
Br. J. Pharmacol
., 122, 1478-1482, 1997). Based on the above, it is considered that in the spinal cord glutamate may be released excessively in the state of neuropathic pain.
On the other hand, the following reports have been published on the involvement of mGluRs in neuropathic pain.
Reference 1 (
Neuroreport
, 9, 731-735, 1998) reported that intrathecally administered antibodies for mGluR1 and mGluR5 before and 24 hours after surgical operation inhibited a development of cold hyperalgesia but did not inhibit a development of mechanical allodynia in rats.
Reference 2 (
Pain
, 77, 59-66, 1998) reported that intrathecal treatment (twice-daily injections on post-operative days 0-8) of a Group I antagonist ((S)-4CPG: (S)-4-carboxyphenylglycine) attenuated cold hyperalgesia on the post-operative days 4 and 8. But it did not have an effect on that on the post-operative days 12 and 16. In addition, it also inhibited a development of mechanical allodynia on the post-operative days 4 and 8, but it did not have an effect on that on the post-operative days 12 and 16. On the other hand, twice-daily intrathecal injections of (S)-4CPG on post-operative days 8-11 did not inhibit development of lowered pain threshold at any day of the test. Therefore, it was discussed that Group I mGluRs are involved in the development, and not the maintenance, of mechanical allodynia and cold hyperalgesia.
The authors of the references 1 and 2 have confirmed prophylactic effects of the intrathecal administration of mGluR1/5 antagonist and antibody for mGluR1 in nerve ligation-induced neuropathic pain animal models. However, since the reference 2 has concluded that mGluR1/R5 antagonist did not improve the well-established mechanical allodynia or cold hyperalgesia, it has been considered that mGluR1 and/or mGluR5 antagonist has an prophylactic effect, which means the prevention of pain threshold reduction after nerve injury, but does not have a therapeutic effect, which means improving lowered pain thresholds to the normal level.
In addition, these references 1 and 2 neither disclose nor suggest the therapeutic effect of systemically administered mGluR1 antagonist on neuropathic pain.
In these references 1 and 2, intrathecal administration is used for the evaluation of drugs in neuropathic pain models. Since it is known that mGluR1 receptor is involved in the nociceptive signaling in the spinal cord, it is likely that the mGluR1/R5 antagonists and antibody for mGluR1 were intrathecally administered in the references 1 and 2. However, these mGluR1/R5 antagonists and antibody for mGluR1 did not show the therapeutic effect on neuropathic pain even by their intrathecal administration, which is thought to be the most efficient administration route to deliver drugs to the action sites.
On the other hand, it has been reported that the mGluR1 receptor is highly expressed in the thalamus and exists particularly on relay neurons in the thalamus, which transmit noxious signals to the cerebral cortex (
Neuron
, 9, 259-270, 1992
; Neurochem. Int
. 24, 451-458, 1994).
Therefore, the present inventors have considered that it is necessary to block mGluR1 in the thalamus in addition to mGluR1 in the spinal cord to obtain a sufficient therapeutic effect for neuropathic pain, and have attempted to evaluate the therapeutic effect of mGluR1 antagonists in neuropathic pain models by systemic administration.
The relationship between mGluR1 in thalamus and neuropathic pain has not been known, and there has been no suggestion from which the therapeutic effect of an mGluR1 antagonist on neuropathic pain by its systemic administration can be predicted.
DISCLOSURE OF THE INVENTION
The object of the invention is to provide excellent systemically active pharmaceuticals for treatment of neuropathic pain.
With the aim of achieving this object, the inventors have conducted studies based on our own ideas and found that an mGluR1 antagonist has therapeutic effects in various neuropathic pain models, thereby accomplishing the invention. STZ (streptozotocin)-induced diabetic mice are used as a neuropathic pain model in which the pain is induced by diabetes-related neurological disorders, and spinal L5/L6 nerve-ligated rats are used as a neuropathic pain model in which the pain is induced by a compression-induced nerve damage (
Pain
, 50, 355-363, 1992). When the effect of the mGluR1 antagonists on lowered pain thresholds by their systemic administration was examined using these models, it was found that the mGluR1 antagonists have an effect which cannot be predicted from the technical levels so far known, namely that the mGluR1 antagonist significantly recovers lowered pain thresholds in these models (therapeutic effect).
The present invention makes it possible to provide pharmaceuticals for neuropathic pain, which are easy for patients to take and have an efficient therapeutic effect with less side effects.
Particularly, the invention relates to the following items.
A pharmaceutical composition for systemic administration for use in treating a neuropathic pain, which contains a compound having mGluR1 antagonistic activity in an amount effective for improving the neuropathic pain and a pharmaceutically acceptable carrier; preferably, the
Hayashibe Satoshi
Kiso Tetsuo
Nagakura Yukinori
Okada Masamichi
Toya Takashi
Criares Theodore J.
Jiang S.
Yamanouchi Pharmaceutical Co. Ltd.
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