Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 15 to 23 amino acid residues in defined sequence
Reexamination Certificate
1998-07-22
2002-06-18
Low, Christopher S. F. (Department: 1654)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
15 to 23 amino acid residues in defined sequence
C604S891100, C424S422000, C514S012200, C514S013800, C514S014800, C435S070100, C530S324000, C530S325000
Reexamination Certificate
active
06407204
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
This invention relates to administration of a therapeutically effective amount of one or more conantokin molecules for production of analgesia or for neuroprotection.
BACKGROUND OF THE INVENTION
Chronic or intractable pain, which may result from degenerative conditions or debilitating diseases, is currently treated with a variety of analgesic compounds, often opioid compounds such as morphine. Likewise, neuropathic pain, typically a chronic condition attributable to injury or partial transection of a peripheral nerve, is also conventionally treated with opioid compounds such as morphine.
Conventional therapies for pain produce analgesia—a loss of sensitivity to pain without the loss of consciousness. Opioid compounds have been used widely to produce analgesia, including plant-derived opioids such as morphine, and endogenous opioids such as met- and leu-enkephalins, as well as &bgr;-endorphin.
Opioid compounds, while effective in producing analgesia for many types of pain, may induce tolerance in some patients. When a patient becomes tolerant, increasing doses of the opioid are required to produce the desired analgesic effect. In addition, these compounds frequently result in a physical dependence in patients, and may have side effects at high doses.
The treatment of painful conditions with NMDA receptor antagonists acting at various sites on the NMDA receptor/channel complex has been limited due to side effects or inactivity. Reports suggest that NMDA antagonists at the channel site may be useful in preventing the development of tolerance (Marek et al. “Excitatory amino acid antagonists (kynurenic acid and MK-801) attenuate the development of morphine tolerance in the rat”,
Brain Res
., 547, pp. 77-81 (1991); Elliott et al., “Dextromethorphan attenuates and reverses analgesic tolerance to morphine”,
Pain
, 59, pp. 361-368. (1994); Mao et al., “Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase”,
J.Neurosci
., 14, pp. 2301-2312 (1994); Manning et al., “Continuous co-administration of dextromethorphan or MK-801 with morphine: attenuation of morphine dependence and naloxone-reversible attenuation of morphine tolerance”,
Pain
, 67, pp. 79-88 (1996).
The analgesic effects and adverse actions of various NMDA receptor antagonists has been shown to vary depending on the site of action and potency of the drug. For example, NMDA receptor antagonists acting at the ion channel in a noncompetitive manner (e.g., MK-801 and phenylcyclidine (PCP)) or competitive inhibitors, show analgesic activity but show motor impairment at equivalent doses (Nasstrom et al., “Antinociceptive actions of different classes of excitatory amino acid receptor antagonists in mice”,
Eur. J. Pharm
., 212, pp. 21-29(1992); Coderre, “Potent analgesia induced in rats by combined action at PCP and polyamine recognition sites of the NMDA receptor complex”
Eur. J. Neurosci
. 5, pp. 390-393 (1993); Milan and Seguin, “Chemically-diverse ligands at the glycine B site coupled to N-methyl-D-aspartate (NMDA) receptors selectively block the late phase of formalin-induced pain in mice”,
Neurosci. Lett
., 178, pp. 139-143 (1994); Yamamoto and Yaksh, “Spinal pharmacology of thermal hyperesthesia induced by incomplete ligation of sciatic nerve”,
Anesthesiol
., 75, pp. 817-826 (1991); Yamamoto and Yaksh, “Comparison of the antinociceptive effects of pre- and posttreatment with intrathecal morphine and MK801, an NMDA antagonist, on the formalin test in the rat”,
Anesthesiol
., 77, pp. 757-763 (1992). Glycine B-site NMDA antagonists appear to have analgesic activity at doses that do not impair motor function (Milan and Seguin, 1994).
Importantly, polyamine site NMDA antagonists (e.g. ifenprodil) did not have an analgesic effect in the formalin test, even when administered at a high dose (Coderre, 1993, supra). This invention provides a family of polyamine-site NMDA antagonist compounds, the conantokins, that do have analgesic effects, and at doses which do not produce overt side effects.
NMDA ion channels are thought to mediate neurotoxicity in many acute and chronic neurodegenerative diseases by overexcitation and excessive calcium entry into nerve cells. Such neurodegenerative disorders include epilepsy, stroke, Parkinson's disease, Huntington's disease and Alzheimer's disease. Methods of preventing or neuroprotecting against such excitoxicity would be desireable. This invention also provides a family of polyamine-site NMDA antagonist compounds, the conantokins, that exhibit neuroprotective effects against excitotoxic damage mediated at least in part by NMDA receptors.
Conantokins are a family of peptides from the Conus snail that are 10-30 amino acids with antagonist activity at the polyamine site of the NMDA receptor. These peptides do not normally contain disulfide residues like other peptides found in Conus venom. The conantokin peptides typically contain the modified amino acid gamma-carboxyglutamate (Gla).
The methods of this invention may be useful in the treatment of pain (whether acute or chronic), including chronic pain, and neuropathic pain, without undesirable side effects. In addition, continuous administration of a conantokin combined with an opioid agonist, may be useful in preventing the development of tolerance of patients to opioid compounds.
The methods of this invention may also be useful for neuroprotection against excitotoxic damage mediated at least in part by NMDA receptors.
SUMMARY OF THE INVENTION
This invention provides novel methods and devices for treating pain by administering a conantokin molecule, preferably directly into the patient's central nervous system (“CNS”), most preferably intrathecally. If administered directly to the central nervous system, the dosage contemplated is between about 1 ng-100 mg per day, preferably between about 100 ng-10 mg per day, most preferably between 1 &mgr;g and 100 &mgr;g per day. If administered peripherally (preferably intravenously), the dosage contemplated is somewhat higher, between about 100 ng-1000 mg per day, preferably between about 10 &mgr;g-100 &mgr;g per day, most preferably between 100 &mgr;g and 10 mg per day.
This invention also provides novel methods and devices for neuroprotection against excitotoxicity mediated at least in part by NMDA receptors. We contemplate similar dosages of conantokin as outlined above for treatment of pain, if delivered directly to the central nervous sytem. Higher dosages for neuroprotection using a conantokin are contemplated for peripheral delivery, between 100 ng to 10,000 mg per day, preferably intravenously or intra-arterially.
In one embodiment, the conantokin is selected from the group consisting of con antokin-G, conantokin-T, con antokin-R, con antokin-Oc, conantokin-Si, and muteins, analogs or active fragments, of the foregoing conantokins.
REFERENCES:
patent: 5364842 (1994-11-01), Justice
patent: 5432155 (1995-07-01), Olivera
patent: 5523323 (1996-06-01), Maccecchini
patent: 5587454 (1996-12-01), Justice
patent: 5854217 (1998-12-01), MacCeccmini
patent: WO 94/06455 (1994-03-01), None
patent: WO 94/07914 (1994-04-01), None
patent: 96/11698 (1996-04-01), None
patent: WO 98/03189 (1998-01-01), None
patent: WO 98/03541 (1998-01-01), None
Advokat et al.,Brain Research,641, 135-140 (1994).
Anson et al.,Letters to Nature,vol. 315, 683-685 (1985).
Berge t al.,Experimental Cell Research,192, 32-40 (1991).
Carter et al.,The Journal of Pharmacology and Experimental Therapeutics,vol. 253, No. 2, 275-482 (1990).
Chandler et al.,The Journal of Biological Chemistry,vol. 268 No. 23, 17173-17178 (1993).
Coderre,APS Journal,vol. 3, No. 4, 232-239 (1994).
Coderre,European Journal of Neuroscience,vol. 5, 390-393 (1993).
Coderre,Pain,59, 353-359 (1994).
Coderre,European Journal of Neuroscience,vol. 5, 390-393 (1993).
Dickenson et al.,Gen. Pharmac.,vol. 28, No. 5, 633-638 (1997).
Dickson et al.,Trends in Pharmacological Sciences,vol. III, 307-309 (1990).
Elliott et al.,Pain,59,
CytoTherapeutics, Inc.
Elrifi Ivor R.
Low Christopher S. F.
Lukton David
Mintz Levin Cohn Ferris Glovsky & Popeo P.C.
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