Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-27
2003-07-01
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S449000, C514S461000, C514S473000
Reexamination Certificate
active
06586458
ABSTRACT:
FIELD OF THE INVENTION
The invention is directed to methods of treating patients for headache by administering compositions containing a 5-HT agonist and a long-acting NSAID. Among the preferred long-acting NSAIDs are cyclooxygenase-2 inhibitors (COX-2 inhibitors).
BACKGROUND OF THE INVENTION
5-hydroxytryptamine (5-HT or 5HT), also known as serotonin or enteramine, is a vasoactive agent and an endogenous neurotransmitter. It acts on receptors found in the central and peripheral nervous system as well as on blood vessels. Other drugs acting at these receptor sites are known as 5-HT agonists or antagonists. The 5-HT receptors have been divided into several sub-classes, some of which themselves contain subtypes. Examples of subtypes of serotonin receptors are 5-HT1, 5-HT1-like, 5-HT1
B
, 5-HT1
D
, 5-HT2, 5-HT3, etc.
5-HT1-like agonists and agonists acting at other 5-HT1 sites make up a group of therapeutics that may be used for the treatment of migraine headache. A representative member of this group is sumatriptan succinate (distributed under the name Imitrex™ by Glaxo Wellcome, and described in U.S. Pat. No. 4,816,470). Ergot alkaloids and related compounds are also known to have 5-HT agonist activity and have been used in migraine therapy. Included among these compounds are ergotamine tartrate, ergonovine maleate, and ergoloid mesylates (e.g., dihydroergocornine, dihydroergocristine, dihydroergocryptine, and dihydroergotamine mesylate (DHE 45)). Unfortunately, it has been reported that of the 50 to 70% of patients who experience migraine symptom relief within two hours after receiving a 5-HT agonist, 30-50% experience migraine symptoms again within the next 24 hours. These subsequent headaches are typically termed “rebound,” “relapse,” “recurrent” or “secondary” headaches.
A variety of analgesics have also been administered to migraine patients. For example, K. M. A. Welch (
New Eng. J. Med
. 329:1476-1483 (1993)) sets forth the following dosages of analgesics as being useful: aspirin, 500-650 mg; acetaminophen, 500 mg; naproxen sodium, 750-825 mg; tolfenamic acid, 200-400 mg; and ibuprofen, 200 mg. However, like the 5-HT agonists, these agents, when taken alone, are rarely effective in providing complete relief symptoms and, after initial remission, migraine symptoms often return.
The problems that occur with migraine headaches may also be present in other types of headache as well. In all cases, an ideal therapy would reduce or eliminate the symptoms associated with the initial attack and minimize the frequency of later recurrences.
RELATED ART
The following studies provide background information that should aid in understanding the present invention.
1. Plosker, et al.,
Drugs
47:622-655 (1994).
2. Sheftel, et al.,
Headache
34:67-72 (1994).
3. Wilkinson, et al.,
Cephalalgia
15:337-357 (1995).
4. Silberstein, S D,
Curr. Opin. Neurol
. 7:258-263 (1994).
5. Welch, K. M. A.,
New Eng. J. Med
. 329:1476-1483 (1993).
6. Kumar, K. L.,
J. Gen. Int. Med
. 9:339-348 (1994).
SUMMARY OF THE INVENTION
The present invention is based upon the discovery that co-administration of a 5-HT agonist together with a long-acting, non-steroidal anti-inflammatory drug (LA-NSAID) represents an improved treatment for a wide variety of headaches. Compared to the administration of either drug alone, the combination produces longer lasting efficacy and a substantial reduction in the frequency relapse of headaches. As used herein, the term “longer lasting efficacy” means that drugs produce relief from symptoms associated with a headache for a longer period of time.
In its first aspect, the invention is directed to a method of treating a patient for headache by administering a 5-HT agonist together with a long-acting, non-steroidal anti-inflammatory drug. These two agents should be concomitantly administered, i.e., they should be given in close enough temporal proximity to allow their individual therapeutic effects to overlap. The amount of 5-HT agonist and LA-NSAID administered should be sufficient to reduce the frequency of headache relapse in patients or produce longer lasting efficacy compared to the administration of either one of these agents in the absence of the other. This procedure may be used to treat headaches falling into any of a wide variety of classes including: migraine headache; tension-type headache; cluster headache and chronic paroxysmal hemicrania; miscellaneous headache unassociated with a structural lesion; headache associated with a non-vascular intracranial disorder; headache associated with the administration of a substance or its withdrawal; headache associated with noncephalic infection; headache associated with a metabolic disorder; headache associated with a disorder of the cranium, neck, eyes, ears, nose, sinuses, teeth, mouth or other facial or cranial structure; cranial neuralgias; and nerve trunk pain and deafferentiation pain. (For a description of classes, see Olesen, et al.,
The Headaches
, pp. 9-14, Raven Press; see also, “Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain,” Headache Classification Committee of the International Headache Society,
Cephalalgia
8(supp. 7):1-96 (1988)).
The invention is also directed to a pharmaceutical composition in unit dose form that is useful in treating headache patients and which contains a 5-HT agonist and a long-acting, non-steroidal, anti-inflammatory drug. The two therapeutic agents, i.e., the 5-HT agonist and LA-NSAID, should be present in amounts such that, upon administration of one or more unit doses of the composition, a patient experiences longer lasting efficacy than with the administration of either agent alone. The composition may be included as part of a therapeutic package in which one or more unit doses are placed in a finished pharmaceutical container. Labeling may be included to provide directions for using the composition in the treatment of headache.
The methods and compositions discussed above are compatible with any dosage form or route of administration. Thus, agents may be administered orally, intranasally, rectally, sublingually, buccally, parenterally, or transdermally. Dosage forms may include tablets (including quick dissolve tablets), trochees, capsules, caplets, dragees, lozenges, parenterals, liquids, powders, and formulations designed for implantation or administration to the surface of the skin. Optionally, these dosage forms may be coordinated or designed for the slow release of therapeutic agents. They can be prepared using methods that are standard in the art and may include additional therapeutic agents, e.g., one or more additional analgesics.
Preferred 5-HT agonists for use in methods and compositions include sumatriptan, eletriptan, rizatriptan, frovatriptan, almotriptan, zolmitriptan, and naratriptan. The most preferred 5-HT agonist is sumatriptan which may be administered in a dosage from about 0.01 to about 300 mg. When administered non-parenterally, the typical dosage of sumatriptan is from about 25 to about 100 mg with about 50 mg being generally preferred and, when administered parenterally, the preferred dosage is about 6 mg. However, these dosages may be varied according to methods standard in the art so that they are optimized for a particular patient or for a particular combination of sumatriptan and long-acting NSAID. For example, effective dosage forms containing naproxen may have more than 100 mg of sumatriptan.
Among the preferred long-acting NSAIDs for use in compositions and methods are: naproxen, flurbiprofen, ketoprofen, oxaprozin, etodolac, indomethacin, ketorolac, nabumetone, mefanamic acid, and piroxican. Of these, the most preferred is naproxen or a pharmaceutically acceptable salt of naproxen. This should be administered to patients and present in a unit dosage of a composition in an amount of greater than 200 mg and preferably between 200 mg and 600 mg. One particularly preferred composition contains sumatriptan in an amount of greater than 25 mg and naproxen in an amount of greater than 200 mg. Although not ess
Delacroix-Muirheid C.
Fitch Even Tabin & Flannery
Jones Dwayne C.
Pozen Inc.
Sanzo Michael A.
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