Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-12
2002-11-26
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06486177
ABSTRACT:
FIELD OF THE INVENTION
In one aspect, the present invention is directed to methods for treating fatigue, neurobehavioral slowing and other cognitive disorders and defects due to cancers and treatments associated with cancers, and similar conditions. In a further aspect, the present invention is directed to methods for treating disorders related to menopause, including executive function defects. The methods involve the administration of a composition comprising D-threo methylphenidate that is substantially free of L-threo methylphenidate and of erythro forms of methylphenidate.
BACKGROUND OF THE INVENTION
Advanced cancer typically produces severe pain in patients. This pain is often controlled by the administration of large doses of analgesics, including opioid analgesics. However, the pain relief is often accompanied by undesirable side-effects such as unacceptable sedation and/or a decrease in cognitive function. These side effects have a significant negative impact on the quality of life of the patient. In addition, cancer patients often display one or more of a decrease in cognitive function, fatigue, and neurobehavioral slowing that is unrelated to the administration of analgesics, but may be related to the underlying cancer, the treatment of the cancer, or both.
Menopause is accompanied by several side effects, including an executive function defect. For example, many menopausal women report impairment in short term memory, inability to screen distractions and sustain attention in organization of thoughts and tasks. In addition, women diagnosed with ADD prior to menopause report exacerbation of ADD symptoms during the protracted perimenopausal period and thereafter. See Brown, T. E., Attention-Deficit Disorders and Comorbidities in Children, Adolescents and Aduts, American Psychiatric Press, Washington, D.C., 2000, at p. 40-41.
Methylphenidate has been used to treat nervous system disorders including Attention Deficit Disorder (ADD), a commonly diagnosed nervous system illness in children, Attention Deficit Hyperactivity Disorder (ADHD), and cognitive decline in patients with Acquired Immunodeficiency Syndrome (AIDS) or AIDS related conditions. See, e.g., Brown, G.,
Intl. J. Psych. Med.
25(1): 21-37 (1995); Holmes et al.,
J. Clin. Psychiatry
50: 5-8 (1989). The racemic form of methylphenidate also has been proposed to improve cognitive function in patients receiving large doses of medication. See, for example, Bruera et al., Pain (1992) 163-166, Yee et al., Journal of Pain and Symptom Management (1994), Vol. 9, No.2, 122-125, and Meyers et al., Journal of Clinical Oncology (1998) Vol. 16, No. 7, 2522-2527.
Methylphenidate exists as four separate optical isomers as follows:
wherein R
2
is phenyl. Pharmaceutically acceptable salts are generally administered clinically. Other phenidate drugs, which also can be administered according to the invention, include those in which the methyl group in the above structures is replaced by C
2
-C
4
alkyl and those in which R
2
is optionally substituted with C
1
-C
4
alkyl.
Clinically, the threo pair of enantiomers of methylphenidate hydrochloride is generally administered for the treatment of ADD and ADHD. The hydrochloride salt is commonly referred to simply as “methylphenidate”. Unless indicated otherwise, the term “methylphenidate” is used broadly herein to include methylphenidate and pharmaceutically acceptable salts thereof, including methylphenidate hydrochloride.
The threo racemate (pair of enantiomers) of methylphenidate is a mild central nervous system stimulant with pharmacological activity qualitatively similar to that of amphetamines. Undesirable side effects associated with the use of the DL-threo racemate of methylphenidate include anorexia, weight loss, insomnia, dizziness and dysphoria. Furthermore, the racemate, which is a Schedule II controlled substance, produces a euphoric effect when administered intravenously or through inhalation or ingestion, and thus carries a high potential for abuse.
Srinivas et al. studied the administration of DL-threo-, D-threo, and L-threo-methylpehnidate to children suffering from ADHD, and reported that the pharmacodynamic activity of DL-threo-methylphenidate resides in the D-threo isomer (
Clin. Pharmacol. Ther.,
52: 561-568 (1992)). While DL-threo-methylphenidate is generally used therapeutically, this racemate includes the L isomer which apparently makes no significant contribution to the pharmacological effectiveness of the drug. The removal of the L isomer is expensive, however, and there has been no reason to do so.
It has been discovered that the use of the D-threo isomer (2R:2′R) of methylphenidate, substantially free of the 1-threo isomer, produces a methylphenidate medication which retains high activity levels and simultaneously may possess reduced euphoric effect and reduced potential for abuse among patients. See U.S. Pat. No. 5,908,850, incorporated herein by reference in its entirety. Thus, D-threo-methylphenidate (2R:2′R) may possesses enhanced therapeutic activity with reduced side effects, and 1-threo-methylphenidate may produce undesirable side effects, euphoria and drug abuse potential in patients.
There remains a need for improved methods for alleviating the undesirable symptoms and side-effects described above. This invention is directed to these, as well as other, important ends.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides methods for treating fatigue, neurobehavioral slowing and cognitive side effects arising from cancer, or from a treatment therefor, such as chemotherapy, radiation therapy and administration of medication to control pain. In further aspects, the invention provides methods for alleviation of depression caused by cognitive dysfunction (a “cognitive side effect”) and fatigue associated with cancer, and treatments therefor. The methods of the invention involve the administration of D-threo-methylphenidate or a pharmaceutically acceptable salt thereof, substantially free of both L-threo-methylphenidate and erythro methylphenidates.
In some embodiments of the invention, methods are provided for alleviating fatigue and/or neurobehavioral slowing arising from an oncological condition, said method comprising the steps of identifying a patient suffering from said fatigue or neurobehavioral slowing, and administering to said patient a therapeutically effective amount of D-threo-methylphenidate (2R:2′R) or a pharmaceutically acceptable salt thereof, substantially free of the 1-threo isomer.
In further aspects, the present invention provides methods for alleviating fatigue or neurobehavioral slowing arising from the administration of a treatment for an oncological condition, said method comprising the steps of identifying a patient suffering from said fatigue or neurobehavioral slowing, and administering to said patient a therapeutically effective amount of D-threo-methylphenidate (2R:2′R) or a pharmaceutically acceptable salt thereof, substantially free of the 1-threo isomer.
Also provided in accordance with the present invention are methods for alleviating a cognitive side effect of a treatment for an oncological condition, comprising the steps of identifying a patient suffering from a cognitive side-effect of a treatment for an oncological condition; and administering to said patient a therapeutically effective amount of D-threo-methylphenidate (2R:2′R) or a pharmaceutically acceptable salt thereof, substantially free of the 1-threo isomer.
In some embodiments of the methods of the invention, the treatment for the oncological condition is the administration of pain management and biological therapies, including pain relief medication, chemotherapy, radiation therapy, and surgery. In some particularly preferred embodiments, the treatment for the oncological condition is chemotherapy or the administration of pain relief medication. In further embodiments of the foregoing methods, the pain relief medication is one or more opioid analgesics, nerve blocks or other psychotropic agents.
In furthe
Faleck Herbert
Khetani Vikram
Zeldis Jerome B.
Celgene Corporation
Henley III Raymond
Woodcock & Washburn LLP
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