U.S. patent application number 11/402385 was filed with the patent office on 2006-08-17 for methods for treatment of cognitive and menopausal disorders with d-threo methylphenidate.
This patent application is currently assigned to Celgene Corporation. Invention is credited to Maghsoud M. Dariani, Herbert J. Faleck, Vikram Khetani, David I. Sterling, Andrew L. Zeitlin, Jerome B. Zeldis.
Application Number | 20060183774 11/402385 |
Document ID | / |
Family ID | 25418099 |
Filed Date | 2006-08-17 |
United States Patent
Application |
20060183774 |
Kind Code |
A1 |
Zeldis; Jerome B. ; et
al. |
August 17, 2006 |
Methods for treatment of cognitive and menopausal disorders with
D-threo methylphenidate
Abstract
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.
Inventors: |
Zeldis; Jerome B.;
(Princeton, NJ) ; Zeitlin; Andrew L.; (Basking
Ridge, NJ) ; Faleck; Herbert J.; (West Orange,
NJ) ; Khetani; Vikram; (Short Hills, NJ) ;
Dariani; Maghsoud M.; (Fanwood, NJ) ; Sterling; David
I.; (Branchburg, NJ) |
Correspondence
Address: |
WOODCOCK WASHBURN LLP
ONE LIBERTY PLACE, 46TH FLOOR
1650 MARKET STREET
PHILADELPHIA
PA
19103
US
|
Assignee: |
Celgene Corporation
|
Family ID: |
25418099 |
Appl. No.: |
11/402385 |
Filed: |
April 11, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10195974 |
Jul 16, 2002 |
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11402385 |
Apr 11, 2006 |
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09903803 |
Jul 12, 2001 |
6486177 |
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10195974 |
Jul 16, 2002 |
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09318151 |
May 25, 1999 |
6355656 |
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09903803 |
Jul 12, 2001 |
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08827230 |
Apr 2, 1997 |
5908850 |
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09318151 |
May 25, 1999 |
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08567131 |
Dec 4, 1995 |
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08827230 |
Apr 2, 1997 |
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Current U.S.
Class: |
514/317 |
Current CPC
Class: |
A61P 25/22 20180101;
C12P 41/006 20130101; A61K 45/06 20130101; A61P 25/26 20180101;
A61P 3/00 20180101; C07D 211/34 20130101; A61P 15/00 20180101; C12P
17/12 20130101; A61K 31/4458 20130101; A61K 2300/00 20130101; A61P
35/00 20180101; A61P 35/04 20180101; A61P 25/00 20180101; A61P
25/28 20180101; A61K 31/4458 20130101; A61P 15/12 20180101; A61P
25/24 20180101; A61P 25/20 20180101; A61P 25/04 20180101; A61P 9/00
20180101 |
Class at
Publication: |
514/317 |
International
Class: |
A61K 31/445 20060101
A61K031/445 |
Claims
1. A method for alleviating fatigue arising from an oncological
condition, said method comprising the steps of: identifying a
patient suffering from said fatigue, and administering to said
patient a therapeutically effective amount of
D-threo-methylphenidate substantially free of the 1-threo
isomer.
2. The method of claim 1 wherein said methylphenidate is in the
form of a pharmaceutically acceptable salt.
3. The method of claim 1 wherein said oncological condition is a
cancer selected from the group consisting of solid tumors and
nonsolid tumors.
4. The method of claim 1 wherein said oncological condition is a
solid tumor.
5. A method for alleviating fatigue arising from the administration
of a treatment for an oncological condition, said method comprising
the steps of: identifying a patient suffering from said fatigue,
and administering to said patient a therapeutically effective
amount of D-threo-methylphenidate substantially free of the 1-threo
isomer.
6. The method of claim 5 wherein said methylphenidate is in the
form of a pharmaceutically acceptable salt.
7. The method of claim 5 wherein said treatment for said
oncological condition is chemotherapy or radiation therapy.
8. The method of claim 5 wherein said treatment for said
oncological condition is chemotherapy.
9. The method of claim 5 wherein said oncological condition is a
cancer selected from the group consisting of solid tumors and
nonsolid tumors.
10. The method of claim 5 wherein said oncological condition is a
solid tumor.
11. A method for alleviating neurobehavioral slowing arising from
an oncological condition, said method comprising the steps of:
identifying a patient suffering from said neurobehavioral slowing,
and administering to said patient a therapeutically effective
amount of D-threo-methylphenidate substantially free of the 1-threo
isomer.
12. The method of claim 11 wherein said methylphenidate is in the
form of a pharmaceutically acceptable salt.
13. The method of claim 11 wherein said oncological condition is a
cancer selected from the group consisting of solid tumors and
nonsolid tumors.
14. The method of claim 11 wherein said oncological condition is a
solid tumor.
15. A method for alleviating 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 neurobehavioral slowing, and administering to
said patient a therapeutically effective amount of
D-threo-methylphenidate substantially free of the 1-threo
isomer.
16. The method of claim 15 wherein said methylphenidate is in the
form of a pharmaceutically acceptable salt.
17. The method of claim 15 wherein said treatment for said
oncological condition is chemotherapy or radiation therapy.
18. The method of claim 15 wherein said treatment for said
oncological condition is chemotherapy.
19. The method of claim 15 wherein said oncological condition is a
cancer selected from the group consisting of solid tumors and
nonsolid tumors.
20. The method of claim 5 wherein said oncological condition is a
solid tumor.
21. A method 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
substantially free of the 1-threo isomer.
22. The method of claim 21 wherein said methylphenidate is in the
form of a pharmaceutically acceptable salt.
23. The method of claim 21 wherein said oncological condition is a
cancer selected from the group consisting of solid tumors and
nonsolid tumors.
24. The method of claim 21 wherein said oncological condition is a
solid tumor.
25. The method of claim 21 wherein said treatment for said
oncological condition is the administration of pain relief
medication, chemotherapy, radiation therapy, or surgery.
26. The method of claim 21 wherein said treatment for said
oncological condition is the administration of pain relief
medication.
27. The method of claim 26 wherein said pain relief medication is
and opioid analgesic.
28. The method of claim 21 wherein said cognitive side effect is
sedation, decreased cognitive function, major depressive disorder,
or neurobehavioral slowing.
29. The method of claim 28 wherein said cognitive side effect is
sedation, decreased cognitive function or neurobehavioral
slowing.
30. The method of claim 28 wherein said cognitive side effect is
sedation.
31. A method for treating a symptom of menopause comprising the
steps of: identifying a patient suffering from a symptom of
menpoause; and administering to said patient a therapeutically
effective amount of D-threo-methylphenidate substantially free of
the 1-threo isomer.
32. The method of claim 31 wherein said methylphenidate is in the
form of a pharmaceutically acceptable salt.
33. The method of claim 31 wherein said symptom of menopause is
decreased cognitive function.
34. The method of claim 31 wherein said symptom of menopause is
vasomotor instability.
35. The method of claim 31 wherein said symptom of menopause is
nervousness.
36. The method of claim 31 wherein said symptom of menopause is
mental depression.
37. The method of claim 31 wherein said symptom of menopause is
excitability.
38. The method of claim 31 wherein said symptom of menopause is
fatigue.
39. The method of claim 31 wherein said symptom of menopause is
apathy.
40. The method of claim 31 wherein said symptom of menopause is
impairment of short term memory.
41. The method of claim 1 wherein said administration of said
D-threo-methylphenidate gives rise to efficacious treatment without
interfering with patient sleep patterns or engendering anoretic
behavior.
42. The method of claim 5 wherein said administration of said
D-threo-methylphenidate gives rise to efficacious treatment without
interfering with patient sleep patterns or engendering anoretic
behavior.
43. The method of claim 11 wherein said administration of said
D-threo-methylphenidate gives rise to efficacious treatment without
interfering with patient sleep patterns or engendering anoretic
behavior.
44. The method of claim 15 wherein said administration of said
D-threo-methylphenidate gives rise to efficacious treatment without
interfering with patient sleep patterns or engendering anoretic
behavior.
45. The method of claim 21 wherein said administration of said
D-threo-methylphenidate gives rise to efficacious treatment without
interfering with patient sleep patterns or engendering anoretic
behavior.
46. The method of claim 31 wherein said administration of said
D-threo-methylphenidate gives rise to efficacious treatment without
interfering with patient sleep patterns or engendering anoretic
behavior.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation in part of U.S. Ser. No.
09/318,151, filed May 25, 1999, which is a continuation in part of
U.S. Ser No. 08/583,317 filed Jan. 5, 1996, now U.S. Pat. No.
5,773,756, and a continuation in part of U.S. Ser. No. 08/827,230,
filed Apr. 2, 1997, now U.S. Pat. No. 5,908,850, which is
continuation of U.S. Ser. No. 08/567,131, filed Dec. 4, 1995. The
contents of each of the foregoing applications are incorporated
herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] 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
[0003] 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.
[0004] 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.
[0005] 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.
[0006] Methylphenidate exists as four separate optical isomers as
follows: ##STR1## wherein R.sub.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.sub.2-C.sub.4 alkyl and those in which
R.sub.2 is optionally substituted with C.sub.1-C.sub.4 alkyl.
[0007] 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.
[0008] 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.
[0009] Srinivas et al. studied the administration of DL-threo,
D-threo, and L-threo-methylphenidate 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.
[0010] 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.
[0011] 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
[0012] 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.
[0013] 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 threo-methylphenidate (2R:2'R)
or a pharmaceutically acceptable salt thereof, substantially free
of the 1-threo isomer.
[0014] 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.
[0015] 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.
[0016] 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.
[0017] In further embodiments of the foregoing methods, the
oncological condition is a cancer selected from the group
consisting of all malginant conditions, inclduing both solid tumors
and nonsolid tumors. In some preferred embodiments, the oncological
condition is a solid tumor.
[0018] In some embodiments of the foregoing methods, the cognitive
side effect is sedation, decreased cognitive function, major
depressive disorder, or neurobehavioral slowing. In some preferred
embodiments, the cognitive side effect is sedation or decreased
cognitive function.
[0019] In further aspects, the present invention provides methods
for treating a symptom of menopause comprising the steps of
identifying a patient suffering from a symptom of menpoause; 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.
[0020] In some embodiments of the foregoing methods, the symptom of
menopause is impairment in short term memory, decreased cognitive
function, mental depression, vasomotor instability, nervousness,
excitability, fatigue, neurobehavioral slowing, and/or apathy.
[0021] In some preferred embodiments of the foregoing methods, the
administration of the D-threo-methylphenidate (2R:2'R), or the
pharmaceutically acceptable salt thereof, gives rise to efficacious
treatment without interfering with patient sleep patterns or
engendering anoretic behavior.
DETAILED DESCRIPTION
[0022] 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. It is now believed that the L isomer may
contribute to the side effects associated with the commercial drug,
and that it is thus desirable to administer only the active D-threo
form of the drug.
[0023] Thus, in some embodiments of the invention, methods are
provided for alleviating fatigue 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.
[0024] 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.
[0025] Also provided in accordance with the present invention are
methods for alleviating a cognitive side effect (e.g.,
neurobehavioral slowing) 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.
[0026] 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.
[0027] In further embodiments of the foregoing methods, the
oncological condition is a cancer selected from the group
consisting of all malginant conditions, inclduing both solid tumors
and nonsolid tumors. In some preferred embodiments, the oncological
condition is a solid tumor.
[0028] In some embodiments of the foregoing methods, the cognitive
side effect is sedation, decreased cognitive function, major
depressive disorder, or neurobehavioral slowing. In some preferred
embodiments, the cognitive side effect is sedation or decreased
cognitive function.
[0029] In further aspects, the present invention provides methods
for treating a symptom of menopause comprising the steps of
identifying a patient suffering from a symptom of menopause; 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.
[0030] In some embodiments of the foregoing methods, the symptom of
menopause is impairment in short term memory, decreased cognitive
function, mental depression, vasomotor instability, nervousness,
excitability, fatigue, neurobehavioral slowing and/or apathy.
[0031] In some preferred embodiments of the foregoing methods, the
administration of the D-threo-methylphenidate (2R:2'R), or the
pharmaceutically acceptable salt thereof, gives rise to efficacious
treatment without interfering with patient sleep patterns or
engendering anoretic behavior.
[0032] The administration of the pharmacodynamically active D-threo
form of methylphenidate may provide efficacious treatment for an
entire day with minimal undesirable side effects such as
interference with patient sleep patterns or anoretic behavior. It
has been surprisingly and unexpectedly discovered that the
beneficial effects of the D-threo isomer persist for a longer
period time when the D-threo isomer is administered alone than when
it is administered in combination with the L-threo isomer.
[0033] While it is not intended that the present invention be bound
by any particular theory, it is believed that the L isomer
functions as an antagonist to the D isomer. Thus, another aspect of
the present invention provides methods for ameliorating or
counteracting the effects of methylphenidate drugs, comprising
administering L-threo methylphenidate to a patient who has a serum
level of D-threo methylphenidate.
[0034] The present inventors have observed that in the context of
ADD, D-threo methylphenidate has a longer duration of action than
DL-methylphenidate of at least six hours. Patients who were given
the D-threo isomer free of the L isomer performed better in
objective tests than patients who received the DL-threo racemate or
a placebo, at the 6 hour time point. In contrast, the patients who
received DL-threo racemate did not perform better after that time
period than those who received a placebo. Furthermore, subjective
observations of the same patients indicated that those who received
only the D-threo isomer experienced beneficial effects of the drug
for longer times than did those who received the DL-threo
racemate.
[0035] It is expected that D-threo methylphenidate will be
particularly useful in treating patients affected by fatigue,
neurobehavioral slowing, and other cognitive defects (`cognitive
side effects") that are due to cancer, and that are exacerbated by
the administration of treatments for cancer such as chemotherapy,
radiation therapy, bone marrow transplants, stem cell transplants
and administration of medication to control pain. Examples of such
cognitive defects include but are not limited to neurobehavioral
slowing, sedation, diminished executive function, decreased
cognitive function, major depressive disorder and impaired quality
of life.
[0036] As used herein, the term "oncological condition" is intended
to mean all malignant conditions, including all cancers, for
example solid tumors and nonsolid tumors. Examples of "oncological
conditions" include cancers of the skin, mouth, brain and other
nervous tissue, bone, lung, colon and rectum, pancreas, prostate,
urinary tract, leukemias and lymphomas.
[0037] As used herein, the term "arising from the administration of
a treatment for an oncological condition" is intended to mean that
the indicated symptom or condition is in whole or in part caused by
(i.e., is a side-effect of) the administration of a therapeutic
agent used for the treatment of cancer, or for the management of a
symptom of the cancer. Examples of agents used for the treatment of
cancer include chemotherapeutic agents, including both chemical and
radiotherapeutics, and radiation. Examples of agents used for the
management of a symptom of the cancer include pain relief
medications such as opioid or opoid-like analgesics and
non-steroidal anti-inflammatory agents.
[0038] As used herein, the term "alleviating a cognitive side
effect of a treatment for an oncological condition" means the
lessening of the severity of a cognitive side effect caused in
whole or in part by the administration of a treatment for an
oncological condition. The term "cognitive side effect" as used
herein denotes an impairment of one or more cognitive functions
that results in whole or in part from the administration of an
agent used for the treatment of cancer. Examples of cognitive side
effects include sedation, neurobehavioral slowing, decreased
cognitive function, depression, apathy, decreased libido and
derpersonalization. The term "decreased cognitive function" is
intended to mean a decrease in any or all aspects of thought,
attention, perception, and/or memory.
[0039] As used herein, the term "menopause" is given its normal
meaning of the period during which marks the permanent cessation of
menstrual activity. The term "symptom of menopause" in intended to
include those symptoms associated with menopause, including
vasomotor instability, nervousness, excitability, fatigue,
neurobehavioral slowing, apathy, mental depression and impairment
of short term memory. As used herein, the term "executive function
defect" is intended to include but is not limited to one or more
defects in the cognitive mechanisms responsible for focusing
attention, goal-related behavior, strategic planning and problem
solving.
[0040] The methods of the invention will find use with patients,
including outpatients, with all types of cancer, either primary or
metastatic.
[0041] According to one method of the present invention, dosage
forms are administered of D-threo methylphenidate substantially
free of L-threo methylphenidate and of erythro methylphenidates.
"Substantially free", as used herein, means that the dosage forms
comprise at least about 95 percent, preferably at least about 97
percent, and more preferably at least about 99 percent of the
D-threo isomer, to the exclusion of the L-threo and erythro forms.
The D-threo form can be isolated by methods known to those skilled
in the art.
[0042] In accordance with the present invention, the D-threo
methylphenidate can be administered in any of a variety of dosage
regimes. Such regimes include chronic single, bolus dosages, i.e.,
where one dose being administered in a predetermined time period,
for example twenty four hours. Further dosage regimes include those
where multiple dosages are manually administered, and dosage forms
where a single dosage form is administered that effectively mimics
multiple dosages, such as pulsatile release dosage forms. Further
dosage forms useful with the present invention include delay
release and extended release (i.e., "time release") dosage forms.
The selection of appropriate dosage forms for an individual patient
will depend upon the individual circumstances, and will be apparent
to those of skill in the art.
[0043] "Chronic", as used herein, refers to continuous, regular,
long-term therapeutic administration, i.e. periodic administration
without substantial interruption, such as, for example, daily, for
a time period of at least several weeks or months to several years,
for the purpose of treating a patient needing treatment.
[0044] "Bolus", as used herein, refers to administration of a drug
as a single event. The term "bolus" is intended to exclude dosage
forms such as sustained release, pulsed release, and time release,
and includes any dosage form which can be used to deliver a single
dose. According to the present invention, a bolus is preferably
administered to a patient in need of treatment once daily, more
preferably in the morning. The bolus dosages of the present
invention may be administered in any conventional form known to
those skilled in the art. Suitable methods for administration
include oral dosage forms, injection, and infusion.
[0045] For pharmaceutical use, the D-threo methylphenidate
substantially free of L-threo methylphenidate and of erythro
methylphenidates as described herein can be taken up in
pharmaceutically acceptable carriers, such as, for example,
solutions, suspensions, tablets, capsules, ointments, elixirs and
injectable compositions. Pharmaceutical preparations generally can
contain from about 1% to about 90% by weight of active ingredient.
Preparations which are in single dose form, "unit dosage form",
preferably contain from about 20% to about 90% active ingredient.
As used herein, the term "active ingredient" refers to D-threo
methylphenidate substantially free of L-threo methylphenidate and
of erythro methylphenidates as described herein, salts thereof, and
mixtures of D-threo methylphenidate as described herein with other
pharmaceutically active compounds. Dosage unit forms such as, for
example, tablets or capsules, typically contain from about 0.001 to
about 1.0 g of active ingredient. Pharmaceutical preparations may
be administered orally, parenterally, or topically. Pharmaceutical
preparations containing compounds described herein may be prepared
by methods known to those skilled in the art, such as, for example,
conventional mixing, granulating, dissolving, or lyophilizing. Oral
dosage forms include capsules, pills, tablets, troches, lozenges,
melts, powders, solutions, suspensions and emulsions. The oral
dosage forms provided by the invention can be in the form of
tablets, caplets, and the like and can be of any shape suitable for
oral administration of a drug, such as spheroidal, cube-shaped,
oval, bean shaped, or ellipsoidal. For oral dosage forms, for
example, the compounds may be combined with one or more solid
pharmaceutically acceptable carriers, optionally granulating the
resulting mixture. Pharmaceutically acceptable adjuvants may
optionally be included, such as, for example, flow-regulating
agents and lubricants. Suitable carriers include, for example,
fillers such as sugars, cellulose preparations, calcium phosphates;
and binders such as methylcellulose, hydroxymethylcellulose, and
starches, such as, for example, maize starch, potato starch, rice
starch, and wheat starch. The dosage form may be in the form of
granules, which may be irregularly shaped. The dosage form can
comprise a capsule containing particles. Examples of orally
administrable pharmaceutical preparations are dry-filled capsules
consisting of gelatin, and soft sealed capsules consisting of
gelatin and a plasticizer such as glycerol or sorbitol. The
dry-filled capsules may contain the active ingredient in the form
of a granulate, for example in admixture with fillers, binders,
glidants, and stabilizers. In soft capsules, the active ingredient
is preferably dissolved or suspended in a suitable liquid adjuvant,
such as, for example, a fatty oil, paraffin oil, or liquid
polyethylene glycol, optionally in the presence of stabilizers.
Other oral administrable forms include syrups containing active
ingredient, for example, in suspended form at a concentration of
from about 0.01% to 20%, or in a similar concentration that
provides a suitable single dose when administered, for example, in
measures of from about 2 to about 5 milliliters. Suitable
excipients for use in oral liquid dosage forms include diluents
such as water and alcohols, for example ethanol, benzyl alcohol and
polyethylene alcohols, either with or without the addition of a
pharmaceutically acceptable surfactant, suspending agent, or
emulsifying agent. Also suitable are powdered or liquid
concentrates for combining with liquids such as milk. Such
concentrates may also be packed in single dose quantities.
[0046] In accordance with the present invention, D-threo
methylphenidate as described herein may be administered
parenterally, that is, subcutaneously, intravenously,
intramuscularly, or interperitoneally, as injectable dosages of the
compound in a physiologically acceptable diluent with a
pharmaceutical carrier. Solutions for parenteral administration may
be in the form of infusion solutions. A pharmaceutical carrier may
be, for example, a sterile liquid or mixture of liquids such as
water, saline, aqueous dextrose and related sugar solutions, an
alcohol such as ethanol, glycols such as propylene glycol or
polyethylene glycol, glycerol ketals such as
2,2-dimethyl-1,3-dioxolane-4-methanol, ethers such as
poly(ethyleneglycol) 400, oils, fatty acids, fatty acid esters or
glycerides, with or without the addition of a pharmaceutically
acceptable surfactant such as a soap or detergent, suspending agent
such as pectin, carbomers, methylcellulose,
hydroxypropylmethylcellulose, or carboxymethylcellulose, or
emulsifying agent or other pharmaceutically acceptable adjuvants.
Examples of oils which may be used in parenteral formulations
include petroleum, animal, vegetable, or synthetic oils such as,
for example, peanut oil, soybean oil, sesame oil, cottonseed oil,
corn oil, olive oil, petrolatum, and mineral oil. Suitable fatty
acids include, for example, oleic acid, stearic acid, and
isostearic acid. Suitable fatty acid esters include ethyl oleate
and isopropyl myristate. Suitable soaps include alkaline metal,
ammonium and triethanolamine salts of fatty acids. Suitable
detergents include cationic detergents such as dimethyl dialkyl
ammonium halides and alkyl pyridinium halides; anionic detergents
such as alkyl, aryl and olefin sulfonates, monoglyceride sulfates
and sulfosuccinates; nonionic detergents such as fatty amine
oxides, fatty acid alkanolamides and polyoxyethylenepropylene
copolymers; and amphoteric detergents such as
alkyl-(-aminopropionates and 2-alkylimidazoline quaternary ammonium
salts; as well as mixtures of detergents. Parenteral preparations
will typically contain at least about 0.01% by weight of active
ingredient in solution. Preservatives and buffers may also be used
advantageously. Injection suspensions may include
viscosity-increasing substances such as, for example, sodium
carboxymethylcellulose, sorbitol or dextran, and may also include
stabilizes. In order to minimize irritation at the site of
injection, injectable compositions may contain a non-ionic
surfactant having a hydrophile-lipophile balance (HLB) of from
about 12 to about 17. The quantity of surfactant in such
formulations ranges from about 5% to about 15% by weight. The
surfactant may be a single component having the above HLB or a
mixture of two or more components having the desired HLB.
Particular examples of useful surfactants include polyethylene
sorbitan fatty acid esters, such as, for example, sorbitan
monooleate.
[0047] In addition to parenteral administration, D-threo
methylphenidate as described herein can be formulated for nasal
administration, particularly in the form of powders, nasal drops,
or aerosols. The compounds of the invention also can be
administered dermally, via, for example, trans-dermal patches.
[0048] The preferred quantity of D-threo methylphenidate to be used
in a dosage for treating a particular patient can be readily
determined by one skilled in the art. Factors determining the
appropriate dosage include the weight and age of the patient, the
type and extent of the disorder being treated, and other conditions
of the patient including other disorders and other medications, if
any, that the patient is taking. Generally, the dosage of D-threo
methylphenidate will be from about 0.01 mg/kg of patient body
weight to about 1 mg/kg of patient body weight. Appropriate
quantities can be determined by one skilled in the art. For
example, a relatively small child will generally require a dose of
from about 0.03 to about 0.3 mg/kg, while a larger child or an
adult may require a dose of from about 0.1 mg/kg to about 0.4 or
0.5 mg/kg.
[0049] A physician treating a patient with cancer will generally
titrate the dose of methylphenidate until the desired therapeutic
effects is achieved. For example, a patient with cancer receiving
an opioid analgesic for pain management will initially be
administered a minimum dose of 2.5 mg of d-MPH b.i.d. at the time
of the opioid analgesic, with dose increasing a clinically
warranted.
[0050] Response by patients with cognitive deficiencies described
herein is generally determined by two types of measurements:
objective measures of a patient's ability to concentrate and remain
focused on a task such as performing a math test; and subjective
scores of a patient's performance.
[0051] The following examples are merely illustrative of the
present invention and should not be considered limiting of the
scope of the invention in any way. These examples and equivalents
thereof will become more apparent to those skilled in the art in
light of the present disclosure and the accompanying claims.
EXAMPLES
Determination of Symptoms
[0052] Patients can be evaluated for cognitive impairment by any of
the tests known in the art. For example, High Sensitivity Cognitive
Screen (HSCS) can test six cognitive domains: memory, language,
visual-motor, spatial, attention/concentration, and self-regulation
and planning (see, for example, Faust D. and Fogel B. S.: The
development and initial validation of a sensitive bedside cognitive
screening test. J. Nerv. Ment. Dis.; 177:25-31, 1989).
[0053] Global cognitive function can be evaluated by the
Mini-Mental State Exam (MMSE; see, for example, Folstein M. F.,
Folstin S. E., McHugh P. R.: "Minimental State": a practical method
for grading the cognitive state of patients for the clinician. J.
Psychiatry Res. 12:189-198, 1975) Attention and concentration can
be evaluated via the Trial Making Test-Part A (See, for example,
Reitan, R. M.: Validity of the Trail Making Test as an indicator of
organic brain damage. Perceptual Motor Skills 8:271-276, 1958), and
the Digit Span, Forward and Backward test (see, for example,
Wechsler D. Wechsler Adult Intelligence Scale-Revised Manual. New
York; Psychological Corporation, 1981)).
[0054] Visuospatial skills can be evaluated by, for example, the
Revised-Rey Osterrieth Complex Figure test, (see, for example,
Osterrieth R. A. Le test de copie d'une fugure complexe. Archives
de Psychologie, 1944, 30, 206-356). Impairment to language
functions can be evaluated by, for example, the Verbal Fluency
(F-A-S) test (see, for example Kaplan, E. F., Goodglass, H.,
Weintraub, S. The Boston Naming Test. Boston: E. Kaplan & H.
Goodglass, 1978).
[0055] Learning impairment can be evaluated by, for example, the
California Verbal Learning Test (see, for example, Delis, D. C.,
Kramer, J. H., Kaplan, E., Ober, B. A. California Verbal Learning
Test-Research Edition. The Psychological Corp., New York,
1987).
[0056] Memory impairment can be evaluated by, for example, the
Revised-Rey Osterrieth Complex Figure, Immediate Recall test and/or
the Revised-Rey Osterrieth Complex Figure, Delayed Recall test,
(see, for example, Osterrieth R A, above); the California Verbal
Learning Test, Immediate Recall, and/or the California Verbal
Learning Test, Delayed Recall, the California Verbal Learning Test,
Recognition (See, for example, Delis et al., above).
[0057] Executive function impairment can be evaluated by, for
example, the Trail Making Test-Part B (See, for example, Reitan et
al., above).
[0058] Quality of Life can be evaluated by the FACIT-F tests
(Fatigue Scale), the FACT-F test (Functional Assessment of Cancer
Therapy--Fatigue Scale), the FACT-G test (Functional Assessment of
Cancer Therapy--General Scale), and the FACT-BR test (Functional
Assessment of Cancer Therapy--Brain Subscale), (see, for example
Cella, D. F., Tulsky, D. S., Gray, G., Sarafian, B., Linn E.
Bonomi, A., et al.: The functional assessment of cancer therapy
scale: development and validation of the general measure. J. Clin.
Oncol. 11:570-579, 1993; Weitzner, M. A., Meyers, C. A., Gelke, C.
K., Byrne, K. S., Cella, D. F., Lein, V. A.: The Functional
Assessment of Cancer Therapy (FACT) scale: Development of a brain
subscale and revalidation of the general version (FACT-G) in
patients with primary brain tumors. Cancer 75:1151-1161, 1995; and
Yellin, S. B., Cella, D. F., Webster, K., Blendowsky, C., Kaplan,
E.,: Measuring fatigue and other anemia-related symptoms with the
Functional Assessment of Cancer Therapy (FACT) Measurement System,
J. Pain Symptom Manage. 13:63-74, 1997). Each of the foregoing
publications are incorporated herein by reference in their
entirety.
[0059] Depression can be evaluated by, for example, the Center for
Epidemiologic Studies Depression (CES-D) Scale (see, for example,
Radloff, L. S.: The CES-D scale: A self-report depression scale for
research in the general population. Applied Psychological
Measurement 1:385-401, 1977), or by Beck Depression Inventory (BDI)
(see, for example, Beck, A. T. and Beamesderfer, A: Assessment of
depression: the Depression Inventory. Mod. Probl.
Pharmacopsychiatry; 7:155-169, 1974).
Example 1
Administration of D-threo-methylpbenidate hydrochloride (d-MPH) in
the Treatment of Cognitive Dysfunction Related to Chemotherapy in
Adult Cancer Patients
[0060] Patients that have received at least one cycle of cytotoxic
chemotherapy, preferably within 2 months prior to treatment, and
who display one or more symptoms of cognitive dysfunction are
evaluated as candidates for d-MPH treatment. Prior to commencement
of treatment, patients are evaluated for the following: medical
history/concomitant illnesses, physical examination, 12-lead
electrocardiogram, routine laboratory tests and assessments of
cognitive function. Tests for cognitive function can include those
know to those of skill in the art, for example those described
above. Patients having no medical contraindication to the use of
methylphenidate are then initially administered d-MPH 5 mg/day (2.5
mg b.i.d given 4 to 6 hours apart). The dose may be increased as
clinically warranted if there are no adverse effects that preclude
dose-escalation and there is no significant therapeutic response.
Daily doses can be administered two or three times per day. The
maximum dose will be 50 mg/day, given two to three times per
day.
[0061] Patients are evaluated periodically for one or more of
fatigue, neurobehavioral slowing, sedation, decreased cognitive
function, and major depressive disorder. Patients receiving the
foregoing treatment will display an alleviation of one or more of
the foregoing symptoms.
Example 2
Administration of D-threo-methylphenidate hydrochloride (d-MPH) in
the Treatment of Menopausal Women
[0062] Menopausal women who display one or more symptoms including
an executive function defect, decreased cognitive function, mental
depression, vasomotor instability, nervousness, excitability,
fatigue, neurobehavioral slowing, apathy, or impairment of short
term memory are evaluated as candidates for d-MPH treatment. Prior
to commencement of treatment, patients are evaluated for the
following: medical history/concomitant illnesses, physical
examination, 12-lead electrocardiogram, routine laboratory tests
and assessments of the severity of the symptom.
[0063] Patients having no medical contraindication to the use of
methylphenidate are then initially administered d-MPH 5 mg/day (2.5
mg b.i.d given 4 to 6 hours apart). The dose may be increased as
clinically warranted if there are no adverse effects that preclude
dose-escalation and there is no significant therapeutic response.
Daily doses can be administered two or three times per day. The
maximum dose will be 50 mg/day, given two to three times per day.
Once a patient's optimal dose has been determined, the patient will
remain on this dose for at least 2 weeks.
[0064] Patients are evaluated for one or more of executive function
defect, decreased cognitive function, mental depression, vasomotor
instability, nervousness, excitability, fatigue, neurobehavioral
slowing, apathy, or impairment of short term memory. Patients
receiving the foregoing treatment will display an alleviation of
one or more of the foregoing symptoms.
Example 3
Administration of D-threo-methylphenidate hydrochloride (d-MPH) in
the Treatment of Menopausal Women having previously diagnosed
Attention Deficit Disorder (ADD)
[0065] Menopausal women who have been previously been diagnosed
with Attention Deficit Disorder ("ADD") and who are suspected
having exacerbated ADD symptoms are evaluated for one or more
symptoms of ADD according to previously published methods (for
example, see American Psychiatric Association. Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).
Washington, D.C., 1994, pp 78-85).
[0066] Patients having no medical contraindication to the use of
methylphenidate are then initially administered d-MPH 5, mg/day
(2.5 mg b.i.d given 4 to 6 hours apart). The dose may be increased
as clinically warranted if there are no adverse effects that
preclude dose-escalation and there is no significant therapeutic
response. Daily doses can be administered two or three times per
day. The maximum dose will generally be approximately 50 mg/day,
given two to three times per day.
[0067] Patients are periodically evaluated for efficacy of
treatment. Patients receiving the foregoing treatment will display
an alleviation of one or more of the foregoing symptoms.
[0068] It is intended that each of the patents, applications, and
printed publications mentioned or referred to in this specification
be hereby incorporated by reference in their entirety.
[0069] As those skilled in the art will appreciate, numerous
changes and modifications may be made to the preferred embodiments
of the invention without departing from the spirit of the
invention. It is intended that all such variations fall within the
scope of the invention.
* * * * *