U.S. patent application number 14/510386 was filed with the patent office on 2015-04-30 for compositions and methods for preventing and/or treating disorders associated with cephalic pain.
The applicant listed for this patent is Richard Andrew Sewell. Invention is credited to Richard Andrew Sewell.
Application Number | 20150118327 14/510386 |
Document ID | / |
Family ID | 41201641 |
Filed Date | 2015-04-30 |
United States Patent
Application |
20150118327 |
Kind Code |
A1 |
Sewell; Richard Andrew |
April 30, 2015 |
COMPOSITIONS AND METHODS FOR PREVENTING AND/OR TREATING DISORDERS
ASSOCIATED WITH CEPHALIC PAIN
Abstract
Compounds, e.g., of formula (I) and (Ia), pharmaceutical
compositions comprising the compounds and methods of using the
compounds and pharmaceutical compositions for treating pain
disorders, e.g., disorders associated with cephalic pain, are
provided.
Inventors: |
Sewell; Richard Andrew; (New
Haven, CT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sewell; Richard Andrew |
New Haven |
CT |
US |
|
|
Family ID: |
41201641 |
Appl. No.: |
14/510386 |
Filed: |
October 9, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12408438 |
Mar 20, 2009 |
8859579 |
|
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14510386 |
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61038537 |
Mar 21, 2008 |
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Current U.S.
Class: |
424/722 ;
206/534; 514/288; 546/69 |
Current CPC
Class: |
C07D 457/06 20130101;
A61J 1/14 20130101; A61K 33/00 20130101; A61K 31/48 20130101; A61P
25/00 20180101; A61K 31/4045 20130101 |
Class at
Publication: |
424/722 ; 546/69;
514/288; 206/534 |
International
Class: |
A61K 31/48 20060101
A61K031/48; A61K 31/4045 20060101 A61K031/4045; A61J 1/14 20060101
A61J001/14; A61K 33/00 20060101 A61K033/00 |
Claims
1. Lysergic acid amide (LSA) in a substantially pure form in an
amount of between 50 .mu.g and about 5000 .mu.g.
2-4. (canceled)
5. A pharmaceutical composition comprising the LSA of claim 1, and
a pharmaceutically acceptable carrier.
6. The pharmaceutical composition of claim 5, which is in form
suitable for parenteral administration or enteral
administration.
7. (canceled)
8. A therapeutic package for dispensing the LSA of claim 1 to, or
for use in dispensing the LSA of claim 1 to, a subject with a
disorder associated with cephalic pain, which comprises: (a) the
LSA of claim 1, wherein the LSA is present in one or more unit
dosage forms suitable for parenteral administration; and (b) a
container containing the unit dosage form or unit dosage forms of
LSA, wherein said package optionally further comprises a package
insert which indicates to physicians and purchasers that the LSA
enclosed therein, when administered as instructed on the package
insert, is effective in treating a disorder associated with
cephalic pain.
9. (canceled)
10. The package of claim 8, wherein the LSA is in a form suitable
for transmucosal administration or subcutaneous administration.
11. The package of claim 10, wherein the LSA is in a form suitable
for sublingual administration, rectal or vaginal
administration.
12-13. (canceled)
14. A therapeutic package for dispensing the LSA of claim 1 to, or
for use in dispensing the LSA of claim 1, to a subject with a
disorder associated with cephalic pain, which comprises (a) the LSA
of claim 1 in one or more unit dosage forms suitable for enteral
administration; and (b) a container containing the unit dosage form
or unit dosage forms of LSA wherein said package optionally further
comprises a package insert which indicates to physicians and
purchasers that the LSA enclosed therein, when administered as
instructed on the package insert, is effective in treating a
disorder associated with cephalic pain.
15-16. (canceled)
17. A method for treating a disorder associated with cephalic pain,
comprising administering to a subject in need of such treatment a
therapeutically effective amount of an ergoline derivative.
18. The method of claim 17, wherein the ergoline derivative is a
substantially pure form of LSA.
19. (canceled)
20. The method of claim 17 wherein said cephalic pain is a
trigeminal autonomic cephalalgia is selected from the group
consisting of episodic and chronic cluster headache (CH), episodic
and chronic paroxysmal hemicrania (PH), and short-lasting
unilateral neuralgiform headache attacks with conjunctival
injection and tearing (SUNCT).
21. The method of claim 20, wherein the trigeminal autonomic
cephalalgia is episodic or chronic CH.
22. The method of claim 20, wherein the disorder associated with
cephalic pain is selected from the group consisting of a vascular
headache, a tension headache, a headache associated with a
substance or its withdrawal.
23. The method of claim 22, wherein the vascular headache is a
migraine headache.
24. The method of claim 17, wherein the therapeutically effective
amount is between about 50 .mu.g and about 5000 .mu.g.
25. The method of claim 17, further comprising administering to the
subject a second compound which acutely relieves at least one
symptom of the disorder associated with cephalic pain.
26. The method of claim 25, wherein the second compound is selected
from the group consisting of oxygen, a serotonin receptor agonist,
an ergot derivative, a hormone, and a local anesthetic.
27. The method of claim 17, further comprising administering a
second compound selected from the group consisting of lithium,
melatonin, a calcium channel blocker, a hormone, an anticonvulsant
agent, an opioid receptor antagonist and a sedative.
28. The method of claim 27, wherein the second compound is an
opioid receptor antagonist.
29. The method of claim 17, comprising administering the ergoline
derivative to the subject at least once a day.
30. The method of claim 17, comprising administering the ergoline
derivative to the subject at least once every other day.
31-36. (canceled)
37. The method of claim 17, wherein the ergoline derivative is
administered enterally, orally, parenterally, transmucosally,
sublingually or subcutaneously.
38-42. (canceled)
43. A method for treating a disorder associated with cephalic pain,
comprising administering to a subject in need of such treatment a
therapeutically effective amount of an ergoline derivative and a
therapeutically effective amount of an opioid receptor
antagonist.
44. The method of claim 43, wherein the ergoline derivative is a
substantially pure form of LSA.
45. The method of claim 43, wherein the ergoline derivative and
opioid receptor antagonist are administered at least once a
day.
46. (canceled)
47. The method of claim 43, further comprising administering oxygen
to the subject.
48. The method of claim 43, wherein the subject has not received a
headache medication for at least five days prior to administration
of the ergoline derivative and the opioid receptor antagonist.
49. The method of claim 17 or claim 43, wherein the subject is a
human.
50. A method for preventing a disorder associated with cephalic
pain in a subject in need thereof, comprising administering to the
subject, during a period in which the subject is not suffering from
cephalic pain, an ergoline derivative.
51. The method of claim 50, wherein the ergoline derivative is a
substantially pure form of LSA.
52. (canceled)
53. The method of, claim 50 wherein said cephalic pain is a
trigeminal autonomic cephalalgia is selected from the group
consisting of episodic and chronic cluster headache (CH), episodic
and chronic paroxysmal hemicrania (PH), and short-lasting
unilateral neuralgiform headache attacks with conjunctival
injection and tearing (SUNCT).
54. The method of claim 53, wherein the trigeminal autonomic
cephalalgia is episodic or chronic CH.
55. The method of claim 54, wherein the administration of the
ergoline derivative is during a period of remission from a CH.
56. The method of claim 53, wherein the disorder associated with
cephalic pain is selected from the group consisting of a vascular
headache, a tension headache, a headache associated with a
substance or its withdrawal.
57. The method of claim 56, wherein the vascular headache is a
migraine headache.
58. The method of claim 50, wherein the therapeutically effective
amount of the ergoline derivative is between about 50 .mu.g and
about 5000 .mu.g.
59. The method of claim 50, wherein the ergoline derivative is
administered at least once a week.
60-64. (canceled)
65. The method of claim 50, further comprising administering a
second compound selected from the group consisting of a mood
stabilizer, a hormone, a calcium channel blocker, an anticonvulsant
agent, an opioid receptor antagonist and a sedative.
66. The method of claim 65, wherein the mood stabilizer is
lithium.
67. The method of claim 65, wherein the hormone is melatonin.
Description
[0001] This application claims priority from 61/038,537, filed Mar.
21, 2008, hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] Compounds, pharmaceutical compositions comprising the
compounds and methods of using the compounds and pharmaceutical
compositions for treating pain disorders, e.g., disorders
associated with cephalic pain, are provided.
BACKGROUND OF THE INVENTION
[0003] Disorders associated with cephalic pain can fall into any of
a wide variety of classes including, for example, vascular
headaches (e.g., a migraine headache), tension headaches, headaches
associated with the use a substance or its withdrawal, and
trigeminal autonomic cephalalgias. The trigeminal autonomic
cephalalgias often induce some of the most severe types of cephalic
pain of any disorder associated with cephalic pain. Examples of
trigeminal autonomic cephalalgias are episodic and chronic cluster
headaches, episodic and chronic paroxysmal hemicranias, and
short-lasting unilateral neuralgiform headache attacks with
conjunctival injection and tearing.
[0004] Cluster headaches (also known as migrainous neuralgia,
Horton's syndrome, Raeder's syndrome, sphenopalatine neuralgia, and
histaminic cephalalgia) are recurrent headaches characterized by
sudden onset and intense pain on one side of the face that begins
around the eye, temple, or cheek. There are two clinical patterns
of cluster headaches: episodic and chronic. About 80-90% of
patients with cluster headaches have them in episodic patterns
which are characterized by one to three short attacks, e.g.,
lasting from fifteen minutes to three hours, of pain around the
eyes per day which are grouped or "clustered" over a stretch of one
to two months and then followed by a pain-free remission period.
Typically, the remission period lasts for at least one month and
often up to a year. The remaining 10% of patients with cluster
headaches have them in chronic patterns which are characterized by
daily occurrences of headaches lasting for more than a year with no
remission period or with remission periods lasting less than one
month. Isselbacher, K. J. et al. (eds). Harrison's Principles of
Internal Medicine, Thirteenth Edition (1994, McGraw-Hill, New York,
N.Y.), pp. 69-70. A single person may experience alternating
episodic and chronic phases of cluster headaches.
[0005] While the underlying cause of cluster headaches is unknown,
the occurrence of such headaches is correlated with abnormal
activation of the posterior hypothalamus. May, A. et al. (1998)
Lancet 352(9124):275-278. Abnormal hypothalamic activation then
does two things. First, it activates the trigeminal nerve, causing
pain in the trigeminal distribution. Second, it causes sympathetic
dysfunction in the form of drooping eyelid and constricted pupil,
and parasympathetic overactivity that is responsible for the runny
eye and stuffy nose that accompany most attacks. Sewell, R. A.,
Halpern, J. H. "Response of Cluster Headache to Psilocybin and
LSD." in Winkelman, M. J. et al. eds. Psychedelic Medicine: New
Evidence for Hallucinogenic Substances as Treatments (Greenwood
Publishing Group, New York, 2007).
[0006] Because the pain of a cluster headache comes on suddenly and
may subside within a short time, over-the-counter pain relievers
such as aspirin or ibuprofen are not effective in treating the
pain. The headache is usually gone before these medications can
provide pain relief. At present, there are several different
approaches for providing acute pain relief for patients suffering
from cluster headaches. These approaches include: (1) treatment
comprising inhalation of oxygen; (2) treatment with an oral,
injectable, or inhalable (e.g., as a nasal spray) form of a
triptan; (3) treatment with an intravenous, injectable, or
inhalable form of an ergot derivative; (4) treatment with an
injectable form of a synthetic somatostatin; and (5) treatment
using nasal drops of local anesthetics. All of these acute
treatments have disadvantages. For example, while inhalation of
100% oxygen through a mask can provide dramatic relief for most who
use it, it can be extremely inconvenient to have to carry around an
oxygen cylinder and regulator. In addition, use of triptans is not
recommended for people with uncontrolled high blood pressure or
ischemic heart disease. While intravenous treatment with ergot
derivatives can be fast acting, it must be provided in a doctor's
office. Moreover, inhaled versions of ergot derivatives work more
slowly and may not provide pain relief in a relevant time frame.
Synthetic somatostatins and local anesthetics work for some people
but are not reliably effective.
[0007] For patients with chronic cluster headaches who do not
respond to any of these treatment approaches and, who if left
without treatment often kill themselves (hence the informal term of
"suicide headache" to characterize a cluster headache), surgery may
be indicated. Sewell, R. A., Halpern, J. H. "Response of Cluster
Headache to Psilocybin and LSD." in Winkelman, M. J. et al. eds.
Psychedelic Medicine: New Evidence for Hallucinogenic Substances as
Treatments (Greenwood Publishing Group, New York, 2007). Candidates
for surgery must have headaches only on one side of the head
because the surgery can be performed only once. Several types of
surgery have been used to treat cluster headaches and they
typically involve procedures attempting to damage the nerve
pathways thought to be the immediate cause of the pain. The most
common of these procedures are directed at the trigeminal nerve and
include conventional surgery, in which the surgeon cuts part of the
trigeminal nerve with a scalpel or uses small burns to destroy part
of the nerve, and radiosurgery, in which the surgeon using a
focused beam of radiation to destroy part of the trigeminal nerve.
Residual muscle weakness in the jaw and sensory loss in certain
areas of the face and head often make these procedures options of
last resort. Cohen, A. S. et al. (June 2007) Headache 969-980;
Franzini, A. et al. (May 2003) Neurosurgery 52(5):1095-1099.
[0008] There are also various options for short-term and long-term
prevention of cluster headaches. These treatment options, which
also all have disadvantages, include: (1) treatment with
corticosteroids (indicated for short term use only as they have
serious side effects (e.g., immunosuppression, osteoporosis,
cataracts, and psychosis) if used long-term; (2) treatment with
ergot derivatives, provided sublingually or rectally (indicated for
short term use of two to three weeks only); (3) treatment with
injectable nerve blockers (indicated for short-term use and must be
administered in a doctor's office); (4) treatment with
anticonvulsants (indicated for both short and long term use); (5)
treatment with methysergide (indicated for short term use only as
prolonged treatment has been associated with rare fibrotic
conditions); (6) treatment with calcium channel blockers (indicated
for both short and long term use but has many side effects
including dizziness, nausea, fatigue, swelling of the ankles and
low blood pressure); (7) treatment with serotonin agonists
(insurance generally covers only a handful of injections per month,
not the required several a day, and the too frequent use of such
compounds can have cardiac implications); (8) treatment with
lithium (indicated for long term use but has many side effects such
as tremor, increased thirst, diarrhea and drowsiness and can cause
kidney and thyroid damage). Cohen, A. S. et al. (June 2007)
Headache 969-980; Sewell, R. A., Halpern, J. H. "Response of
Cluster Headache to Psilocybin and LSD." in Winkelman, M. J. et al.
eds. Psychedelic Medicine: New Evidence for Hallucinogenic
Substances as Treatments (Greenwood Publishing Group, New York,
2007); http://www.mayoclinic.com/health/cluster-headache/DS00487.
Thus, there exists a need for new medications and methods of
treatment and/or prevention using medications which avoid some of
the disadvantages experienced by patients using these traditional
treatment methods.
SUMMARY OF THE INVENTION
[0009] The present invention is directed to various compositions
and methods for preventing and treating disorders associated with
cephalic pain. Compositions of the invention include ergoline
derivatives, e.g., substantially pure forms of ergoline
derivatives, e.g., substantially pure forms of lysergic acid amide
(LSA, also known as ergine) and 2-bromo-LSD. Exemplary ergoline
derivatives include those described herein, for example, compounds
of formulas (I) and (Ia). In some embodiments, the ergoline
derivative is LSA, ergonovine, methergine, methysergide, or
lysergic acid diethylamide (LSD), e.g., 2-bromo-LSD. In some
embodiments, the ergoline derivative is not methergine. In some
embodiments, the ergoline derivative is not methysergide. In some
embodiments, the ergoline derivative is neither methergine nor
methysergide. In some embodiments, the ergoline derivative is a
peptide alkaloid, such as ergotamine, dihydroergotamine
ergocristine, ergocornine, ergocryptine, bromocriptine, or
ergovaline. In some embodiments the peptide alkaloid is not
dihydroergotamine. In some embodiment, the peptide alkaloid is not
ergotamine. In some embodiments, the peptide alkaloid is neither
dihydroergotamine nor ergotamine. In some embodiments, when the
method of the invention for preventing or treating disorders
associated with cephalic pain are those in which the ergoline
derivative, e.g., LSA, 2-bromo-LSD, is used in combination with
another therapeutic agent described herein, the ergoline
derivative, e.g., LSA, 2-bromo-LSD, is not in substantially pure
form. In other embodiments, when the method of the invention for
preventing or treating disorders associated with cephalic pain are
those in which the ergoline derivative, e.g., LSA, 2-bromo-LSD, is
used in combination with another therapeutic agent described
herein, the ergoline derivative, e.g., LSA, 2-bromo-LSD, is in
substantially pure form.
[0010] The ergoline derivatives are provided in amounts effective,
e.g., in an amount between about 50 .mu.g and about 5000 .mu.g,
e.g., in an amount between 100 .mu.g and about 4000 .mu.g, e.g., in
an amount between about 100 .mu.g and about 3000 .mu.g, e.g., in an
amount between about 100 .mu.g and about 2000 .mu.g, to prevent or
treat disorders associated with cephalic pain. These compositions
can further include pharmaceutically acceptable carriers. In
certain aspects of the invention, the compositions and
pharmaceutical compositions are formulated such that they are
suitable for various routes of administration. In one embodiment,
the compositions are produced in a form suitable for parenteral
administration, e.g., subcutaneous administration, intravenous
administration, intramuscular administration, and transmucosal
administration such as sublingual administration, rectal
administration, or vaginal administration. In another embodiment,
the compositions are produced in a form suitable for enteral
administration, e.g., oral administration.
[0011] The compositions of the invention can be provided in
therapeutic packages for dispensing to, or for use in dispensing
to, a subject, e.g., a human, with a disorder associated with
cephalic pain. The therapeutic packages typically contain a
substantially pure form of an ergoline derivative, e.g., LSA,
2-bromo-LSD, of the invention, in one or more unit dosage forms or
in a multiple dosage form, suitable for parenteral or enteral
administration as well as a container containing the ergoline
derivative in one or more unit dosage forms or in multiple dosage
form. In certain embodiments, the therapeutic packages also include
a package insert or other United States Food and Drug
Administration (FDA) approved label or document which indicates to
physicians and/or purchasers that the ergoline derivative enclosed
therein, when administered as instructed on the package insert or
FDA approved label or document, is effective in preventing or
treating a disorder, e.g., cluster headache, associated with
cephalic pain.
[0012] Another aspect of the invention is a method for treating a
disorder associated with cephalic pain which comprises
administering, e.g, enterally, e.g., orally, or parenterally, e.g.,
subcutaneously, intravenously, transmucosally (e.g., sublingually,
buccally, rectally or vaginally) to a subject in need of such
treatment a therapeutically effective amount of an ergoline
derivative, e.g., LSA, e.g., a substantially pure form of LSA,
2-bromo-LSD, e.g., a substantially pure form of 2-bromo-LSD, of the
invention. In one embodiment, the subject in need of such treatment
is a human who suffers from, is suffering from, or is susceptible
to a disorder associated with cephalic pain. One class of disorders
associated with cephalic pain includes the disorders which have
been characterized as the trigeminal autonomic cephalalgias.
Examples of trigeminal autonomic cephalalgias that can be treated
according to the present invention are episodic and chronic cluster
headache (CH), episodic and chronic paroxysmal hemicrania (PH), and
short-lasting unilateral neuralgiform headache attacks with
conjunctival injection and tearing (SUNCT). In another embodiment,
the disorder associated with cephalic pain is vascular headache
(e.g., a migraine headache), a tension headache, or a headache
associated with the use of a substance (e.g., triptans such as
sumatriptan, benzodiazepines such as alprazolam, analgesics such as
ibuprofen, ergots such as ergotamine, opioids such as morphine,
recreational drugs such as caffeine, nicotine, alcohol, and hormone
replacement therapy containing, for example, estrogen) or its
withdrawal. The ergoline derivatives are provided in
therapeutically effective amounts (i.e., amounts effective to treat
a disorder associated with cephalic pain, e.g., in an amount
between about 100 .mu.g and about 5.0 mg, e.g., in an amount
between 200 .mu.g and about 2.0 mg, e.g., in an amount between
about 200 .mu.g about 1.0 mg), to treat disorders associated with
cephalic pain.
[0013] The methods of the invention can further include
administering to the subject a second compound which acutely
relieves at least one symptom of a disorder associated with
cephalic pain, e.g., administering a compound described herein in
combination with a second compound. Examples of second compounds
which acutely relieve at least one symptom of a disorder associated
with cephalic pain include oxygen, serotonin receptor agonists
(e.g., triptans such as sumatriptan, eletriptan, rizatriptan,
frovatriptan, almotriptan, zolmitriptan, and naratriptan), ergot
derivatives (e.g., dihydroergotamine, and ergotamine tartrate),
hormones (e.g., corticosteroids (e.g., prednisone, cortisol),
testosterone, growth hormone, luteinizing hormone, somatostatin,
and prolactin), and local anesthetics (e.g., amino ester local
anesthetics (e.g., benzocaine, chloroprocaine, cocaine, procaine,
and tetracaine/amethocaine), amino amide local anesthetics (e.g.,
bupivacaine levobupiva, lidocaine/lignocaine, mepivacaine,
prilocaine, ropivacaine, articaine, trimecaine, and combinations
thereof (e.g., lidocaine and prilocaine, in the case of local
anesthetics). Alternatively, or in addition to administering such
shorter acting second compounds, other compounds, e.g., longer
acting compounds, for use in treating a disorder associated with
cephalic pain can be administered with the ergoline derivatives of
the invention. In this embodiment, such compounds include lithium,
melatonin, calcium channel blockers (e.g., verapamil, diltiazem,
nifedipine, nimodipine), hormones (see examples described herein),
anticonvulsant agents (e.g., topiramate, valproic acid,
gabapentin), opioid receptor antagonists (e.g., naltrexone
hydrochloride, naloxone, buprenorphine, nalmefene, nalorphone) and
sedatives (e.g., benzodiazepines, barbiturates, meclobamate,
chloral hydrate, sodium oxybate).
[0014] In the methods of the present invention, the ergoline
derivatives, e.g., LSA, e.g., substantially pure forms of LSA,
2-bromo-LSD, e.g., substantially pure forms of 2-bromo-LSD, and/or
the other compounds, e.g., longer acting compounds or the shorter
acting compounds, described herein can be administered at least
once a day, at least once every other day, at least once every two
days, at least once every three days, at least once every four
days, or at least once every five days or more. In one embodiment,
the ergoline derivative and/or the additional or other compound
are/is administered on one of these schedules and at least three
times or for at least three days. In certain embodiments, the
subject, e.g., a human, has not received a headache medication
(e.g., the subject has undergone a "washout" period in which he or
she has been weaned from any headache medication) for at least one
day, two days, three days, four days, or five days prior to
administration of the ergoline derivative and/or the additional or
other compound.
[0015] Other aspects of the invention include methods for treating
a disorder associated with cephalic pain which comprise
administering to a subject, e.g., a human, e.g., a human who has
not received a headache medication for at least five days, in need
of such treatment a therapeutically effective amount of an ergoline
derivative, e.g., LSA, e.g., a substantially pure form of LSA,
2-bromo-LSD, e.g., a substantially pure form of 2-bromo-LSD, and a
therapeutically effective amount of an opioid receptor antagonist.
The ergoline derivative and the opioid receptor antagonist can be
administered concurrently or sequentially (e.g., either the
ergoline derivative is administered prior to the opioid receptor
antagonist or the opioid receptor antagonist is administered prior
to the ergoline derivative). The ergoline derivative and the opioid
receptor antagonist can be administered by any of the routes (and
by the same or different routes) described herein at least once a
day for at least three days. In addition, any of the short acting
compounds described herein can also be administered with the
ergoline derivative and the opioid receptor antagonist. In one
embodiment, such short acting compound administered with the
ergoline derivative and the opioid receptor antagonist is
oxygen.
[0016] Yet other aspects of the invention include methods for
preventing, e.g., extending remission periods of, a disorder
associated with cephalic pain in a subject in need thereof, which
comprise administering to the subject a therapeutically effective
amount of an ergoline derivative, e.g., LSA, e.g., a substantially
pure form of LSA, 2-bromo-LSD, e.g, a substantially pure form of
2-bromo-LSD, during a period in which the subject is not suffering
from cephalic pain. Examples of disorders associated with cephalic
pain which can be prevented according to the method of the present
invention include trigeminal autonomic cephalalgias such as
episodic and chronic (CH), episodic and chronic (PH), and SUNCT. In
one embodiment, the ergoline derivative is administered to a
subject who suffers from a trigeminal autonomic cephalalagia, e.g.,
CH, and is in a remission period. Other examples of disorders
associated with cephalic pain which can be prevented according to
the method of the present invention include vascular headache
(e.g., a migraine headache), a tension headache, and a headache
associated with the use of a substance or its withdrawal. To
prevent a disorder associated with cephalic pain, a subject can be
administered a therapeutically effective amount, as described
herein, of an ergoline derivative, as described herein, at least
once a week, at least once every two weeks, at least once every
three weeks, at least once every four weeks, at least once every
two months, or at least once every three months or more. Other
compounds which are used to treat disorders associated with
cephalic pain, including, for example, lithium, melatonin, calcium
channel blockers, hormones, anticonvulsant agents, opioid receptor
antagonists, and sedatives, as described herein, can be
administered with the ergoline derivative to prevent such disorders
(e.g., to extend remission periods).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0017] The present invention is directed to compositions and
methods for use in the prevention and/or treatment of disorders
associated with cephalic pain. Typically, the compositions include
at least one ergoline derivative, e.g., an ergoline derivative in
substantially pure form. As used herein, the term "ergoline
derivative" refers to a compound of formula (I) or formula (Ia),
and pharmaceutically acceptable salts thereof.
[0018] In some embodiments, the ergoline derivative is a compound
of formula (I),
##STR00001## [0019] wherein [0020] R.sup.1 is H, C.sub.1-C.sub.6
alkyl, or a nitrogen protecting group; [0021] R.sup.2 is H or halo;
[0022] R.sup.3 is H, C.sub.1-C.sub.6 alkyl, or a nitrogen
protecting group; (in some preferred embodiments, R.sup.2 is
methyl) [0023] each R.sup.4 and R.sup.5 are independently H,
C.sub.1-C.sub.6 alkyl, optionally substituted with R.sup.6; or and
[0024] wherein R.sup.6 is --OH, or one of R.sup.4 or R.sup.5 is
[0024] ##STR00002## [0025] R.sup.7 is C.sub.1-C.sub.6 alkyl; [0026]
R.sup.8 is C.sub.1-C.sub.6 alkyl or arylalkyl.
[0027] In some embodiments, R.sup.1 is H or C.sub.1-C.sub.6 alkyl;
R.sup.2 is H; R.sup.3 is H or C.sub.1-C.sub.6 alkyl; (in some
highly preferred embodiments, R.sup.3 is methyl); each R.sup.3 and
R.sup.4 are independently H, C.sub.1-C.sub.6 alkyl, optionally
substituted with R.sup.6; and R.sup.6 is --OH.
[0028] In some embodiments, R.sup.1 is H or C.sub.1-C.sub.6 alkyl;
R.sup.2 is methyl;each R.sup.4 and R.sup.5 are independently H,
C.sub.1-C.sub.6 alkyl, optionally substituted with R.sup.5; and
R.sup.5 is --OH.
[0029] In some embodiments, R.sup.1 is H or methyl.
[0030] In some embodiments, R.sup.2 is H. In some embodiments,
R.sup.2 is halo, for example, bromo.
[0031] In some embodiments R.sup.3 is methyl.
[0032] In some embodiments, R.sup.4 is H. In some embodiments
R.sup.4 is alkyl, for example, a branched alkyl. In some
embodiments, R.sup.4 is alkyl substituted with OH. In some
embodiments, R.sup.4 is a branched alkyl substituted with OH. In
some embodiments, R.sup.4 is
##STR00003##
In some embodiments, R.sup.4 is
##STR00004##
In some embodiments, R.sup.4 is ethyl.
[0033] In some embodiments, R.sup.5 is H. In some embodiments,
R.sup.5 is ethyl. In some embodiments, both R.sup.4 and R.sup.5 are
H. In some embodiments, both R.sup.4 and R.sup.5 are ethyl. In some
embodiments, R.sup.4 alkyl substituted with OH and R.sup.5 is H. In
some embodiments, R.sup.4 is
##STR00005##
and R.sup.5 is H. In some embodiments, R.sup.4 is
##STR00006##
and R.sup.5 is H. In some embodiments, R.sup.4 is H; and R.sup.5
is
##STR00007##
[0034] In some preferred embodiments, R.sup.1, R.sup.2, R.sup.4 and
R.sup.5 are each H, and R.sup.3 is methyl (i.e., LSA, ergine).
[0035] In some preferred embodiments, R.sup.1, R.sup.2, and R.sup.5
are each H, R.sup.4 is
##STR00008##
and R.sup.3 is methyl (i.e., ergonovine).
[0036] In some preferred embodiments, R.sup.1, R.sup.2, and R.sup.5
are each H, R.sup.4 is
##STR00009##
and R.sup.3 is methyl (i.e., methergine).
[0037] In some preferred embodiments, R.sup.1 and R.sup.3 are each
methyl, R.sup.4 is
##STR00010##
and R.sup.5 and R.sup.2 are each H (i.e., methylsergide).
[0038] In some preferred embodiments, R.sup.1 and R.sup.2 are each
H, R.sup.3 is methyl, and each of R.sup.4 and R.sup.5 are ethyl
(i.e., LSD).
[0039] In some embodiments, R.sup.1 is H, or C.sub.1-C.sub.6 alkyl,
or a nitrogen protecting group; R.sup.2 is H or halo; R.sup.3 is H,
or C.sub.1-C.sub.6 alkyl, or a nitrogen protecting group; R.sup.4
is H; R.sup.5 is
##STR00011##
R.sup.7 is C.sub.1-C.sub.6 alkyl; and R.sup.8 is C.sub.1-C.sub.6
alkyl or arylalkyl.
[0040] In some embodiments, R.sup.1 is H; R.sup.2 is H or halo;
R.sup.3 is H, or C.sub.1-C.sub.6 alkyl, or a nitrogen protecting
group; R.sup.4 is H; R.sup.5 is
##STR00012##
R.sup.7 is C.sub.1-C.sub.6 alkyl; and R.sup.8 is C.sub.1-C.sub.6
alkyl or arylalkyl.
[0041] In some embodiments, R.sup.1 is H, or C.sub.1-C.sub.6 alkyl,
or a nitrogen protecting group; R.sup.2 is H or halo; R.sup.3 is
C.sub.1-C.sub.6 alkyl; R.sup.4 is H; R.sup.5 is
##STR00013##
R.sup.7 is C.sub.1-C.sub.6 alkyl; and R.sup.8 is C.sub.1-C.sub.6
alkyl or arylalkyl.
[0042] In some embodiments, R.sup.7 is a branched C.sub.1-C.sub.6
alkyl. In some embodiments, R.sup.7 is
##STR00014##
In some embodiments, R.sup.7 is methyl.
[0043] In some embodiments, R.sup.8 is C.sub.1-C.sub.6 alkyl. In
some embodiments, R.sup.8 is a branched C.sub.1-C.sub.6 alkyl. In
some embodiments, R.sup.8 is
##STR00015##
In some embodiments, R.sup.8 is
##STR00016##
In some embodiments, R.sup.8 is arylalkyl. In some embodiments,
R.sup.8 is benzyl.
[0044] In some preferred embodiments, R.sup.1 is H; R.sup.2 is H or
halo; R.sup.3 is methyl; R.sup.4 is H; R.sup.5 is
##STR00017##
R.sup.7 is C.sub.1-C.sub.6 alkyl; and R.sup.8 is C.sub.1-C.sub.6
alkyl or arylalkyl. In some embodiments, R.sup.2 is H. In some
embodiments, R.sup.2 is bromo. In some embodiments, R.sup.7 is
methyl. In some embodiments, R.sup.7 is
##STR00018##
In some embodiments, R.sup.8 is
##STR00019##
In some embodiments, R.sup.8 is
##STR00020##
In some embodiments, R.sup.8 is benzyl.
[0045] In some embodiments, R.sup.1, R.sup.2, and R.sup.4 are each
H; R.sup.5 is
##STR00021##
R.sup.3 and R.sup.7 are each methyl; and R.sup.8 is benzyl (i.e.,
ergotamine).
[0046] In some embodiments, R.sup.1, R.sup.2, and R.sup.4 are each
H; R.sup.3 is methyl; R.sup.5 is
##STR00022##
R.sup.7 is
##STR00023##
[0047] and R.sup.8 is benzyl (i.e., ergocristine).
[0048] In some embodiments, R.sup.1, R.sup.2, and R.sup.4 are each
H; R.sup.3 is methyl; R.sup.5 is
##STR00024##
and R.sup.7 and R.sup.8 are each
##STR00025##
(i.e., ergocornine).
[0049] In some embodiments, R.sup.1, R.sup.2, and R.sup.4 are each
H; R.sup.3 is methyl; R.sup.5 is
##STR00026##
R.sup.7 is
##STR00027##
[0050] and R.sup.8 is
##STR00028##
[0051] (i.e., ergocryptine).
[0052] In some embodiments, R.sup.1 and R.sup.4 are each H;
R.sup.2 is bromo; R.sup.3 is methyl; R.sup.5 is
##STR00029##
R.sup.7 is
##STR00030##
[0053] and R.sup.8 is
##STR00031##
[0054] (i.e., bromocriptine).
[0055] In some embodiments, R.sup.1, R.sup.2, and R.sup.4 are each
H; R.sup.5 is
##STR00032##
R.sup.3 and R.sup.7 are each methyl; and R.sup.8 is
##STR00033##
(i.e. ergovaline).
[0056] In some embodiments, the invention features a composition
comprising a compound of formula (Ia), wherein the compound has an
enantiomeric excess of at least about 60% of the compound of
formula (Ia)
##STR00034## [0057] wherein [0058] R.sup.1 is H, C.sub.1-C.sub.6
alkyl, or a nitrogen protecting group; [0059] R.sup.2 is H or halo;
[0060] R.sup.3 is H, C.sub.1-C.sub.6 alkyl, or a nitrogen
protecting group; (in some preferred embodiments, R.sup.2 is
methyl) [0061] each R.sup.4 and R.sup.5 are independently H,
C.sub.1-C.sub.6 alkyl, optionally substituted with R.sup.6; or and
[0062] wherein R.sup.6 is --OH, or one of R.sup.4 or R.sup.5 is
[0062] ##STR00035## [0063] R.sup.7 is C.sub.1-C.sub.6 alkyl; [0064]
R.sup.8 is C.sub.1-C.sub.6 alkyl or arylalkyl.
[0065] In some embodiments, R.sup.1 is H or C.sub.1-C.sub.6 alkyl;
R.sup.2 is H; R.sup.3 is H or C.sub.1-C.sub.6 alkyl; (in some
highly preferred embodiments, R.sup.3 is methyl); each R.sup.3 and
R.sup.4 are independently H, C.sub.1-C.sub.6 alkyl, optionally
substituted with R.sup.6; and R.sup.6 is --OH.
[0066] In some embodiments, R.sup.1 is H or C.sub.1-C.sub.6 alkyl;
R.sup.2 is methyl;each R.sup.4 and R.sup.5 are independently H,
C.sub.1-C.sub.6 alkyl, optionally substituted with R.sup.5; and
R.sup.5 is --OH.
[0067] In some embodiments, R.sup.1 is H or methyl.
[0068] In some embodiments, R.sup.2 is H. In some embodiments,
R.sup.2 is halo, for example, bromo.
[0069] In some embodiments R.sup.3 is methyl.
[0070] In some embodiments, R.sup.4 is H. In some embodiments
R.sup.4 is alkyl, for example, a branched alkyl. In some
embodiments, R.sup.4 is alkyl substituted with OH. In some
embodiments, R.sup.4 is a branched alkyl substituted with OH. In
some embodiments, R.sup.4 is
##STR00036##
In some embodiments, R.sup.4 is
##STR00037##
In some embodiments, R.sup.4 is ethyl.
[0071] In some embodiments, R.sup.5 is H. In some embodiments,
R.sup.5 is ethyl. In some embodiments, both R.sup.4 and R.sup.5 are
H. In some embodiments, both R.sup.4 and R.sup.5 are ethyl. In some
embodiments, R.sup.4 alkyl substituted with OH and R.sup.5 is
H.
[0072] In some embodiments, R.sup.4 is
##STR00038##
and R.sup.5 is H. In some embodiments, R.sup.4 is
##STR00039##
and R.sup.5 is H. In some embodiments, R.sup.4 is H; and R.sup.5
is
##STR00040##
[0073] In some preferred embodiments, R.sup.1, R.sup.2, R.sup.4 and
R.sup.5 are each H, and R.sup.3 is methyl (i.e., LSA, ergine).
[0074] In some preferred embodiments, R.sup.1, R.sup.2, and R.sup.5
are each H, R.sup.4 is
##STR00041##
and R.sup.3 is methyl (i.e., ergonovine).
[0075] In some preferred embodiments, R.sup.1, R.sup.2, and R.sup.5
are each H, R.sup.4 is
##STR00042##
and R.sup.3 is methyl (i.e., methergine).
[0076] In some preferred embodiments, R.sup.1 and R.sup.3 are each
methyl, R.sup.4 is
##STR00043##
and R.sup.5 and R.sup.2 are each H (i.e., methysergide).
[0077] In some preferred embodiments, R.sup.1 and R.sup.2 are each
H, R.sup.3 is methyl, and each of R.sup.4 and R.sup.5 are ethyl
(i.e., LSD).
[0078] In some embodiments, R.sup.1 is H, or C.sub.1-C.sub.6 alkyl,
or a nitrogen protecting group; R.sup.2 is H or halo; R.sup.3 is H,
or C.sub.1-C.sub.6 alkyl, or a nitrogen protecting group; R.sup.4
is H;
R.sup.5 is
##STR00044##
[0079] R.sup.7 is C.sub.1-C.sub.6 alkyl; and R.sup.8 is
C.sub.1-C.sub.6 alkyl or arylalkyl.
[0080] In some embodiments, R.sup.1 is H; R.sup.2 is H or halo;
R.sup.3 is H, or C.sub.1-C.sub.6 alkyl, or a nitrogen protecting
group; R.sup.4 is H; R.sup.5 is
##STR00045##
R.sup.7 is C.sub.1-C.sub.6 alkyl; and R.sup.8 is C.sub.1-C.sub.6
alkyl or arylalkyl.
[0081] In some embodiments, R.sup.1 is H, or C.sub.1-C.sub.6 alkyl,
or a nitrogen protecting group; R.sup.2 is H or halo; R.sup.3 is
C.sub.1-C.sub.6 alkyl; R.sup.4 is H; R.sup.5 is
##STR00046##
R.sup.7 is C.sub.1-C.sub.6 alkyl; and R.sup.8 is C.sub.1-C.sub.6
alkyl or arylalkyl.
[0082] In some embodiments, R.sup.7 is a branched C.sub.1-C.sub.6
alkyl. In some embodiments, R.sup.7 is
##STR00047##
In some embodiments, R.sup.7 is methyl.
[0083] In some embodiments, R.sup.8 is C.sub.1-C.sub.6 alkyl. In
some embodiments, R.sup.8 is a branched C.sub.1-C.sub.6 alkyl. In
some embodiments, R.sup.8 is
##STR00048##
In some embodiments, R.sup.8 is
##STR00049##
In some embodiments, R.sup.8 is arylalkyl. In some embodiments,
R.sup.8 is benzyl.
[0084] In some preferred embodiments, R.sup.1 is H; R.sup.2 is H or
halo; R.sup.3 is methyl; R.sup.4 is H; R.sup.5 is
##STR00050##
R.sup.7 is C.sub.1-C.sub.6 alkyl; and R.sup.8 is C.sub.1-C.sub.6
alkyl or arylalkyl. In some embodiments, R.sup.2 is H. In some
embodiments, R.sup.2 is bromo. In some embodiments, R.sup.7 is
methyl. In some embodiments, R.sup.7 is
##STR00051##
In some embodiments, R.sup.8 is
##STR00052##
In some embodiments, R.sup.8 is
##STR00053##
In some embodiments, R.sup.8 is benzyl.
[0085] In some embodiments, R.sup.1, R.sup.2, and R.sup.4 are each
H; R.sup.5 is
##STR00054##
R.sup.3 and R.sup.7 are each methyl; and R.sup.8 is benzyl (i.e.,
ergotamine).
[0086] In some embodiments, R.sup.1, R.sup.2, and R.sup.4 are each
H; R.sup.3 is methyl; R.sup.5 is
##STR00055##
R.sup.7 is
##STR00056##
[0087] and R.sup.8 is benzyl (i.e., ergocristine).
[0088] In some embodiments, R.sup.1, R.sup.2, and R.sup.4 are each
H; R.sup.3 is methyl; R.sup.5 is
##STR00057##
and R.sup.7 and R.sup.8 are each
##STR00058##
(i.e., ergocornine).
[0089] In some embodiments, R.sup.1, R.sup.2, and R.sup.4 are each
H; R.sup.3 is methyl; R.sup.5 is
##STR00059##
R.sup.7 is
##STR00060##
[0090] and R.sup.8 is
##STR00061##
[0091] (i.e., ergocryptine).
[0092] In some embodiments, R.sup.1 and R.sup.4 are each H;
R.sup.2 is bromo; R.sup.3 is methyl; R.sup.5 is
##STR00062##
R.sup.7 is
##STR00063##
[0093] and R.sup.8 is
##STR00064##
[0094] (i.e., bromocriptine).
[0095] In some embodiments, R.sup.1, R.sup.2, and R.sup.4 are each
H; R.sup.5 is
##STR00065##
R.sup.3 and R.sup.7 are each methyl; and R.sup.8 is
##STR00066##
(i.e., ergovaline).
[0096] In some embodiments, the invention features a composition
comprising a compound of formula (Ia), wherein the compound has an
enantiomeric excess of at least about 65% of the compound of
formula (Ia), e.g., at least about 70%, at least about 75%, at
least about 80%, at least about 85%, at least about 90%, at least
about 95%, at least about 98%, at least about 99%.
[0097] Preferred ergoline derivatives are LSA, ergonovine,
methergine, methysergide, LSD, and 2-bromo-LSD. Preferred ergoline
derivatives also include peptide alkaloids, such as ergotamine,
ergocristine, ergocornine, ergocryptine, bromocriptine, or
ergovaline.
[0098] The compounds of this invention can contain one or more
asymmetric centers and thus occur as racemates and racemic
mixtures, single enantiomers, individual diastereomers and
diastereomeric mixtures. All such isomeric forms of these compounds
are expressly included in the present invention. The compounds of
this invention can also contain linkages (e.g., carbon-carbon
bonds) or substituents that can restrict bond rotation, e.g.,
restriction resulting from the presence of a ring or double bond.
Techniques useful for the separation of isomers, e.g.,
stereoisomers are within skill of the art and are described in
Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds, Wiley Interscience, NY, 1994. For example a
stereoisomer of a compound described herein can be resolved to a
high enantiomeric excess (e.g., 60%, 70%, 80%, 85%, 90%, 95%, 99%
or greater) via formation of diasteromeric salts, e.g., with a
chiral base, e.g., (+) or (-) a-methylbenzylamine, or via high
performance liquid chromatography using a chiral column.
[0099] In some instances, a compound disclosed herein is
administered (for example, in a composition) where one isomer
(e.g., the R isomer or S isomer) is present in high enantiomeric
excess.
[0100] The compounds described herein include the compounds
themselves, as well as their salts. A salt, for example, can be
formed between an anion and a positively charged substituent (e.g.,
amino) on a compound described herein. Suitable anions include
chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate,
methanesulfonate, trifluoroacetate, and acetate. Likewise, a salt
can also be formed between a cation and a negatively charged
substituent (e.g., carboxylate) on a compound described herein.
Suitable cations include sodium ion, potassium ion, magnesium ion,
calcium ion, and an ammonium cation such as tetramethylammonium
ion. Pharmaceutically acceptable salts of the compounds described
herein include those derived from pharmaceutically acceptable
inorganic and organic acids and bases.
[0101] Examples of suitable acid salts include acetate, adipate,
alginate, aspartate, benzoate, benzenesulfonate, bisulfate,
butyrate, citrate, camphorate, camphorsulfonate, digluconate,
dodecylsulfate, ethanesulfonate, formate, fumarate,
glucoheptanoate, glycolate, hemisulfate, heptanoate, hexanoate,
hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,
lactate, maleate, malonate, methanesulfonate,
2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate,
persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,
propionate, salicylate, succinate, sulfate, tartrate, thiocyanate,
tosylate and undecanoate. Other acids, such as oxalic, while not in
themselves pharmaceutically acceptable, can be employed in the
preparation of salts useful as intermediates in obtaining the
compounds described herein and their pharmaceutically acceptable
acid addition salts.
[0102] Salts derived from appropriate bases include alkali metal
(e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium
and N-(alkyl)4 salts. The compounds described herein also include
the quaternization of any basic nitrogen-containing groups of the
compounds disclosed herein. Water or oil-soluble or dispersible
products can be obtained by such quaternization. Salt forms of the
compounds of any of the compounds described herein can be amino
acid salts of carboxy groups (e.g. L-arginine, -lysine, -histidine
salts).
[0103] In some embodiments, a compound described herein includes a
prodrug of that compound. Examples of prodrugs include esters and
other pharmaceutically acceptable derivatives, which, upon
administration to a subject, are capable of providing active
compounds. The compounds described herein can be modified by
appending appropriate functionalities to enhance selected
biological properties, e.g., targeting to a particular tissue. Such
modifications are known in the art and include those which increase
biological penetration into a given biological compartment (e.g.,
blood, lymphatic system, central nervous system), increase oral
availability, increase solubility to allow administration by
injection, alter metabolism and alter rate of excretion.
[0104] The term "halo" or "halogen" refers to any radical of
fluorine, chlorine, bromine or iodine.
[0105] The term "alkyl" refers to a hydrocarbon chain that may be a
straight chain or branched chain, containing the indicated number
of carbon atoms. For example, C1-C12 alkyl indicates that the group
may have from 1 to 12 (inclusive) carbon atoms in it.
[0106] The terms "arylalkyl" or "aralkyl" refer to an alkyl moiety
in which an alkyl hydrogen atom is replaced by an aryl group.
Aralkyl includes groups in which more than one hydrogen atom has
been replaced by an aryl group. Examples of "arylalkyl" or
"aralkyl" include benzyl, 2-phenylethyl, 3-phenylpropyl,
9-fluorenyl, benzhydryl, and trityl groups.
[0107] The term "nitrogen protecting group" refers to a moiety that
is positioned on a nitrogen atom of a compound described herein.
The compound protects the nitrogen from participating in a chemical
reaction under certain conditions and can be readily removed, thus
providing the unprotected, free nitrogen atom. An example of a
nitrogen protecting group includes, but is not limited to,
tert-butoxycarbonyl.
[0108] As used herein, a "substantially pure form of" a compound
described herein, e.g., an ergoline derivative, e.g., LSA,
2-bromo-LSD, refers to a composition, in liquid or solid form,
containing at least about 50 weight percent, more preferably at
least about 60 weight percent, yet more preferably at least about
70 weight percent, even more preferably at least about 80, 81, 82,
83, 84, 85, 86, 87, 88, or 89 weight percent, and most preferably
at least about 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100
weight percent of the compound, e.g., the ergoline derivative,
e.g., LSA, 2-bromo-LSD, based on the total weight of the
composition.
[0109] In some embodiments, an ergoline derivative, such as a
compound described herein, is found in nature, as a component of a
natural product and in the presence of other alkaloids. In some
embodiments, an ergoline derivative described herein is a component
of a mixture that includes one or more other components, for
example a non-ergoline derivative alkaloid.
[0110] In some embodiments, a composition comprising an ergoline
derivative described herein is substantially free of non-ergoline
derivative alkaloids. As used herein, "substantially free" when
referring to a composition, liquid or solid, of an ergoline
derivative as described herein, means the composition, liquid or
solid contains less than about 50 weight percent of another
component such as a non-ergoline derivative alkaloid, more
preferably less than about 40, weight percent, yet more preferably
less than about 30 weight percent, even more preferably less than
about 20, 19, 18, 17, 16, 15, 14, 13, 12, or 11 weight percent, and
most preferably less than about 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1
weight percent of another component such as a non-ergoline
derivative alkaloid.
[0111] The ergoline derivatives and pharmaceutically acceptable
salts thereof of the invention can be admixed or combined with a
pharmaceutically acceptable carrier to produce pharmaceutical
compositions. As used herein, a "pharmaceutically acceptable
carrier" refers to a pharmaceutically acceptable material,
composition or vehicle, suitable for administration to mammals,
e.g., humans. The carriers include liquid or solid filler, diluent,
excipient, solvent or encapsulating material, involved in carrying
or transporting the subject agent from one organ, or portion of the
body, to another organ, or portion of the body. Each carrier must
be "acceptable" in the sense of being compatible with the other
ingredients of the formulation and not injurious to the
subject.
[0112] Forms suitable for parenteral administration include
subcutaneous, intracutaneous, intravenous, intramuscular,
intraarticular, intraarterial, intrasynovial, intrasternal,
intrathecal, intralesional and intracranial injection or infusion
techniques.
[0113] Forms suitable for enteral administration include any form
of administration suitable for delivery to any part of the
gastrointestinal tract, including small and large intestines (i.e.,
the gastrointestinal tract). Methods of enteral administration
include oral, sublingual (dissolving the drug under the tongue),
and rectal. Exemplary administration forms include tablets,
capsules, drops, gastric feeding tube, duodenal feeding tube,
gastrostomy, suppository and enema.
[0114] As used herein, "administered in combination" or a combined
administration of two compounds or agents means that two or more
compounds or agents are administered to a subject at the same time
or within an interval such that there is overlap of an effect of
each agent on the patient. Preferably they are administered within
15, 10, 5, or 1 minute of one another. Preferably the
administrations of the compounds or agents are spaced sufficiently
close together such that a combinatorial effect is achieved. The
compounds or agents can be administered simultaneously, for example
in a combined unit dose (providing simultaneous delivery of both
agents). Alternatively, the compounds or agents can be administered
at a specified time interval, for example, an interval of minutes,
hours, days or weeks. Generally, the compounds or agents are
concurrently bioavailable, e.g., detectable, in the subject.
[0115] In a preferred embodiment, the compounds or agents are
administered essentially simultaneously, for example two unit
dosages administered at the same time, or a combined unit dosage of
the two agents. In another preferred embodiment, the compounds or
agents are delivered in separate unit dosages. The compounds or
agents can be administered in any order, or as one or more
preparations that includes two or more agents. In a preferred
embodiment, at least one administration of one of the compounds or
agents, e.g., the first compound or agent, is made within minutes,
one, two, three, or four hours, or even within one or two days of
the other compound or agent, e.g., the second compound or agent. In
some cases, combinations can achieve synergistic results, e.g.,
greater than additive results, e.g., at least 20, 50, 70, or 100%
greater than additive.
[0116] The invention is also directed to therapeutic packages for
dispensing, or for use in dispensing, ergoline derivatives of the
invention to a subject with a disorder associated with cephalic
pain. Such therapeutic packages are combinations of two or more
components which are packed for sale, storage, or transportation at
least one component of which is intended for therapeutic use, e.g.,
intended for therapeutic use in a subject, e.g., a human. Such
therapeutic packages can be used to dispense a compound or agent of
the invention to a subject to treat or prevent a disorder described
herein (e.g., supply to a subject, e.g., supply a compound to a
subject, e.g., a human), according to a prescription or other
written order issued by a physician or other qualified practitioner
that authorizes a pharmacy to supply a specific medication to a
subject). In one embodiment of the invention, the therapeutic
package comprises (a) an ergoline derivative, e.g., a substantially
pure form of an ergoline derivative, e.g., LSA, e.g., LSA in
substantially pure form, e.g., 2-bromo-LSD, e.g., a substantially
pure form of 2-bromo-LSD, which is in a form suitable for
parenteral administration or which is in a form suitable for
enteral administration and which is in one or more unit dosage
forms or multiple dosage form; and (b) a container containing the
ergoline derivative in one or more unit dosage forms or multiple
dosage form. In another embodiment, the therapeutic packages can
further include a package insert which indicates to physicians and
purchasers that the ergoline derivative, e.g., LSA, 2-bromo-LSD,
enclosed therein, when administered as instructed on the package
insert, is effective in treating or preventing a disorder
associated with cephalic pain, e.g., cluster headache.
[0117] A unit dosage form of an ergoline derivative or other
compound described herein refers to a preparation of such ergoline
derivative or other compound in a form specifically for use as a
single administration or a single dose. In one embodiment, a unit
dosage form of an ergoline derivative of the invention includes
from about 25 .mu.g to about 5000 .mu.g. A multiple dosage form of
an ergoline derivative or other compound described herein refers to
a preparation or preparations of such ergoline derivative or other
compounds in a form or forms specifically for use as multiple
administrations or multiple doses.
[0118] Containers which can be used in the therapeutic packages of
the invention are objects which can be used to hold the ergoline
derivatives. Such objects include vials, bottles, tubes, syringes
(e.g., pre-filled syringes containing one or more doses) or other
containers for single or multiple administrations. Such containers
can be made of glass or a polymer material such as polypropylene,
polyolefin, polyethylene, or polyvinylchloride, for example.
Preferred containers can include a seal, or other closure system,
such as a rubber stopper that can be penetrated by a needle in
order to withdraw a single dose and then re-seal upon removal of
the needle. All such containers for injectable liquids, lyophilized
formulations, reconstituted lyophilized formulations or
reconstitutable powders for injection known in the art are
contemplated for use in the present disclosed compositions and
methods. The formulations provided herein can be formulated in a
variety of concentrations in various vial sizes for various
administration dosages. For example, the dosages can be formulated
in a 1/4, 1/2, 1 or 2 ml vial, or any other size vial or other
container known by one of skill in the art.
[0119] Package inserts which can be included in the therapeutic
packages of the invention are printed materials or printed
documents which include the pharmacologic description of a drug (in
this case, the ergoline derivative or other compound described
herein) including approved chemical and proprietary names,
regulatory authority, e.g., U.S. Food & Drug Administration
(FDA), approved indications and usage, contraindications, warnings,
precautions, adverse reactions, drug abuse and dependence
information, overdosage discussion, dosage and administration,
formulations, and appropriate references, all as set forth as
required by detailed regulatory, e.g., FDA, specifications. In one
embodiment, the approved indications and usages include
instructions on how to use the ergoline derivatives of the
invention to prevent or treat a disorder associated with cephalic
pain, e.g., a cluster headache. In another embodiment, the approved
indications and usages include instructions on how to use ergoline
derivatives of the invention in combination with one or more other
compounds, e.g., one or more compounds described herein, e.g.,
opioid receptor antagonists, to treat or prevent a disorder
associated with cephalic pain, e.g., a cluster headache.
[0120] The ergoline derivatives of the invention and the additional
preventative or therapeutic compounds described herein can be
administered according to any technique deemed suitable by one of
skill in the art. For example, the ergoline derivatives or various
compositions thereof of the invention, can be administered by any
of the following means: (a) enterally, e.g., orally (by mouth),
rectally (e.g., in the form of a suppository or an enema), by
feeding tube (e.g., gastric feeding tube, duodenal feeding tube,
gastrostromy); (b) parenterally, e.g., subcutaneously,
intravenously, intramuscularly, intradermally (into the skin
itself), transdermally (diffusion through skin, e.g., intact skin),
intra-arterially, intra-peritoneally, intracardiac (into the heart)
administration, intraosseous (into the bone marrow) administration,
intrathecally (into the spinal canal), transmucosally (diffusion
through a mucous membrane, e.g., insufflation (snorting), nasally,
e.g., intranasally), sublingually (under the tongue), buccally
(through the cheek), vaginally, by inhalation (e.g., pulmonary
administration); (c) topically; (d) epidurally (injection or
infusion into the epidural space); and (e) intravitreally. If the
ergoline derivative or the additional preventative or therapeutic
compound described herein is to be used acutely, e.g., to abort an
attack of a disorder associated with cephalic pain, methods or
routes of administration which result in rapid onset of action are
preferred. These methods or routes of administration include
administration by parenteral (e.g., subcutaneous (e.g.,
subcutaneous periorbital administration), intramuscular or
intravenous administration) or pulmonary (e.g., by inhalation) or
transmucosal (e.g., through a nasal spray) routes.
[0121] The ergoline derivatives of the invention, pharmaceutically
acceptable salts thereof, and/or pharmaceutical compositions
thereof can be used to treat disorders or conditions associated
with cephalic pain. In some embodiments, the methods of the
invention include methods for treating a disorder associated with
cephalic pain by administering a therapeutically effective amount
of the ergoline derivative, alone or in combination with the
additional preventative and/or therapeutic compounds described
herein, to a subject in need of such treatment.
[0122] As used herein, the terms "treating" or "treatment" of any
disease or disorder refers, in one embodiment, to ameliorating the
disease or disorder (i.e., arresting or reducing the development of
the disease or at least one of the clinical symptoms thereof) that
exists in a subject. In another embodiment, "treating" or
"treatment" refers to ameliorating at least one physical parameter,
which may or may not be indiscernible by the subject. In yet
another embodiment, "treating or treatment" refers to modulating
the disease, either physically (e.g., stabilization of a
discernible symptom) or physiologically (e.g., stabilization of a
physical parameter) or both. Subjects who suffer from CH, for
example, often experience one or more of the following symptoms:
severe, unilateral pain attacks localized to orbital, supraorbital,
temporal or combinations of these sites and accompanied by,
ipsilateral to the site of pain, one or more of: lacrimation or
conjunctival injection, rhinorrhea or nasal congestion, cranial
and/or facial sweating, miosis and/or ptosis, edema of the eyelid
or orofacial tissues (including the gingival and palate), facial
flushing or pallor, swelling around the eye and orofacial tissues
(including the mouth), thermography determined "cold spot" at the
site of pain (usually supraorbital). These subjects can also suffer
from one or more of the following: bradycardia, vertigo and ataxia,
syncope, hypertension, increased gastrointestinal acid,
hyperalgesia or allodynia at the site of pain, posturing, twitching
and paresthesia of body parts. Subjects who suffer from migraines,
for example, often experience one or more of the following
symptoms: aura (visual, sensory, and/or motor), photophobia,
phonophobia, osmophobia, nausea, vomiting, vertigo, and
paresthesias. Thus, treating a subject according to the methods of
the present invention can include alleviating or reducing one, two,
three or more of the above-listed symptoms.
[0123] As used herein, a disorder or condition associated with
cephalic pain is a disorder or condition which has as one of its
symptoms cephalic/head pain (e.g., headache). Examples of such
disorders or conditions include trigeminal autonomic cephalalgias
such as episodic and chronic cluster headache (CH), episodic and
chronic paroxysmal hemicrania (PH), and short-lasting unilateral
neuralgiform headache attacks with conjunctival injection and
tearing (SUNCT). Other examples of disorders or conditions which
can be treated according to the present invention include vascular
headaches (e.g., migraine headaches), tension headaches, headaches
associated with the use of a substance (e.g., triptans such as
sumatriptan, benzodiazepines such as alprazolam, analgesics such as
ibuprofen, ergots such as ergotamine, opioids such as morphine,
recreational drugs such as caffeine, nicotine, alcohol, and hormone
replacement therapy containing, for example, estrogen) or its
withdrawal. Yet additional examples of disorders or conditions
associated with cephalic pain include miscellaneous headache
unassociated with a structural lesion, headache associated with a
nonvascular intracranial disorder, headache associated with a
non-cephalic infection, headache associated with a metabolic
disorder, headache associated with a disorder of the cranium, neck,
eyes, nose, sinuses, teeth, mouth, or other facial or cranial
structure, nerve trunk pain and deafferentiation pain.
[0124] As used herein, an "effective amount" or "therapeutically
effective amount" means an amount of an ergoline derivative or
another therapeutic or preventative compound, e.g., the short and
long acting compounds, described herein, that when administered to
a subject for preventing or treating a disease or disorder, is
sufficient to effect such prevention or treatment of the disease or
disorder. An effective amount can vary depending on, among other
things, the ergoline derivative used, the disease and its severity
and the age, weight, etc. of the subject to be treated. The dosage
and frequency of administration of the ergoline derivatives or
therapeutic or preventative compound described herein, can be
determined by one skilled in the art. The amount of such compound
that will be effective in the treatment of a disorder or condition
will vary with the nature and severity of the disorder or
condition, and the route by which the active ingredient is
administered. The frequency and dosage will also vary according to
factors specific for each patient depending on the severity of the
disorder or condition, the route of administration, as well as age,
body weight, response, and the past medical history of the patient.
Effective doses can be extrapolated from dose-response curves
derived from in vitro or animal model test systems.
[0125] In some embodiments, the dose comprises the ergoline
derivative in an amount:
[0126] between about 25 .mu.g and about 10 mg, preferably
[0127] between about any of: 25, 30, 35, 40, 45, 50, 75, 100, 125,
150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450,
475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775,
800, 825, 850, 875, 900, 925, 950, 975, and 1000 .mu.g (i.e., 1
mg); and any of: about 1000, 1250, 1500, 1750, 2000, 2250, 2500,
2750, 3000, 3250, 3500, 3750, 4000, 4250, 4500, 4750, 5000, 5250,
5500, 5750, 6000, 6250, 6500, 6750, 7000, 7250, 7500, 7750, 8000,
8250, 8500, 8750, 9000, 9250, 9500, 9750 .mu.g, and 10 mg; and more
preferably
[0128] between about 50 .mu.g and about 2000 .mu.g.
[0129] As used herein, the term "about" refers to a value that is
no more than 20% above or below the value being modified by the
term. For example, the term "about 4 mg" means a range of from 3.2
mg to 4.8 mg.
[0130] In certain embodiments, the ergoline derivative is
administered at a dosage described herein at least once a day, at
least once every other day, at least once every third day, at least
once every fourth day, or at least once every fifth day or more
days to treat or prevent a disorder associated with cephalic pain.
The ergoline derivative can thus be administered at a dose
described herein at least once a day, at least once every other
day, at least once every third day, at least once every fourth day,
or at least once every fifth day or more for at least one day, two
days, three days, four days, five days or more or at least once a
day, at least once every other day, at least once every third day,
at least once every fourth day, or at least once every fifth day or
more at least three times. In one embodiment, the ergoline
derivative is administered at least once a day for at least three
days. In another embodiment, the ergoline derivative is
administered at least once every fifth day three times. In yet
other embodiments, the subject to whom the ergoline derivative is
administered has not received a headache medication (e.g., has been
weaned off any headache medication that he or she was already
taking) for at least one day, two days, three days, four days, or
five days or more prior to administration of the ergoline
derivative.
[0131] In other embodiments, the dose of the ergoline derivative
administered to the subject is decreased over the course of
repeated administrations. In yet other embodiments, the dose of the
ergoline derivative administered to a subject is increased over the
course of repeated administrations.
[0132] In certain embodiments, the methods and formulations can be
practiced as a single, one time dose or chronically. By chronic it
is meant that the methods and compositions of the invention are
practiced more than once to a given subject or individual. For
example, chronic administration can be multiple doses of a
pharmaceutical composition administered to a subject, on a weekly
basis, a biweekly basis, monthly basis, or more or less frequently,
as will be apparent to those of skill in the art. Chronic
administration can continue for weeks, months, or years if
appropriate according to the judgment of the practitioner of skill
in the art. Furthermore, if certain doses, in the judgment of the
practitioner of skill in the art, show tolerability profiles which
may not be acceptable, the practitioner can reduce the dose to
reduce such profiles.
[0133] An effective amount of an ergoline derivative described
herein will provide therapeutic benefit without causing substantial
toxicity. Toxicity of an ergoline derivative can be determined by
standard pharmaceutical procedures in cell cultures or experimental
animals, for example, by determining the LD50 (the dose lethal to
50% of the population) or the LD100 (the dose lethal to 100% of the
population). The dose ratio between toxic and therapeutic effect is
the therapeutic index. Compounds which exhibit high therapeutic
indices are preferred. The data obtained from these cell culture
assays and animal studies can be used in formulating a dosage range
that is not toxic for use in human. The dosage of the compounds
described herein lies preferably within a range of circulating
concentrations that include the effective dose with little or no
toxicity. The dosage may vary within this range depending upon the
dosage form employed and the route of administration utilized. The
exact formulation, route of administration and dosage can be chosen
by the individual physician in view of the patient's condition.
(See, e.g., Fingl et al., 1996, In: The Pharmacological Basis of
Therapeutics, 9th ed., Chapter 2, p. 29, Elliot M. Ross)]
[0134] As used herein, "subject" refers to an animal such as a
mammal, including but not limited to, a primate (e.g., human), cow,
sheep, goat, horse, dog, cat, rabbit, rat, mouse and the like. In
preferred embodiments, the subject is human. In other preferred
embodiments, the subject is a human who is in need of treatment or
preventative therapy according to the present invention, e.g., a
human who has or who suffers from, or is susceptible to, a disorder
associated with cephalic pain. In another embodiment, the subject
is a human who has not received a headache medication for a certain
period of time (e.g., at least one day, at least two days, at least
three days, at least four days, at least five days or more) prior
to administration of the ergoline derivative. In yet other
embodiments, the subject is a human who has received a headache
medication prior to administration of the ergoline derivative but
in amounts less than that subject would normally take absent the
administration of the ergoline derivative.
[0135] For acute treatment of disorders associated with cephalic
pain, the ergoline derivatives can be administered to a subject in
need thereof in combination with a second compound or agent which
acutely relieves at least one symptom of such disorder. Examples of
such compounds or agents which acutely relieve at least one symptom
of a disorder associated with cephalic pain include gases, e.g.,
oxygen, serotonin receptor agonists (e.g., triptans such as
sumatriptan, eletriptan, rizatriptan, frovatriptan, almotriptan,
zolmitriptan, and naratriptan), ergot derivatives (e.g.,
dihydroergotamine, and ergotamine tartrate), hormones (e.g.,
corticosteroids (e.g., prednisone, cortisol), testosterone, growth
hormone, luteinizing hormone, somatostatin, and prolactin), and
local anesthetics (e.g., amino ester local anesthetics (e.g.,
benzocaine, chloroprocaine, cocaine, procaine, and
tetracaine/amethocaine), amino amide local anesthetics (e.g.,
bupivacaine levobupiva, lidocaine/lignocaine, mepivacaine,
prilocaine, ropivacaine, articaine, trimecaine, and combinations
thereof (e.g., lidocaine and prilocaine). Moreover, more than one
of these second compounds or agents can be administered to the
subject with the ergoline derivative in the methods of the
invention. Table I below provides a sample list of these compounds
or agents together with examples of dosages and routes of
administration that can be used in combination with the ergoline
derivatives described herein to treat disorders described herein,
e.g., especially to acutely treat a disorder described herein.
[0136] In one embodiment, the methods of the invention include
methods of treating disorders associated with cephalic pain, e.g.,
cluster headaches, by administering an ergoline derivative
described herein, e.g., a substantially pure form of an ergoline
derivative described herein, and by administering, as needed to
treat acute attacks of cephalic pain during the period in which the
ergoline derivative is being administered, a second compound or
agent (e.g., one or more of those agents listed in Table I) which
acutely relieves at least one symptom of such disorder. An example
of this method of treatment is when a subject is being treated with
three doses of LSA, e.g., a substantially pure form of LSA, or
2-bromo-LSD, e.g., a substantially pure form of 2-bromo-LSD, spaced
five days apart and to treat cephalic pain attacks that occur
during this treatment period, either inhaled oxygen or intranasal
lidocaine is also administered.
[0137] In another embodiment, the methods of the invention include
methods of treating disorders associated with cephalic pain, e.g.,
cluster headaches, by administering an ergoline derivative
described herein, e.g., a substantially pure form of an ergoline
derivative described herein, and by administering, after treatment
with the ergoline derivative has ended, a second compound or agent
(e.g., one or more of those agents listed in Table I) which acutely
relieves at least one symptom of such disorder. In this method, the
second compound or agent is used to treat "breakthrough" attacks
that can occur following a complete course of treatment with an
ergoline derivative.
TABLE-US-00001 TABLE I Compound Specific Route of Class Compound
Dose Administration Gas Oxygen (e.g., 7-12 L/minute Inhalation
(e.g. 100% oxygen) for 15-30 by facial mask) minutes Serotonin
Sumatriptan (a) 6 mg; or (a) Subcutanous receptor (b) 20 mg
injection; or (b) agonist nasal spray Zolmitriptan 5 mg or 10 mg
Nasal spray Ergot Dihydroergotamine 1 mg (2 sprays Nasal spray
derivative each nostril)- may repeat once, if needed
Dihydroergotamine 0.5-1.0 mg Intravenous or intramuscular injection
Ergotamine 1-2 mg (max. 6 Oral tablets mg/day) Local Lidocaine 4
sprays (e.g., Nasal spray anesthetic (e.g., 4-6%)
ipsilaterally)
[0138] In some embodiments, the methods of the invention include
methods for treating a disorder associated with cephalic pain by
administering a therapeutically effective amount of the ergoline
derivative in combination with a therapeutically effective amount
of an opioid receptor antagonist to a subject in need of such
treatment.
[0139] As used herein, the term "opioid receptor antagonist" refers
to a compound which binds to an opioid receptor but which does not
elicit a biological response by binding to the receptor. Opioid
receptor antagonists can bind to one or more (and in any
combination) of the opioid receptors (e.g., delta, kappa, or mu and
their subclasses). Examples of opioid receptor antagonists that can
be used according to the methods of the invention include naloxone
(e.g., naloxone hydrochloride) and naltrexone (e.g., naltrexone
hydrochloride). In some embodiments, the opioid receptor antagonist
is administered to the subject prior to (e.g., immediately prior
to, e.g, within minutes or hours of) or concurrently with
administration of the ergoline derivatives described herein. In
some embodiments, the opioid receptor antagonist is administered to
a subject after (e.g., immediately after, e.g., within minutes or
hours after) the ergoline derivatives described herein. In other
embodiments, the use of the opioid receptor antagonist increases
the potency of the ergoline derivative and can decrease waiting
periods between doses of the ergoline derivative. For example,
instead of taking 0.5 mg of LSA every five days for three doses,
the subject will be able to take 0.1 mg of LSA combined with 50 mg
or less of naltrexone every day for three days with the same
effect. Thus, use of an opioid receptor antagonist in combination
with an ergoline derivative described herein to treat or prevent
the disorders described herein allows the use of a lesser dose of
the ergoline derivative to achieve the same result.
[0140] In one embodiment, the opioid receptor antagonist is
naloxone which can be administered, for example, either
transmucosally (e.g., sublingually, e.g., in tablet form),
intravenously, subcutaneously, or orally. For intravenous
administration, naloxone can be administered at a dose of between
about 0.1 mg and about 2 mg every 2 to 3 minutes as needed. In
another embodiment, the opioid receptor antagonist is naltrexone
hydrochloride which can be administered, for example, orally (in
tablet form) at a dose of between about 5 mg and about 125 mg,
preferably of between about 25 mg and 100 mg, and most preferably
at about 50 mg.
[0141] The invention is also directed to methods for preventing a
disorder associated with cephalic pain in a subject in need thereof
which comprise administering to the subject, during a period in
which the subject is not suffering from cephalic pain, a
therapeutically effective amount of an ergoline derivative, alone
or in combination with another preventative or therapeutic compound
such as a mood stabilizer, e.g., lithium, a hormone, e.g.,
melatonin, a calcium channel blocker, a hormone, an anticonvulsant
agent, an opioid receptor antagonist, a vanilloid, and a sedative
(e.g., prochlorperzine). For example, lithium can be administered
orally either twice a day or dialing in an extended release
formulation. Melatonin can be administered orally daily. Calcium
channel blockers can be administered orally up to three times a
day. Vanilloids, e.g., capsaicin, can be administered by placing a
cotton swab in the nostril during an acute cephalic pain attack.
Hormones such as dihydroepiandrosterone (DHEA) can be administered
in the form of a nasal spray during an acute cephalic pain attack.
Sedatives can also be administered during an acute attack of
cephalic pain.
[0142] As used herein, "preventing" or "prevention" of any disease
or disorder refers to a reduction in the risk of acquiring a
disease, disorder, or condition (i.e., causing at least one of the
clinical symptoms of the disease or disorder not to develop in a
subject who may be predisposed or susceptible to the disease or
disorder or who already suffers from the disease or disorder but
who is in a remission period). In one embodiment, the subject does
not yet experience or display symptoms of the disease or disorder.
In another embodiment, the subject has or suffers from a disorder
associated with cephalic pain but is not, at the time of
administration of the ergoline derivative, alone or in combination
with another compound described herein, experiencing cephalic pain,
e.g., the subject is in a remission period (i.e., a period during
which the symptoms of the disease, disorder, or condition have
abated or subsided) from the cephalic pain. Preferably, the terms
preventing and prevention refer to the use of a compound or
composition in a subject who is in remission from the disorder and,
when the subject is treated according to the prevention methods
described herein, the remission period is extended. Table II below
provides a sample list of compounds or agents together with
examples of dosages and routes of administration that can be used
in combination with the ergoline derivatives described herein to
prevent disorders described herein.
TABLE-US-00002 TABLE II Route of Specific Adminis- Compound Class
Compound Dose tration Calcium channel Verapamil 360-720 mg/d oral
blocker Corticosteroid Prednisone 60-80 mg/d oral Mood stabilizer
Lithium 300-1200 mg/d oral Anti-convulsant Valproic acid 1000-1250
mg/d oral Topiramate 50-200 mg/d oral Gabapentin 300-900 mg/d oral
Hormone Melatonin 3-10 mg/nightly oral Vanilloid Capsaicin Place
via cotton intranasal (0.025% swab in nostril for 7 d cream)
[0143] In other embodiments, the methods of the invention include
administering both an ergoline derivative, e.g., LSA, e.g., LSA in
substantially pure form, e.g., 2-bromo-LSD, e.g., a substantially
pure form of 2-bromo-LSD, with a leukotriene antagonist drug to a
treat or prevent a disorder described herein. In other embodiments,
the methods of the invention include administering both the
ergoline derivative, e.g., LSA, e.g., LSA in substantially pure
form, e.g., 2-bromo-LSD, e.g., a substantially pure form of
2-bromo-LSD, with a non-steroidal anti-inflammatory drug (NSAID),
e.g., naproxen, flurbiprofen, ketoprofen, oxaprozin, etodolac,
indomethacain, ketorolac, nabumetone, mefanamic acid, and
piroxican, a COX-2 inhibitor (e.g., celecoxib, rofecoxib,
meloxicam) to a treat or prevent a disorder described herein. A
preferred COX-2 inhibitor is celecoxib which can be used at a dose
of between 50 and 500 mg. In one embodiment, the ergoline
derivative, e.g., LSA, 2-bromo-LSD, and the NSAID are used together
with a serotonin receptor agonist to treat or prevent a disorder
described herein. In other embodiments, the methods of the
invention include administering both the ergoline derivative, e.g.,
LSA, 2-bromo-LSD, and an antipsychotic drug to treat or prevent a
disorder described herein. In yet other embodiments, the methods of
the invention include administering both the ergoline derivative,
e.g., LSA, 2-bromo-LSD, and a B vitamin, e.g., riboflavin and/or
niacin, to a treat or prevent a disorder described herein.
[0144] All publications, patents and patent applications cited in
this specification are herein incorporated by reference as if each
individual publication or patent application were specifically and
individually indicated to be incorporated by reference. Although
the foregoing invention has been described in some detail by way of
illustration and example for purposes of clarity of understanding,
it will be readily apparent to those of ordinary skill in the art
in light of the teachings of this invention that certain changes
and modifications may be made thereto without departing from the
spirit or scope of the appended claims.
* * * * *
References