What is claimed is:
1. A method of regulating a neurotransmitter system by inducing a
counteradaptation in a
patient, the neurotransmitter system including a type of receptor, the method
comprising:
repeatedly administering to the patient a ligand for the type of receptor,
each
administration having an administration half-life, thereby causing the ligand
to bind
receptors of that type during a first time period associated with each
administration, thereby
inducing, maintaining or improving a counteradaptation,
wherein the counteradaptation causes the regulation of the neurotransmitter
system,
and
wherein the ratio of the administration half-life to the period between
administrations is no greater than 1/2.
2. The method of claim 1, wherein before the ligand is repeatedly administered
to the
patient, a counteradaptation is induced by giving the patient a ligand for the
type of
receptor, and the repeated administration of the ligand maintains or improves
the
counteradaptation.
3. The method of claim 1 or claim 2, wherein the regulation of the
neurotransmitter system
causes a therapeutic benefit with respect to an undesirable mental,
neurological or
physiological condition linked to the type of receptor.
4. The method of any one of claims 1-3, wherein the ligand is an agonist for
receptors of
the type of receptor, and the regulation is a down-regulation of the
neurotransmitter system.
5. The method of claim 4, wherein an undesirable mental, neurological or
physiological
condition is positively linked to the type of receptor.
6. The method of any one of claims 4-5, wherein the counteradaptation is at
least one of
a decrease in the biosynthesis or release of a neurotransmitter binding to
receptors
of the type of receptor;
an increase in the reuptake of a neurotransmitter binding to receptors of the
type of
receptor;
86
a decrease in the number of the type of receptors and/or binding sites on
receptors
of the type of receptor; and
a decrease in the sensitivity of receptors of the type of receptor to binding
by
natural neurotransmitter and/or receptor agonists.
7. The method of any one of claims 4-6, wherein an antagonist for receptors of
the type of
receptor is not administered during the first time period associated with each
administration.
8. The method of any one of claims 4-7, wherein each administration has a
second time
period associated therewith, the second time period being subsequent to the
first time
period associated with the administration, and wherein an antagonist for
receptors of the
type of receptor is administered during one or more of the second time
periods.
9. The method of any one of claims 1-3, wherein the ligand is an antagonist
for receptors
of the type of receptor, and the regulation is an up-regulation of the
neurotransmitter
system.
10. The method of claim 9, wherein an undesirable mental, neurological or
physiological
condition is negatively linked to the type of receptor.
11. The method of claim 9 or claim 10, wherein the counteradaptation is at
least one of:
an increase in the biosynthesis or release of a neurotransmitter binding to
receptors
of the type of receptor;
a decrease in the reuptake of a neurotransmitter binding to receptors of the
type of
receptor;
an increase in the number of the type of receptors and/or binding sites on
receptors
of the type of receptors; and
an increase in the sensitivity of the receptors to binding by ligands and/or
receptor
agonists.
12. The method of any one of claims 9-11, wherein an agonist for receptors of
the type of
receptor is not administered during the first time period associated with each
administration.
87
13. The method of any one of claims 9-12, wherein each administration has a
second time
period associated therewith, the second time period being subsequent to the
first time
period associated with the administration, and wherein an agonist for
receptors of the type
of receptor is administered during one or more of the second time periods.
14. The method of any one of claims 1-13, wherein a substantial fraction of
the receptors
of the type of receptor are bound by the ligand during each first time period.
15. The method of claim 14, wherein at least about 30% of the receptors are
bound by the
ligand during each first time period.
16. The method of claim 14, wherein at least about 50% of the receptors are
bound by the
ligand during each first time period.
17. The method of claim 14, wherein at least about 75% of the receptors are
bound by the
ligand during each first time period.
18. The method of claim 14, wherein at least about 90% of the receptors are
bound by the
ligand during each first time period.
19. The method of any one of claims 1-18, wherein each first time period is at
least about
five minutes in duration.
20. The method of any one of claims 1-18, wherein each first time period is at
least about
thirty minutes in duration.
21. The method of any one of claims 1-18, wherein each first time period is at
least about
an hour in duration.
22. The method of any one of claims 1-18, wherein each first time period is at
least about
two hours in duration.
88
23. The method of any one of claims 1-18, wherein each first time period is at
least about
four hours in duration.
24. The method of any one of claims 1-23, wherein each first time period is
less than about
twenty four hours in duration
25. The method of any one of claims 1-23, wherein each first time period is
less than about
sixteen hours in duration.
26. The method of any one of claims 1-23, wherein each first time period is
less than about
twelve hours in duration.
27. The method of any one of claims 1-23, wherein each first time period is
less than about
eight hours in duration
28. The method of any one of claims 1-23, wherein each first time period is
less than about
six hours in duration.
29. The method of any one of claims 1-28, wherein each administration has a
second time
period associated therewith, the second time period being subsequent to the
first time
period associated with the administration, and wherein a substantial fraction
of the
receptors remain unbound to the ligand during each second time period.
30. The method of claim 29, wherein no more than about 50% of the receptors
are bound
to the ligand during each second time period.
31. The method of claim 29, wherein no more than about 25% of the receptors
are bound
to the ligand during each second time period.
32. The method of claim 29, wherein no no more than about 10% of the receptors
are
bound to the ligand during each second time period.
33. The method of any one of claims 13-18 or 29-32, wherein each second time
period is
at least about two hours in duration.
89
34. The method of any one of claims 13-18 or 29-32, wherein each second time
period is
at least about ten hours in duration.
35. The method of any one of claims 13-18 or 29-32, wherein each second time
period is
at least about fifteen hours in duration.
36. The method of any one of claims 13-18 or 29-32, wherein each second time
period is
no more than about twenty hours in duration.
37. The method of any one of claims 13-18 or 29-32, wherein each second time
period is
no more than about thirty hours in duration.
38. The method of any one of claims 13-18 or 29-32, wherein each second time
period is
no more than about fifty hours in duration.
39. The method of any one of claims 1-39, wherein the ratio of the
administration half-life
to the period between administrations is no greater than 1/3.
40. The method of any one of claims 1-39, wherein the ratio of the
administration half-life
of the ligand to the period between administrations is no greater than 1/5.
41. The method of any one of claims 1-39, wherein the ratio of the
administration half-life
of the ligand to the period between administrations is no greater than 1/8.
42. The method of any one of claims 1-39, wherein the ratio of the
administration half-life
of the ligand to the period between administrations is no greater than 1/12.
43. The method of any one of claims 1-42, wherein the ratio of the
administration half-life
of the ligand to the period between administrations is greater than 1/24.
44. The method of any one of claims 1-42, wherein the ratio of the
administration half-life
of the ligand to the period between administrations is greater than 1/12.
45. The method of any one of claims 1-42, wherein the ratio of the
administration half-life
of the ligand to the period between administrations is greater than 1/8.
46. The method of any one of claims 1-42, wherein the ratio of the
administration half-life
of the ligand to the period between administrations is greater than 1/5.
47. The method of any one of claims 1-42, wherein the ratio of the
administration half-life
of the ligand to the period between administrations is greater than 1/4.
48. The method of any one of claims 1-42, wherein the ratio of the
administration half-life
of the ligand to the period between administrationsis greater than 1/3.
49. The method of any one of claims 1-48, wherein the dose of ligand at each
administration is increased over time.
50. The method of any one of claims 1-49, wherein the dose of ligand at each
administration is increased intermittently over time.
51. The method of claim 50, wherein the dose is increased with a period
between increases
of no less than a week.
52. The method of claim 50, wherein the dose is increased with a period
between increases
of no less than two weeks.
53. The method of claim 50, wherein the dose is increased with a period
between increases
of no less than three weeks.
54. The method of claim 50, wherein the dose is increased with a period
between increases
of no less than a month.
55. The method of claim 50, wherein the dose is increased with a period
between increases
of no less than two months.
91
56. The method of claim 50, wherein the dose is increased with a period
between increases
of no less than three months.
57. The method of claim 50, wherein the dose is increased with a period
between increases
of no less than six months.
58. The method of claim 50, wherein the dose is increased with a period
between increases
of no less than one year.
59. The method of any one of claims 50-58, wherein at each increase in dosage,
the dose is
increased by at least 5% of the initial dose.
60. The method of any one of claims 50-58, wherein at each increase in dosage,
the dose is
increased by at least 10% of the initial dose.
61. The method of any one of claims 50-58, wherein at each increase in dosage,
the dose is
increased by at least 25% of the initial dose.
62. The method of any one of claims 50-58, wherein at each increase in dosage,
the dose is
increased by at least 50% of the initial dose.
63. The method of any one of claims 50-58, wherein at each increase in dosage,
the dose is
increased by at least 100% of the initial dose.
64. The method of any one of claims 50-63, wherein the maximum dosage is
within three
hundred times the initial dosage.
65. The method of any one of claims 50-63, wherein the maximum dosage is
within one
hundred times the initial dosage.
66. The method of any one of claims 50-63, wherein the maximum dosage is
within fifty
times the initial dosage.
92
67. The method of any one of claims 50-63, wherein the maximum dosage is
within
twenty times the initial dosage.
68. The method of any one of claims 1-67, wherein the administration of the
ligand is
performed daily.
69. The method of any one of claims 1-68, wherein the period between
administrations is
two days or greater.
70. The method of any one of claims 1-68, wherein the period between
administrations is
three days or greater.
71. The method of any one of claims 1-68, wherein the period between
administrations is
five days or greater.
72. The method of any one of claims 1-68, wherein the period between
administrations is
one week or greater.
73. The method of any one of claims 1-68, wherein the period between
administrations is
two weeks or greater.
74. The method of any one of claims 1-68, wherein the period between
administrations is
one month or greater.
75. The method of any one of claims 1-74, wherein the administration half-life
is less than
about sixteen hours.
76. The method of any one of claims 1-74, wherein the administration half-life
is less than
about twelve hours.
77. The method of any one of claims 1-74, wherein the administration half-life
is less than
about eight hours.
93
78. The method of any one of claims 1-74, wherein the administration half-life
is less than
about four hours.
79. The method of any one of claims 1-78, wherein the administration half-life
is greater
than about four hours.
80. The method of any one of claims 1-78, wherein the administration half-life
is greater
than about twelve hours.
81. The method of any one of claims 1-78, wherein the administration half-life
is greater
than about sixteen hours.
82. The method of any one of claims 1-78, wherein the administration half-life
is greater
than about thirty hours.
83. The method of any one of claims 1-82, wherein the compound half-life of
the ligand is
less than about sixteen hours.
84. The method of any one of claims 1-82, wherein the compound half-life of
the ligand is
less than about twelve hours.
85. The method of any one of claims 1-82, wherein the compound half-life of
the ligand is
less than about eight hours.
86. The method of any one of claims 1-82, wherein the compound half-life of
the ligand is
less than about four hours.
87. The method of any one of claims 1-86, wherein the compound half-life of
the ligand is
greater than about four hours.
88. The method of any one of claims 1-86, wherein the compound half-life of
the ligand is
greater than about sixteen hours.
94
89. The method of any one of claims 1-86, wherein the compound half-life of
the ligand is
greater than about thirty hours.
90. The method of any one of claims 1-86, wherein the compound half-life of
the ligand is
greater than about twelve hours.
91. The method of claim 90, wherein the compound half-life of the ligand is
greater than
about twelve hours, and wherein the method further comprises the step of
administering repeatedly and with a period of less than every two days a
second
ligand for the type of receptor, each administration of the second ligand
having an
administration half-life of less than about eight hours.
92. The method of claim 91, wherein the ligand having the compound half-life
greater than
about twelve hours is an agonist, and the second ligand is an agonist.
93. The method of claim 91, wherein the ligand having the compound half-life
greater than
about twelve hours is an antagonist, and the second ligand is an antagonist.
94. The method of any one of claims 1-93, wherein the administration is
repeated at least
five times.
95. The method of any one of claims 1-93, wherein the administration is
repeated at least
ten times.
96. The method of any one of claims 1-93, wherein the administration is
repeated at least
twenty-five times.
97. The method of any one of claims 1-93, wherein the administration is
repeated at least
fifty times.
98. The method of any one of claims 1-97, wherein the dose of the ligand is
sufficient to
trigger a counteradaptive response, but low enough that direct effects of
ligand-receptor
binding are low and tolerable to the patient.
99. The method of any one of claims 1-98, wherein a substantial fraction of
the first time
period occurs while the patient is asleep.
100. The method of any one of claims 1-99, wherein at least 40% of the first
time period
occurs while the patient is asleep.
101. The method of any one of claims 1-99, wherein at least 60% of the first
time period
occurs while the patient is asleep.
102. The method of any one of claims 1-99, wherein at least 85% of the first
time period
occurs while the patient is asleep.
103. The method of any one of claims 1-102, wherein each administration of the
ligand is
performed within the hour before the patient goes to bed.
104. The method of any one of claims 1-102, wherein each administration of the
ligand is
performed more than one hour before the patient goes to bed.
105. The method of any one of claims 1-104, wherein each administration of the
ligand is
performed orally, transdermally, through inhalation, subcutaneously,
intravenously,
intramuscularly, intraspinally, intrathecally, transmucosally, or using an
osmotic pump, a
microcapsule, an implant or a suspension.
106. The method of any one of claims 1-105, further comprising the step of:
administering an anxiolytic agent in combination with the ligand.
107. The method of claim 106, wherein the anxiolytic agent affects a GABA
pathway.
108. The method of claim 106, wherein the anxiolytic agent is a
benzodiazepine.
109. The method of claim 108, wherein the benzodiazepine is selected from the
group
consisting of diazepam, lorazepam, alprazolam, temazepam, flurazepam, and
chlodiazepoxide.
96
110. The method of any one of claims 1-109, further comprising the step of:
administering a hypnotic agent in combination with the ligand.
111. The method of any one of claims 1-110, further comprising the step of:
administering in combination with the ligand a compound selected from the
group
consisting of a TCA, an MAOI, an SSRI, an NRI, an SNRI, a CRF modulating
agent, a
serotonin pre-synaptic autoreceptor antagonist, 5HT1 agonist, a dynorphin
antagonist, a
GABA-A modulating agent, a serotonin 5H2C and/or 5H2B modulating agent, a beta-
3
adrenoceptor agonist, an NMDA antagonist, a V1B antagonist, a GPCR modulating
agent,
and a substance P antagonist.
112. The method according to claim 111 wherein the compound is selected from
the
group consisting of fluoxetine, paroxetine, sertraline, fluvoxamine,
citalopram,
escitalopram, venlafaxine and reboxetine.
113. The method of any one of claims 1-112, further comprising the step of
administering autoimmune therapy in combination with the ligand during the
first
time period.
114. The method of claim 113 wherein the autoimmune therapy is selected from
the group
consisting of corticosteroids, chlorambucil, cyclosporine, cyclophosphamide,
methotrexatate, azathioprine, TNF.alpha. antagonists, systemic enzyme therapy,
gene therapy,
irradiation therapy.
115. The method of claim 113, wherein the autoimmune medication is not
administered
during the second time period.
116. The method of any one of claims 1-112, further comprising the step of
administering an antiviral agent in combination with the ligand during the
first time
period.
117. The method of claim 116, wherein the antiviral agent is selected from the
group
consisting of interferon, ribavirin, protease inhibitors, amantadine,
rimantadine, pleconaril,
antibodies (monoclonal, anti-VAP, receptor anti-idiotypic, extraneous receptor
and
97
synthetic receptor mimics), acyclovir, zidovudine (AZT), lamivudine, RNAase H
inhibitors, integrase inhibitors, attachment blockers of transcription factors
to viral DNA,
antisense molecules, synthetic ribozymes, zanamivir, and osletamivir.
118. The method of claim 116, wherein the autoimmune medication is not
administered
during the second time period.
119. The method of any one of claims 1-112, further comprising the step of
administering an antimicrobial agent in combination with the ligand during the
first
time period.
120. The method of claim 119, wherein the antimicrobial agent is not
administered during
the second time period.
121. The method of any one of claims 1-112, further comprising the step of
administering an antifungal agent in combination with the ligand during the
first
time period.
122. The method of claim 121, wherein the antimicrobial agent is not
administered during
the second time period.
123. The method of any one of claims 1-112, further comprising the step of:
administering an antineoplastic agent in combination with the ligand during
the first
time period.
124. The method of claim 123, wherein the antineoplastic agent is not
administered during
the second time period.
125. The method of any one of claims 1-112, further comprising the step of
administering
an anti-cancer agent in combination with the ligand during the first time
period.
126. The method of claim 125, wherein the anti-cancer agent is not
administered during
the second time period.
98
127. The method of claim 125 or claim 126, wherein the anti-cancer agent is
selected from
the group consisting of adriamycin, busulfan, carboplatin, chlorambucil,
cisplatin,
cyclophosphamide, ifosfamide, mechlorethamine, melphalan, procarbazine,
temozolamide,
daunorubicin, doxorubicin, idarubicin, bleomycin, mitomycin, mitoxantrone,
plicamycin,
cytarabine fluorouracil, hydroxyurea, methotrexate, asparaginase,
pegaspargase, irinotecan,
topotecan, bicalutamide, estramustine, flutamide, leuprolide, megestrol,
nilutamide,
testosterone, triptorelin, anastrazole, letrozole, aldesleukin, alemtuzumab,
gemtuzumab,
toremifene, trastuzumab, etoposide, docetaxel, paclitaxel, vinblastine,
vincristine,
vinorelbine, altretamine, Erlotinib, gleevec, curcumin, tamoxifen, bortezomib,
gefitinib,
imatinib, cancer cell growth inhibitors derived from 3,4-methylenedioxy-5,4'-
dimethoxy-
3'-amino-Z-stilbene, hydroxyphenstatin and its sodium diphosphate prodrug,
histone
deacetylase inhibitors, suberoylanilide hydroxamic acid, trichostatin A,
sodium butyrate,
metformin, five-lipoxygenase (5-LO) antagonists, antisense oligonucleotides
targeting the
RI.alpha. regulatory subunit of protein kinase A type I, Vitamin E and its
analogs, vitamin E
succinate (VES), and gene therapy.
128. The method of any one of claims 1-127, wherein
the neurotransmitter system is the SP system;
the type of receptor is SP receptors;
the ligand is an SP receptor agonist; and
the counteradaptation causes a down-regulation of the SP system.
129. The method of claim 128, wherein the counteradaptation is at least one
of:
a decrease in the biosynthesis or release of SP, NKA, and/or NKB at the
receptor
terminals or by the pituitary gland;
a decrease in the number of the receptors and/or binding sites on the
receptors; and
a decrease in the sensitivity of the receptors to binding by SP receptor
agonists
and/or SP, NKA, and/or NKB.
130. The method of any one of claims 128-129, wherein the SP receptor agonist
is peptide-
based.
99
131. The method of any one of claims 128-129, wherein the SP receptor agonist
is an
analogue of SP, NKA, and/or NKB, or a pharmaceutically-accepted salt or
derivative
thereof.
132. The method of any one of claims 128-129, wherein the SP receptor agonist
is
Substance P; Substance P, free acid; Biotin-Substance P; [Cys3,6, Tyr8, Pro9]-
Substance P;
(Disulfide bridge: 3-6), [Cys3,6, Tyr8, Pro1o]-Substance P; (Disulfide bridge:
3-6), [4-
Chloro-Phe7,8]-Substance P; [4-Benzoyl-Phe8]-Substance P; [Succinyl-Asp6, N-Me-
Phe8]-
Substance P (6-11)(Senktide); [Tyr8]-Substance P; [Tyr9]-Substance P; or Shark
Substance
P Peptide.
133. The method of any one of claims 128-129, wherein the SP receptor agonist
is an
NKA or NKB analogue having a C-terminal heptapeptide similar to NKA(4-10) or
NKB
(4-10), or a pharmaceutically acceptable salt or carrier thereof.
134. The method of any one of claims 128-129, wherein the SP receptor agonist
is
[Gln4]-NKA, [GlN4]-NKA(4-10), [Phe 7]-NKA, [Phe7]-NKA(4-10), [Ile7]-NKA,
[Ile7]-
NKA(4-10), [Lys5,MeLeu9,Nle10]-NKA(4-10), [Nle10]-NKA(4-10), .beta.-Ala8]-
NKA(4-10),
[Ala5]-NKA(4-10), [Gln4]-NKB, [GlN4]-NKB(4-10), [Phe-7]-NKB, [Phe7]-NKB(4-10),
[Ile7]-NKB, [Ile7]-NKB(4-10), [Lys5 ,MeLeu9,N1e10]-NKB(4-10), [N1e10]-NKB(4-
10), .beta.-
Ala8]-NKB(4-10), [Ala5] NKB(4-10), GR 73,632 [delta-Aminovaleryl [Pro9, N-Me-
Leu10]-substance P(7-11)], [Glu(OBz1)11]substance P and hemokinin 1(HK-1) (a
substance P homolog) or a pharmaceutically acceptable salt or carrier thereof.
135. The method of any one of claims 128-129, wherein the SP receptor agonist
is [Arg]-
NKB or a pharmaceutically acceptable salt or carrier thereof.
136. The method of any one of claims 128-129, wherein the SP receptor agonist
is an
NKA or NKB analogue having Val7 replaced with MePhe or a pharmaceutically
acceptable
salt or carrier thereof.
137. The method of any one of claims 128-136, wherein the initial dosage of
the SP
receptor agonist is about 0.1 to 100 µg/kg/day initial dose and 100 to 1000
gg/kg/day for 8
hours slow release.
100
138. The method of any one of claims 128-136, wherein the initial dosage of
the SP
receptor agonist is between about 1 to 50 µg/kg/day initial dose and 20 to
50 g/kg/day for
8 hours slow release.
139. The method of any one of claims 128-138, wherein the method is used to
address an
undesirable mental, neurological or physiological condition in a patient.
140. The method of claim 139, wherein the undesirable mental, neurological or
physiological condition is chronic pain, a mood disorder, an eating disorder,
an anxiety
disorder, a motivational problem, a substance abuse disorder, an inflammatory
condition,
nausea or emesis, urinary incontinence, skin rashes, erythema, or eruptions.
141. The method of claim 139, wherein the undesirable mental, neurological or
physiological condition is fibromyalgia, chronic fatigue syndrome, chronic
back pain,
chronic headaches, chronic cancer pain, shingles, reflex sympathetic
dystrophy,
neuropathy, or inflammatory pain.
142. The method of claim 139, wherein the undesirable mental, neurological or
physiological condition is pain that is anticipated to occur in the future.
143. The method of claim 141, wherein the pain anticipated to occur in the
future is pain
from a medical procedure, or pain due to physical exertion.
144. The method of claim 139, wherein the undesirable mental, neurological or
physiological condition is a major depressive disorder, post-traumatic
depression,
temporary depressed mood, manic-depressive disorder, dysthymic disorder,
generalized
mood disorder, anhedonia, or non-organic sexual disfunction.
145. The method of claim 139, wherein the undesirable mental, neurological or
physiological condition is overeating, obesity, anorexia or bulimia.
146. The method of claim 139, wherein the undesirable mental, neurological or
physiological condition is a generalized anxiety state, a panic disorder, a
phobia, obsessive-
101
compulsive disorder, attention deficit hyperactivity disorder, Tourette's
Syndrome, a
hysteria sleep disorder, or a breathing-related sleep disorder.
147. The method of claim 139, wherein the undesirable mental, neurological or
physiological condition is a lack of motivation due to learning or memory
problems.
148. The method of claim 139, wherein the undesirable mental, neurological or
physiological condition is abuse of a substance selected from the group
consisting of
narcotics, alcohol, nicotine, stimulants, anxiolytics, CNS depressants,
hallucinogens and
marijuana.
149. The method of claim 139, wherein the undesirable mental, neurological or
physiological condition is asthma, arthritis, rhinitis, conjunctivitis,
inflammatory bowel
disease, inflammation of the skin or mucosa, or acute pancreatitis.
150. The method of claim 139, wherein the undesirable mental, neurological or
physiological condition is nausea or emesis arising from chemotherapy.
151. The method of any one of claims 128-150, wherein the method is used as an
adjunct
treatment for cancer.
152. The method of any one of claims 128-151, wherein an SP receptor
antagonist is not
administered during the first time period associated with each administration.
153. The method of any one of claims 128-152, wherein an SP receptor
antagonist is
administered during one or more of the second time periods.
154. The method of claim 153, wherein the SP receptor antagonist is SR 48968,
L-
760735, CP-96,345, NKP608, L-AT, MK-869, L-742,694, L-733060, CP-99,994,
P-122,721, CP 122,171, GSK 597599, GSK 679769, GSK 823296, Saredutant,
Talnetant,
Osanetant, and pharmaceutically acceptable salts, analogues, and derivatives
thereof.
155. The method of claim 154, wherein initial dosage of SP receptor antagonist
is
equivalent to 12 mg/kg/hour for 8 hours of L-760735; about 30 gg/kg/hour of CP-
96,345;
102
0.1 to 10 mg/kg/administration of SSR240600; 0.01 to 0.1 mg/kg/administration
of
NKP608; 1 to 10 mg/kg/administration of L-AT; 0.01 to 3 mg/kg/administration
of MK-
869; 1 to 30 mg/kg of L-742,694; 1 to 10 mg/kg/administration of L-733,060; 3
to 30
mg/kg/administration of CP-99,994 or CP-122,721; and about 100
mg/administration of
Saredutant.
156. The method of any one of claims 128-155, wherein the down-regulation of
the SP
system causes a therapeutic benefit with respect to an undesirable mental,
neurological or
physiological condition.
157. The method of any one of claims 1-127, wherein
the neurotransmitter system is the endogenous endorphin system;
the type of receptor is mu and/or delta opiate receptors;
the ligand is a mu and/or delta opiate receptor antagonist; and
the counteradaptation causes an up-regulation of the endogenous endorphin
system.
158. The method of claim 157, wherein the counteradaptation is at least one
of:
an increase in the biosynthesis or release of endorphins at receptor terminals
and/or
by the pituitary gland;
an increase in the number of the receptors and/or endorphin binding sites on
the
receptors; and
an increase in the sensitivity of the receptors to binding by mu and/or delta
opiate
agonists and/or endorphins.
159. The method of any one of claims 157-158, wherein the counteradaptation is
at least
one of:
an increase in the biosynthesis or release of endorphins at receptor terminals
and by
the pituitary gland; and
an increase in the number of the receptors and/or endorphin binding sites on
the
receptors.
160. The method of any one of claims 157-159, wherein the mu and/or delta
opiate
receptor antagonist is a specific mu receptor antagonist or a specific delta
receptor
antagonist.
103
161. The method of any one of claims 157-159, wherein the mu and/or delta
opiate
receptor antagonist is a specific mu opiate receptor antagonist selected from
the group
consisting of clocinnamox mesylate, CTAP, CTOP, etonitazenyl isothiocyanate,
.beta.-
funaltrexamine hydrochloride, naloxonazine dihydrochloride, Cyprodime, and
pharmaceutically acceptable salts, analogues, and derivatives thereof.
162. The method of any one of claims 157-159, wherein the mu and/or delta
opiate
receptor antagonist is a specific delta opiate receptor antagonist selected
from the group
consisting of naltrindole, N-benzylnaltrindole HCI, BNTX maleate, ICI-154,129,
ICI-
174,864, naltriben mesylate, SDM25N HCI, 7-benzylidenenaltrexone, and
pharmaceutically acceptable salts, analogues, and derivatives thereof.
163. The method of any one of claims 157-159, wherein the mu and/or delta
opiate
receptor antagonist is a non-specific opiate antagonist.
164. The method of any one of claims 157-159, wherein the mu and/or delta
opiate
receptor antagonist is naloxone, naltrexone, nalmefene, or nalbuphine, or a
pharmaceutically acceptable salt or derivative thereof.
165. The method according to any one of claims 157-159, wherein the delta
opiate
receptor antagonist is a compound having the structure
<IMG>
wherein
R is allyl, methylallyl, cyclopropylmethyl, dimethylallyl, tetrahodrofurfuryl
or
cyclobutylmethyl;
R1 is H, (C1-C18 hydrocarbyl)-, (C1-C18 hydrocarbyl)-CO-, (C1-C18
hydrocarbyl)2N-CO-
,(C1-C18 hydrocarbyl)-SO2-, (C1-C18 hydrocarbyl)-O-CO-, Ph-CO-, Ph-SO2-, Ph-
NH-CO, wherein each Ph is optionally substituted with one or more substituents
104
independently selected from the group consisting of (C1-C12 hydrocarbyl), (C1-
C12
hydrocarbyl)-O-, Cl, F, Br, I, CF3, R4O-, and R42N-, in which each R4 is
independently selected from the group consisting of H, (C1-C4 alkyl), H-CO-
and
(C1-C4 alkyl)-CO-;
each R2a and R2b is independently selected from the group consisting of H, (C1-
C6
alkyl), (C1-C6 alkyl)-O-, (C1-C6 alkyl)-CO-O-, R5-O-, R5 2N-, R5-CO-NH-, R5 -S-
,
and NO2, in which each R5 is independently selected from the group consisting
of
H, (C1-C6 alkyl), (C3-C10 cycloalkyl), (C6-C10 aryl), (C1-C6 alkyl)-CO-, (C3-
C10
cycloalkyl)-CO-, (C6-C10 aryl)-CO-, each of which is optionally substituted
with 1-
3 substituents selected from the group consisting of (C1-C12 hydrocarbyl), (C1-
C12
hydrocarbyl)-O-, Cl, F, Br, I, CF3, R4O-, and R4 2N-; or R2a and R2b together
form
O= or CH2=; and
R3 is H, OH, CH3 or OCH3,
or an N-oxide or pharmaceutically acceptable salt thereof.
166. The method of claim 165, wherein R is allyl.
167. The method of claim 165 or claim 166, wherein R1 is not H.
168. The method of claim 165 or claim 166, wherein R1 is o-aminobenzoyl or o-
(acetyloxy)benzoyl.
169. The method of claim 165 or claim 166, wherein R1 is(C1-C18 alkyl) or (C1-
C18
alkyl)CO-.
170. The method of claim 165 or claim 166, wherein R1 is (C1-C6 alkyl)CO-.
171. The method of any one of claims 165-170, wherein R2a and R2b together do
not make
O =.
172. The method of any one of claims 165-170, wherein R2a and R2b are H, or
together
form CH2=.
173. The method of any one of claims 165-172, wherein R3 is not OH.
105
174. The method of any one of claims 161-173, wherein the initial dosage of
the mu
and/or delta opiate receptor antagonist is equivalent to between about 2
mg/administration
and about 200 mg/administration of naloxone.
175. The method of any one of claims 161-173, wherein the initial dosage of
the mu
and/or delta opiate receptor antagonist is equivalent to between about 10
mg/administration
and about 100 mg/administration of naloxone.
176. The method of any one of claims 157-158, wherein the mu and/or delta
opiate
receptor antagonist is naloxone or a pharmaceutically acceptable salt or
prodrug thereof.
177. The method of claim 176 wherein each dosage of naloxone is greater than
10
mg/administration; greater than 10.5 mg/administration; greater than 11
mg/administration;
or greater than 15 mg/administration.
178. The method of any one of claims 176-177, wherein the initial dosage of
naloxone is
between 10 and 50 mg/administration.
179. The method of any one of claims 176-177, wherein the initial dosage of
naloxone is
between 5 and 500 mg/administration.
180. The method of any one of claims 176-179, wherein the maximum dosage of
naloxone
is no greater than 3000 mg/administration.
181. The method of any one of claims 157-180, wherein the mu and/or delta
opiate
receptor antagonist is administered using a time-release or slow-release
formulation.
182. The method of any one of claims 157-180, wherein the mu and/or delta
opiate
receptor antagonist is administered orally, transdermally, intraspinally,
intrathecally, via
inhalation, subcutaneously, intravenously, intramuscularly, or transmucosally,
or via
osmotic pump, microcapsule, implant, or suspension.
106
183. The method of any one of claims 157-180, wherein the mu and/or delta
opiate
receptor antagonist is administered transdermally.
184. The method of any one of claims 181-183, wherein the mu and/or delta
opiate
receptor antagonist is released over a time period between 2 and 12 hours in
duration;
between 2 and.6 hours in duration; or between 6 and 12 hours in duration.
185. The method of any one of claims 157-180, wherein the mu and/or delta
opiate
receptor antagonist is administered as a rapidly absorbed loading dose.
186. The method of any one of claims 157-180, wherein the mu and/or delta
opiate
receptor antagonist is administered using both a rapidly absorbed loading
dose, and
transdermal administration or a time-release or slow-release formulation.
187. The method of any one of claims 157-186, wherein a specific mu and/or
delta
receptor antagonist and a non-specific mu and/or delta receptor antagonist are
administered
substantially simultaneously.
188. The method of any one of claims 157-186, wherein a specific mu and/or
delta
receptor antagonist and a non-specific mu and/or delta receptor antagonist are
administered
sequentially.
189. The method of any one of claims 157-188, wherein the undesirable mental,
neurological or physiological condition is pain, a mood disorder, an eating
disorder, an
anxiety disorder, a motivational problem, a substance abuse disorder,
insufficient
motivation or performance, an immune system-related condition, and a wound in
need of
healing.
190. The method of any one of claims 157-189, wherein the method is used to
address the
undesirable mental, neurological or physiological condition in a patient.
191. The method of claim 190, wherein the undesirable mental, neurological or
physiological condition is pain that is expected to occur in the future, a
chronic pain
syndrome, or acute pain.
107
192. The method of claim 190, wherein the undesirable mental, neurological or
physiological condition is pain expected to occur due to a future operation,
pain expected
to occur due to future physical exertion, fibromyalgia, chronic fatigue
syndrome, chronic
back pain, chronic headaches, shingles, reflex sympathetic dystrophy,
neuropathy,
inflammatory pain, or chronic cancer pain.
193. The method of claim 190, wherein the undesirable mental, neurological or
physiological condition is a major depressive disorder, post traumatic
depression, a
temporary depressed mood, a manic-depressive disorder, a dysthymic disorder, a
generalized mood disorder, anhedonia, or non-organic sexual dysfunction.
194. The method of claim 190, wherein the undesirable mental, neurological or
physiological condition is overeating, obesity, anorexia, or bulimia.
195. The method of claim 190, wherein the undesirable mental, neurological or
physiological condition is a generalized anxiety state, a panic disorder,
Tourette's
Syndrome, a hysteria sleep disorder, or a breathing-related sleep disorder.
196. The method of claim 190, wherein the undesirable mental, neurological or
physiological condition is a lack of motivation due to learning or memory
problems.
197. The method of claim 190, wherein the undesirable mental, neurological or
physiological condition is abuse of a substance selected from the group
consisting of
narcotics, alcohol, nicotine, stimulants, anxiolytics, CNS depressants,
hallucinogens and
marijuana.
198. The method of claim 190, wherein the undesirable mental, neurological or
physiological condition is insufficient motivation or preparation for a
desired mental or
physical activity.
199. The method of claim 198, wherein the desired activity is physical
training, athletics,
studying, or testing.
108
200. The method of any one of claims 157-199, wherein the method is used as an
adjunct
treatment for cancer, infection, AIDS, or a wound.
201. The method of any one of 157-200, wherein a mu and/or delta opiate
receptor agonist
is not administered during the first time period associated with each
administration.
202. The method of any one of claims 157-201, wherein a mu and/or delta opiate
receptor
agonist is administered during one or more of the second time periods.
203. The method of any one of claims 157-201, wherein a CRF receptor
antagonist is
administered during one or more of the second time periods.
204. The method of claim 203, wherein the CRF receptor antagonist is selected
from the
group consisting of R121919, DMP696, antalarmin, CP-154,526, SSR125543A, 2-
arylamino-4-trifluoromethyl-aminomethylthiazole antagonists, astressin, alpha-
helical CRF
compounds and pharmaceutically acceptable salts, analogues, and derivatives
thereof.
205. The method of any one of claims 157-204, wherein a CRF receptor agonist
is
repeatedly administered in combination with the mu and/or delta opiate
receptor antagonist,
each administration of the CRF receptor agonist having an administration half-
life, wherein
the ratio of the administration half-life to the period between
administrations is no greater
than 1/2.
206. The method of any one of claims 157-204, wherein a CRF receptor agonist
is
administered during one or more of the second time periods.
207. The method of any one of claims 157-206, wherein the up-regulation of the
endogenous endorphin system causes a therapeutic benefit with respect to an
undesirable
mental, neurological or physiological condition linked to the mu and/or delta
opiate
receptors.
208. The method of any one of claims 1-127, wherein
the neurotransmitter system is the dynorphin system;
the type of receptor is kappa receptors;
109
the ligand is a kappa receptor agonist; and
the counteradaptation causes a down-regulation of the dynorphin system.
209. The method of claim 208, wherein the counteradaptation is at least one
of:
a decrease in the biosynthesis or release of dynorphins at the receptor
terminals or
by the pituitary gland;
a decrease in the number of the kappa receptors and/or binding sites on the
kappa
receptors; and
a decrease in the sensitivity of the kappa receptors to binding by dappa
receptor
agonists and/or dynorphins.
210. The method of any one of claims 208-209, wherein the kappa receptor
agonist is
peptide-based.
211. The method of any one of claims 208-209, wherein the kappa receptor
agonist is
dynorphin or a pharmaceutically acceptable salt, carrier, or analogue thereof.
212. The method of any one of claims 208-209, wherein the kappa receptor
agonist is a
nonbenzomorphan; enadoline; PD117302; CAM569; PD123497; GR 89,696; U69,593;
TRK-820; trans-3,4-dichloro-N-methyl-N-[1-(1-pyrrolidinyl)cyclohexyl]benzene-
acetamide; asimadoline (EMD-61753); benzeneacetamide; thiomorpholine;
piperidine;
benzo[b]thiophene-4-acetamide; trans-(+/-)-(PD-117302); 4-benzofuranacetamide
(PD-
129190); 2,6-methano-3-bezazocin-8-ol (MR-1268); morphinan-3-ol (KT-90); GR-
45809;
1-piperazinecarboxylic acid (GR-89696); GR-103545; piperzaine; GR-94839;
xorphanl;
benzeneacetamide (RU-49679); fedotozine; benzeneacetamide (DuP-747); HN-11608;
apadoline (RP-60180); spiradoline mesylate; benzeneacetamide trans-U-50488
methane
sulfate; 3FLB; FE200665; FE200666; an analogue of MPCB-GRRI or MPCB-RRI, an
analogue of the C-terminal fragment of dynorphin A(1-8), or a pharmaceutically-
accepted
salt or carrier thereof.
213. The method of any one of claims 208-212, wherein the initial dosage of
the kappa
receptor agonist is equivalent to between 0.0005 and 0.05 mg/kg/administration
of
dynorphin; between 5 and 700 mg/administration of enadoline; between 1 and 500
µg/administration of FE 20665; between 0.5 and 100 µg/administration;
between 0.01 and
110
1 mg/kg/administration of U69,593; between 0.05 and 5 mg/kg/administration of
TRK 820;
between 0.01 and 1 mg/kg/administration U 50 488; or between 0.01 and 1
mg/kg/administration of PD 117302.
214. The method of any one of claims 208-212, wherein the initial dosage of
the kappa
receptor agonist is equivalent to between 0.005 and 0.02 mg/kg/administration
of
dynorphin; between 100 and 500 mg/administration of enadoline; between 3 and
100
µg/administration of FE 20665; between 1 and 80 µg/administration of FE
20666; between
0.1 and 0.7 mg/kg/administration of U69,593; between 0.5 and 3
mg/kg/administration of
TRK 820; between 0.5 and 7 mg/kg/administration U 50 488 or between 0.1 and
0.7
mg/kg/administration of PD 117302.
215. The method of any one of claims 208-212, wherein the kappa receptor
agonist is
Salvinorin A or an analog or prodrug thereof
216. The method of claim 215, wherein the initial dose of Salvinorin A is
between 5 and
200 µg/administration.
217. The method of any one of claims 215-216, wherein the maximum dose of
Salvinorin
A is at least 5000 µg/administration.
218. The method of any one of claims 215-217, wherein the Salvinorin A is
administered
transmucosally.
219. The method of any one of claims 215-218, wherein the Salvinorin A is
administered
as a slow-release formulation.
220. The method of claim 219, wherein the Salvinorin A is administered over a
period two
to six hours in duration.
221. The method of any one of claims 208-220, wherein a peptide-based kappa
receptor
agonist and a non-peptide-based kappa receptor agonist are administered
substantially
simultaneously.
111
222. The method of any one of claims 208-220, wherein a peptide-based kappa
receptor
agonist and a non-peptide-based kappa receptor agonist are administered
sequentially.
223. The method of any one of claims 208-222, wherein the method is used to
address an
undesirable mental, neurological or physiological condition in a patient.
224. The method of claim 223, wherein the condition is pain, a mood disorder,
an eating
disorder, an anxiety disorder, a motivational problem, a substance abuse
disorder, or
insufficient motivation or performance.
225. The method of claim 223õ wherein the condition is pain that is expected
to occur in
the future; a chronic pain syndrome; or acute pain.
226. The method of claim 223,, wherein the condition is pain expected to occur
due to a
future operation; pain expected to occur due to future physical exertion;
fibromyalgia;
chronic fatigue syndrome; chronic back pain; chronic headaches; shingles;
reflex
sympathetic dystrophy; neuropathy; inflammatory pain; or chronic cancer pain.
227. The method of claim 223, wherein the condition is a major depressive
disorder; post
traumatic depression; a temporary depressed mood; a manic-depressive disorder;
a
dysthymic disorder; a generalized mood disorder; anhedonia; or non-organic
sexual
dysfunction.
228. The method of claim 223, wherein the condition is overeating; obesity;
anorexia; or
bulimia.
229. The method of claim 223, wherein the condition is a generalized anxiety
state; a panic
disorder; Tourette's Syndrome; a hysteria sleep disorder; or a breathing-
related sleep
disorder.
230. The method of claim 223, wherein the condition is a lack of motivation
due to
learning or memory problems.
112
231. The method of claim 223, wherein the condition is abuse of a substance
selected from
the group consisting of narcotics, alcohol, nicotine, stimulants, anxiolytics,
CNS
depressants, hallucinogens and marijuana.
232. The method of claim 223, wherein the condition is insufficient motivation
or
preparation for a desired mental or physical activity.
233. The method of claim 232, wherein the desired activity is physical
training; athletics;
studying; or testing.
234. The method of any one of claims 208-233, wherein the method is used as an
adjunct
treatment for cancer.
235. The method of any one of claims 208-234, wherein kappa receptor
antagonist is not
administered during the first time period associated with each administration.
236. The method of any one of claims 208-234, wherein a kappa receptor
antagonist is
administered during one or more of the second time periods.
237. The method of any one of claims 208-236, wherein the down-regulation of
the
dynorphin system causes a therapeutic benefit with respect to an undesirable
mental,
neurological or physiological condition linked to the kappa receptors.
238. The method of any one of claims 1-127, wherein
the neurotransmitter system is the serotonin system; and
the counteradaptation causes an up-regulation of the serotonin system.
239. The method of claim 238, wherein
the type of receptor is serotonin pre-synaptic autoreceptors; and
the ligand is a serotonin pre-synaptic autoreceptor agonist.
240. The method of claim 239, wherein the counteradaptation is at least one
of:
an increase in the biosynthesis and/or release of serotonin at the synaptic
cleft;
a decrease in the reuptake of serotonin;
113
a decrease in the number of serotonin pre-synaptic autoreceptors;
a decrease in the sensitivity of the serotonin pre-synaptic autoreceptors to
serotonin
and/or serotonin pre-synaptic autoreceptor agonists;
an increase in the number of serotonin post-synaptic receptors; or
an increase in the sensitivity of the serotonin post-synaptic receptors to
serotonin or
serotonin post-synaptic receptor agonists.
241. The method of any one of claims 239-240, wherein the serotonin pre-
synapatic
autoreceptors are 5HT1A autoreceptors and/or 5HT1B autoreceptors.
242. The method of any one of claims 239-242, wherein the serotonin pre-
synaptic
autoreceptor agonist is EMD-68843, buspirone, gepirone, ipsapirone,
tandospirone,
Lesopitron, zalospirone, MDL-73005EF, or BP-554.
243. The method of any one of claims 239-242, wherein the initial dosage of
the serotonin
pre-synaptic autoreceptor agonist is equivalent to between 1 and 400
mg/administration of
EMD-68843, between 1 and 500 mg/administration buspirone between 1 and 500
mg/administration lesopitron, between 1 and 500 mg/administration gepirone,
between 5
and 500 mg tandospirone, or between 1 and 200 mg zalospirone.
244. The method of any one of claims 239-242 wherein the initial dosage of the
serotonin
pre-synaptic autoreceptor agonist is equivalent to between 10 and 100
mg/administration of
EMD-68843, between 10 and 100 mg/administration buspirone between 10 and 200
mg/administration lesopitron, between 10 and 100 mg/administration gepirone,
between 20
and 200 mg tandospirone, or between 10 and 100 mg zalospirone.
245. The method of any one of claims 239-244, wherein serotonin pre-synaptic
autoreceptor antagonist is not administered during the first time period
associated with each
administration.
246. The method of any one of claims 239-245, wherein a serotonin pre-synaptic
autoreceptor antagonist is administered during one or more of the second time
periods.
247. The method of claim 238, wherein
114
the type of receptor is serotonin post-synaptic receptors; and
the ligand is a serotonin post-synaptic autoreceptor antagonist.
248. The method of claim 247, wherein the counteradaptation is at least one
of:
an increase in the biosynthesis and/or release of serotonin at the synaptic
cleft;
a decrease in the reuptake of serotonin;
an increase in the number of serotonin post-synaptic receptors;
an increase in the sensitivity of the serotonin post-synaptic receptors to
serotonin
and/or serotonin post-synaptic receptor agonists;
a decrease in the number of serotonin pre-synaptic autoreceptors;
a decrease in the sensitivity of the serotonin pre-synaptic autoreceptors to
serotonin
and/or serotonin pre-synaptic autoreceptor agonists.
249. The method of any one of claims 247-248, wherein the serotonin post-
synapatic
receptors are 5HT1 receptors; 5HT2 receptors; 5HT3 receptors; 5HT4 receptors;
5HT5
receptors; 5HT6 receptors; 5HT7 receptors; or receptors of a subtype thereof.
250. The method of any one of claims 247-249, wherein the serotonin post-
synaptic
receptor antagonist is (S)-WAY-100135, WAY-100635, buspirone, gepirone,
ipsapirone,
tandospirone, Lesopitron, zalospirone, MDL-73005EF, or BP-554.
251. The method of any one of claims 247-250, wherein the initial dosage of
the serotonin
post-synaptic receptor antagonist is equivalent to between about 0.01 and 5
mg/kg/administration of WAY-100635.
252. The method of any one of claims 247-250, wherein the initial dosage of
the serotonin
post-synaptic receptor antagonist is equivalent to between about 0.025 and 1
mg/kg/administration of WAY-100635.
253. The method of any one of claims 247-252, further comprising the step of
administering a serotonin pre-synaptic autoreceptor agonist in combination
with the
serotonin post-synaptic receptor antagonist.
115
254. The method of any one of claims 247-252, wherein the serotonin post-
synaptic
receptor antagonist is also a serotonin pre-synaptic autoreceptor agonist.
255. The method of any one of 247-254, wherein a serotonin post-synaptic
receptor
agonist is not administered during the first time period associated with each
administration.
256. The method of any one of claims 247-255, wherein a serotonin post-
synaptic receptor
agonist is administered during one or more of the second time periods.
257. The method of any one of claims 238-256, further comprising the step of
administering a norepinephrine pre-synaptic alpha-2 adrenergic receptor
agonist
and/or a norepinephrine post-synaptic adrenergic receptor antagonist in
combination with
the ligand.
258. The method of any one of claims 238-257, wherein the up-regulation of the
serotonin
system causes a therapeutic benefit with respect to an undesirable mental,
neurological or
physiological condition linked to the receptors.
259. The method of any one of claims 1-127, wherein
the neurotransmitter system is the norepinephrine system; and
the counteradaptation causes an up-regulation of the norepinephrine system.
260. The method of claim 259, wherein
the type of receptor is norepinephrine pre-synaptic alpha-2 adrenergic
receptors;
the ligand is an norepinephrine pre-synaptic alpha-2 adrenergic receptor
agonist.
261. The method of claim 260, wherein the counteradaptation is at least one
of:
an increase in the biosynthesis and/or release of norepinephrine at the
synaptic cleft;
a decrease in reuptake of norepinephrine;
a decrease in the number of norepinephrine pre-synaptic alpha-2 adrenergic
receptors;
a decrease in the sensitivity of the norepinephrine pre-synaptic alpha-2
adrenergic
receptors to norepinephrine and/or norepinephrine pre-synaptic alpha-2
adrenergic receptor
agonists;
116
an increase in the number of norepinephrine post-synaptic adrenergic
receptors; or
an increase in the sensitivity of the norepinephrine post-synaptic adrenergic
receptors to norepinephrine and/or norepinephrine post-synaptic adrenergic
receptor
agonists.
262. The method of any one of claims 260-261, wherein the norepinephrine pre-
synaptic
alpha-2 adrenergic receptor agonist is clonidine, guanfacine, lofexidine,
detomidine,
dexmedetomidine, mivazerol, or alpha-methylnoradreniline.
263. The method of any one of claims 260-262, wherein the initial dosage of
the
norepinephrine pre-synaptic alpha-2 adrenergic receptor agonist is equivalent
to between
0.1 and 10 µg/kg/administration of clonidine, between 0.01 and 10
mg/administration
guanfacine, between 0.01 and 1 mg/administration lofexidine, between 1 and 100
µg/kg/administration detomidine, between 0.05 and 5 µg/kg/administration
dexmedetomidine, between 0.05 and 10 µg/kg/administration mivazerol, or
between 5 and
500 ng/kg/administration of alpha-methylnoradreniline.
264. The method of any one of claims 260-262, wherein the initial dosage of
the
norepinephrine pre-synaptic alpha-2 adrenergic receptor agonist is equivalent
to between
0.1 and 0.5 mg/administration of clonidine, between 0.1 and 5
mg/administration
guanfacine, between 0.05 and 0.5 mg/administration lofexidine, between 10 and
80
µg/kg/administration detomidine, between 0.1 and 3 µg/kg/administration
dexmedetomidine, between 0.5 and 5 µg/kg/administration of mivazerol, or
between 10
and 100 ng/kg/administration of alpha-methylnoradreniline.
265. The method of any one of claims 260-262, wherein norepinephrine pre-
synaptic
alpha-2 adrenergic receptor antagonist is not administered during the first
time period
associated with each administration.
266. The method of any one of claims 260-263, wherein a norepinephrine pre-
synaptic
alpha-2 adrenergic receptor antagonist is administered during one or more of
the second
time periods.
267. The method of claim 259, wherein
117
the type of receptor is norepinephrine post-synaptic adrenergic receptors;
the ligand is a norepinephrine post-synaptic adrenergic receptor antagonist;
and
the undesirable mental, neurological or physiological condition is negatively
linked
to the norepinephrine post-synaptic adrenergic receptors.
268. The method of claim 267, wherein the counteradaptation is at least one
of:
an increase in the biosynthesis or release of norepinephrine at the synaptic
cleft;
a decrease in the reuptake of norepinephrine;
an increase in the number of norepinephrine post-synaptic adrenergic
receptors;
an increase in the sensitivity of the norepinephrine post-synaptic adrenergic
receptors to norepinephrine and/or norepinephrine post-synaptic adrenergic
receptor
agonists;
a decrease in the number of norepinephrine pre-synaptic alpha-2 adrenergic
receptors; or
a decrease in the sensitivity of the norepinephrine pre-synaptic alpha-2
adrenergic
receptors to norepinephrine and/or norepinephrine pre-synaptic alpha-2
adrenergic receptor
agonists.
269. The method of any one of claims 267-268, wherein the norepinephrine post-
synapatic
adrenergic receptors are alpha receptors; beta receptors; or receptors of a
subtype thereof.
270. The method of any one of claims 267-269, wherein the norepinephrine post-
synaptic
adrenergic receptor antagonist is idazoxan, SKF 104078, or SKF 104856.
271. The method of any one of claims 267-270, wherein the initial dosage of
the
norepinephrine post-synaptic adrenergic receptor antagonist is equivalent to
between 0.5
and 100 mg/administration of idazoxan.
272. The method of any one of claims 267-270, wherein the initial dosage of
the
norepinephrine post-synaptic adrenergic receptor antagonist equivalent to
between 5 and 50
mg/administration of idazoxan.
273. The method of any one of claims 267-272, further comprising the step of
118
administering a norepinephrine pre-synaptic alpha-2 adrenergic receptor
agonist in
combination with the norepinephrine post-synaptic adrenergic receptor
antagonist.
274. The method of any one of claims 267-272, wherein the norepinephrine post-
synaptic
adrenergic receptor antagonist is also a norepinephrine pre-synaptic alpha-2
adrenergic
receptor agonist.
275. The method of any one of claims 267-274, wherein a norepinephrine post-
synaptic
adrenergic receptor agonist is not administered during the first time period
associated with
each administration.
276. The method of any one of claims 267-275, wherein a norepinephrine post-
synaptic
adrenergic receptor agonist is administered during one or more of the second
time periods.
277. The method of any one of claims 267-276, further comprising the step of
administering a serotonin pre-synaptic autoreceptor agonist or a serotonin
post-
synaptic receptor antagonist in combination with the ligand.
278. The method of any one of claims 259-277, wherein the method is used to
address an
undesirable mental, neurological or physiological condition in a patient, the
undesirable
mental, neurological or physiological condition being linked to serotonin
receptors.
279. The method of claim 278, wherein the condition is a mood disorder; an
eating
disorder, a pain disorder, a substance abuse disorder, an anxiety disorder, or
an obsessive-
compulsive disorder.
280. The method of any one of claims 259-278, wherein the method is used as an
adjunct
treatment for cancer.
281. The method of any one of claims 259-279, wherein the up-regulation of the
norepinephrine system causes a therapeutic benefit with respect to an
undesirable mental,
neurological or physiological condition linked to the receptors.
282. The method of any one of claims 1-127, wherein
119
the neurotransmitter system is the CRF system;
the type of receptor is CRF receptors;
the ligand is an CRF receptor agonist; and
the counteradaptation causes a down-regulation of the CRF system.
283. The method of claim 282, wherein the counteradaptation is at least one
of:
a decrease in the biosynthesis or release of corticotropin releasing factor by
the
hypothalamus;
a decrease in the number of the CRF receptors and/or binding sites on the CRF
receptors; and
a decrease in the sensitivity of the receptors to binding by CRF receptor
agonists
and/or corticotropin releasing factor.
284. The method of any one of claims 282-283, wherein the CRF receptor agonist
is
peptide-based.
285. The method of any one of claims 282-283, wherein the CRF receptor agonist
is an
analogue of corticotropin releasing factor, or a pharmaceutically acceptable
salt or
derivative thereof.
286. The method of any one of claims 282-283, wherein the CRF receptor agonist
is
cortagine.
287. The method of any one of claims 282-286, wherein the initial dosage of
the CRF
receptor agonist is from about 0.1 to 100 µg/kg/day initial dose and 100 to
1000 µg/kg/day
for 8 hours slow release.
288. The method of any one of claims 282-286, wherein the initial dosage of
the CRF
receptor agonist is between about 1 to 50 µg/kg/day initial dose and 20 to
50 µg/kg/day for
8 hours slow release.
289. The method of any one of claims 282-288, wherein the method is used to
address an
undesirable mental, neurological or physiological condition in a patient, the
undesirable
mental, neurological or physiological condition being positively linked to CRF
receptors.
120
290. The method of claim 289, wherein the undesirable mental, neurological or
physiological condition is melancholic depression.
291. The method of claim 289, wherein the undesirable mental, neurological or
physiological condition is insufficient memory.
292. The method of claim 289, wherein the undesirable mental, neurological or
physiological condition is anxiety or an anxiety-related disorder.
293. The method of claim 289, wherein the undesirable mental, neurological or
physiological condition is an undereating disorder.
294. The method of claim 289, wherein the undesirable mental, neurological or
physiological condition is a need for increased memory that is anticipated to
occur in the
future.
295. The method of claim 289, wherein the undesirable mental, neurological or
physiological condition is stress that is anticipated to occur in the future.
296. The method of claim 289, wherein the undesirable mental, neurological or
physiological condition is post-traumatic stress disorder.
297. The method of claim 289 wherein the undesirable mental, neurological or
physiological condition is poor appetite.
298. The method of claim 289, wherein the undesirable mental, neurological or
physiological condition is a lack of motivation due to learning or memory
problems.
299. The method of any one of claims 282-298, wherein the method further
comprises
administering in combination with the CRF agonist during the first time period
a mu and/or
delta opiate receptor antagonist with a ratio of administration half-life to
the period
between administrations no greater than 1/2.
121
300. The method of any one of claims 282-299, wherein neither a CRF receptor
antagonist
nor an AVP receptor antagonist is administered during the first time period
associated with
each administration.
301. The method of any one of claims 282-300, wherein a CRF receptor
antagonist and/or
an AVP receptor antagonist is administered during one or more of the second
time periods
associated with each administration.
302. The method of claim 301, wherein the CRF receptor antagonist is selected
from the
group consisting of R121919, DMP696, antalarmin, CP-154,526, SSR125543A, 2-
arylamino-4-trifluoromethyl-aminomethylthiazole antagonists, astressin, alpha-
helical CRF
compounds and pharmaceutically acceptable salts, analogues, and derivatives
thereof.
303. The method of any one of claims 282-302, wherein the down-regulation of
the CRF
system causes a therapeutic benefit with respect to an undesirable mental,
neurological or
physiological condition positively linked to CRF receptors.
304. The method of any one of claims 1-127, wherein
the neurotransmitter system is the CRF system;
the type of receptor is CRF receptors;
the ligand is an CRF receptor antagonist; and
the counteradaptation causes a up-regulation of the CRF system.
305. The method of claim 304, wherein the counteradaptation is at least one
of:
an increase in the biosynthesis or release of corticotropin releasing factor
by the
hypothalamus;
an increase in the number of the CRF receptors and/or binding sites on the CRF
receptors; and
an increase in the sensitivity of the receptors to binding by CRF receptor
agonists
and/or corticotropin releasing factor.
306. The method of any one of claims 304-305, wherein the CRF receptor
antagonist is
selected from the group consisting of R121919, DMP696, antalarmin, CP-154,526,
SSR125543A, 2-arylamino-4-trifluoromethyl-aminomethylthiazole antagonists,
astressin,
122
alpha-helical CRF compounds and pharmaceutically acceptable salts, analogues,
and
derivatives thereof.
307. The method of any one of claims 304-306, wherein the initial dosage of
the CRF
receptor antagonist is from about 0.1 to 100 µg/kg/day initial dose and 100
to 1000
µg/kg/day for 8 hours slow release.
308. The method of any one of claims 304-306, wherein the initial dosage of
the CRF
receptor antagonist is between about 1 to 50 µg/kg/day initial dose and 20
to 50 µg/kg/day
for 8 hours slow release.
309. The method of any one of claims 304-308, wherein the method is used to
address an
undesirable mental, neurological or physiological condition in a patient, the
undesirable
mental, neurological or physiological condition being negatively linked to CRF
receptors.
310. The method of claim 309, wherein the undesirable mental, neurological or
physiological condition is atypical depression.
311. The method of claim 309, wherein the undesirable mental, neurological or
physiological condition is weight gain or an overeating disorder.
312. The method of claim 309, wherein the undesirable mental, neurological or
physiological condition is lethargy or fatigue.
313. The method of any one of claims 304-312, wherein the method further
comprises
administering in combination with the CRF agonist during the first time period
a mu and/or
delta opiate receptor antagonist with a ratio of administration half-life to
the period
between administrations no greater than 1/2.
314. The method of any one of claims 304-313, wherein neither a CRF receptor
agonist
nor an AVP receptor agonist is administered during the first time period
associated with
each administration.
123
315. The method of any one of claims 304-314, wherein a CRF receptor agonist
and/or an
AVP receptor agonist is administered during one or more of the second time
periods
associated with each administration.
316. The method of claim 315, wherein the CRF receptor agonist is an analogue
of
corticotropin releasing factor, cortagine, or a pharmaceutically acceptable
salt or derivative
thereof.
317. The method of any one of claims 304-316, wherein the down-regulation of
the CRF
system causes a therapeutic benefit with respect to an undesirable mental,
neurological or
physiological condition negatively linked to CRF receptors.
318. The method of any one of claims 1-127, wherein
the neurotransmitter system is the AVP system;
the type of receptor is AVP receptors;
the ligand is an AVP receptor agonist; and
the counteradaptation causes a down-regulation of the AVP system.
319. The method of claim 318, wherein the counteradaptation is at least one
of:
a decrease in the biosynthesis or release of arginine vasopressin by the
hypothalamus;
a decrease in the number of the AVP receptors and/or binding sites on the AVP
receptors; and
a decrease in the sensitivity of the receptors to binding by AVP receptor
agonists
and/or arginine vasopressin.
320. The method of any one of claims 318-319, wherein the AVP receptor agonist
is
peptide-based.
321. The method of any one of claims 318-319, wherein the AVP receptor agonist
is
selected from the group consisting of felypressin, desmopressin, and
pharmaceutically
acceptable salts, analogues, and derivatives thereof.
124
322. The method of any one of claims 318-321, wherein the initial dosage of
the AVP
receptor agonist is between about 0.1 to 100 gg/kg/day initial dose and 100 to
1000
gg/kg/day for 8 hours slow release.
323. The method of any one of claims 318-321, wherein the initial dosage of
the AVP
receptor agonist is between about 1 to 50 µg/kg/day initial dose and 20 to
50 µg/kg/day for
8 hours slow release.
324. The method of any one of claims 318-323, wherein the method is used to
address an
undesirable mental, neurological or physiological condition in a patient, the
undesirable
mental, neurological or physiological condition being positively linked to AVP
receptors.
325. The method of claim 324, wherein the undesirable mental, neurological or
physiological condition is melancholic depression.
326. The method of claim 324, wherein the undesirable mental, neurological or
physiological condition is insufficient memory.
327. The method of claim 324, wherein the undesirable mental, neurological or
physiological condition is anxiety or an anxiety-related disorder.
328. The method of claim 324, wherein the undesirable mental, neurological or
physiological condition is an undereating disorder.
329. The method of claim 324, wherein the undesirable mental, neurological or
physiological condition is a need for increased memory that is anticipated to
occur in the
future.
330. The method of claim 324, wherein the undesirable mental, neurological or
physiological condition is stress that is anticipated to occur in the future.
331. The method of claim 324, wherein the undesirable mental, neurological or
physiological condition is post-traumatic stress disorder.
125
332. The method of claim 324 wherein the undesirable mental, neurological or
physiological condition is poor appetite.
333. The method of claim 324, wherein the undesirable mental, neurological or
physiological condition is a lack of motivation due to learning or memory
problems.
334. The method of any one of claims 318-333, wherein the method further
comprises
administering in combination with the AVP receptor agonist a mu and/or delta
opiate
receptor antagonist with a ratio of administration half-life to the period
between
administrations is no greater than 1/2.
335. The method of any one of claims 318-334, wherein the method further
comprises
administering in combination with the AVP receptor agonist a CRF receptor
agonist with a
ratio of administration half-life to the period between administrations is no
greater than 1/2.
336. The method of any one of claims 318-325, wherein neither a CRF receptor
antagonist
nor a AVP receptor antagonist is administered during the first time period
associated with
each administration.
337. The method of any one of claims 318-336, wherein a CRF receptor
antagonist and/or
an AVP receptor antagonist is administered during one or more of the second
time periods
associated with each administration.
338. The method of claim 337, wherein the AVP receptor antagonist is selected
from the
group consisting of d(CH2)5Tyr(Me)AVP, Phaa-d-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-
Tyr-NH2, [Lys(3N3 Phpa)8]HO-LVA, [d(CH2)5, D-Ile2, Ile4]-AVP, and [125I]-
d(CH2)5[D-Tyr(Et)2, Val4, Tyr-NH29] AVP, OPC-21268 (1-(1-[4-(3-
acetylaminopropoxy) benzoyl]-4-piperidyl)-3,4-dihydro-2(1H)-quinolinone); R
49059;
OPC-31260 (5-dimethylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-
tetrahydro-
1H-benzazepine); conivaptan; VPA 985 and YM 471 [(Z)-4'-[4,4-difluoro-5-[2-(4-
dimethylaminopiperidino)-2-oxoethylidene]-2,3,4,5-tetrahydro-1H-1-benzoazepine-
1-
carbonyl]-2-phenylbenzanilide monohydrochloride] and pharmaceutically
acceptable salts,
analogues, and derivatives thereof.
126
339. The method of any one of claims 318-338, wherein the down-regulation of
the AVP
system causes a therapeutic benefit with respect to an undesirable mental,
neurological or
physiological condition linked to AVP receptors.
340. The method of any one of claims 1-127, wherein
the neurotransmitter system is the AVP system;
the type of receptor is AVP receptors;
the ligand is an AVP receptor antagonist; and
the counteradaptation causes a up-regulation of the AVP system.
341. The method of claim 340, wherein the counteradaptation is at least one
of:
an increase in the biosynthesis or release of arginine vasopressin by the
hypothalamus;
an increase in the number of the AVP receptors and/or binding sites on the AVP
receptors; and
an increase in the sensitivity of the receptors to binding by AVP receptor
agonists
and/or arginine vasopressin.
342. The method of any one of claims 340-341, wherein the AVP receptor
antagonist is
selected from the group consisting of d(CH2)5Tyr(Me)AVP, Phaa-d-Tyr(Me)-Phe-
Gln-
Asn-Arg-Pro-Arg-Tyr-NH2, [Lys(3N3 Phpa)8]HO-LVA, [d(CH2)5, D-Ile2, Ile4]-AVP,
and [125I]-d(CH2)5[D-Tyr(Et)2, Val4, Tyr-NH29] AVP, OPC-21268 (1-(1-[4-(3-
acetylaminopropoxy) benzoyl]-4-piperidyl)-3,4-dihydro-2(1H)-quinolinone); R
49059;
OPC-31260 (5-dimethylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-
tetrahydro-
1H-benzazepine); conivaptan; VPA 985 and YM 471[(Z)-4'-[4,4-difluoro-5-[2-(4-
dimethylaminopiperidino)-2-oxoethylidene]-2,3,4,5-tetrahydro-1H-1-benzoazepine-
1-
carbonyl]-2-phenylbenzanilide rnonohydrochloride] and pharmaceutically
acceptable salts,
analogues, and derivatives thereof.
343. The method of any one of claims 340-342, wherein the initial dosage of
the AVP
receptor antagonist is from about 0.1 to 100 µg/kg/day initial dose and 100
to 1000
µg/kg/day for 8 hours slow release.
127
344. The method of any one of claims 340-342, wherein the initial dosage of
the AVP
receptor antagonist is between about 1 to 50 µg/kg/day initial dose and 20
to 50 gg/kg/day
for 8 hours slow release.
345. The method of any one of claims 340-344, wherein the method is used to
address an
undesirable mental, neurological or physiological condition in a patient, the
undesirable
mental, neurological or physiological condition being negatively linked to AVP
receptors.
346. The method of claim 345, wherein the undesirable mental, neurological or
physiological condition is atypical depression.
347. The method of claim 345, wherein the undesirable mental, neurological or
physiological condition is weight gain or an overeating disorder.
348. The method of claim 345, wherein the undesirable mental, neurological or
physiological condition is lethargy or fatigue.
349. The method of any one of claims 340-348, wherein the method further
comprises
administering in combination with the AVP agonist during the first time period
a mu and/or
delta opiate receptor antagonist with a ratio of administration half-life to
the period
between administrations no greater than 1/2.
350. The method of any one of claims 340-349, wherein neither a AVP receptor
agonist
nor an AVP receptor agonist is administered during the first time period
associated with
each administration.
351. The method of any one of claims 340-350, wherein a AVP receptor agonist
and/or an
AVP receptor agonist is administered during one or more of the second time
periods
associated with each administration.
352. The method of claim 351, wherein the AVP receptor agonist is selected
from the
group consisting of felypressin, desmopressin, and pharmaceutically acceptable
salts,
analogues, and derivatives thereof.
128
353. The method of any one of claims 340-352, wherein the down-regulation of
the AVP
system causes a therapeutic benefit with respect to an undesirable mental,
neurological or
physiological condition negatively linked to AVP receptors.
354. The method of any one of claims 1-127, wherein the method is used to
address or
treat an undesirable mental, neurological or physiological condition in a
patient, the
undesirable mental, neurological or physiological condition being linked to
receptors of the
type of receptor.
355. The method of claim 354, wherein the condition is a mood disorder, an
eating
disorder, a pain disorder, a substance abuse disorder, an anxiety disorder, or
an obsessive-
compulsive disorder.
356. The method of any one of claims 1-353, wherein the method is used to
address or
treat an undesirable immune system-related condition in a patient in need
thereof, the
immune-system related condition being linked to receptors of the type of
receptors, the
method resulting in an up-regulation of the immune system.
357. The method of claim 356, wherein the neurotransmitter system is the
endogenous
endorphin system, the type of receptor is delta opiate receptors, and the
ligand is a delta
opiate receptor antagonist.
358. The method of any one of claims 356-357, wherein the undesirable immune
system-
related condition is cancer.
359. The method of any one of claims 356-357, wherein the undesirable immune
system-
related condition is a cancer having cancer cells substantially free of zeta
receptors.
360. The method of any one of claims 356-357, wherein the undesirable immune
system-
related condition is an autoimmune disorder, a congenital immune deficiency,
an immune
deficiency due to immunosuppressant therapy, or an acquired immune deficiency.
361. The method of any one of claims 356-357, wherein the autoimmune disorder
is
selected from the group consisting of rheumatoid arthritis, multiple
sclerosis, systemic
129
lupus erythematosus, Addison's disease, ALS (Lou Gehrig's Disease),
Alzheimer's
Disease, Ankylosing Spondylitis, Autism Spectrum Disorders, Autoimmune
Hemolytic
Anemia, Autoimmune Progesterone Dermatitis, Behcet's Disease, Celiac Disease,
Chronic
Fatigue Syndrome, Churg-Strauss (allergic granulomatosis), CREST syndrome,
Crohn's
Disease, Dermatomyositis, Diabetes Mellitus, Emphysema (COPD), Endometriosis,
Fibromyalgia, Goodpasture's disease, Graves disease, Hashimoto's thyroiditis,
Interstitial
Granulomatous Dermatitis, Irritable Bowel Syndrome (IBS), Mixed Connective
Tissue
Disease, autoimmune-related connective tissue disorders, Myasthenia Gravis,
Parkinson's
Disease, Pemphigoid, Pernicious Anemia, Primary Lateral Sclerosis (PLS),
Polychondritis
(Relapsing), Polymyalgia Rheumatica, Polymyositis, Psoriasis, Sarcoidosis,
Scleroderma,
Sjogren's syndrome,Transverse Myelitis, Ulcerative Colitis, Vasculitis,
Wegener's
Granulomatosis, and autoimmune disorders secondary to infectious processes,
administration of vaccines or environmental reactions.
362. The method of any one of claims 356-357, wherein the undesirable immune
system-
related condition is an infection.
363. The method of any one of claims 356-357, wherein the method is used to
lessen the
likelihood of becoming infected with an infectious microbe or virus.
364. The method of claim 363, wherein the method is used to lessen the
likelihood of
becoming infected with a bacteria, virus, fungus, parasite, mycobacteria,
yeast, Chlamydia,
protazon, helminth or rickettsia.
365. The method of any one of claims 356-357, wherein the immune system-
related
condition is the administration of a vaccine, and the up-regulation of the
immune system
results in the increased development of antibodies to an agent targeted by the
vaccine.
366. The method of any one of claims 1-353, wherein the method is used to
address or
treat a cariovascular or lipid or cholesterol metabolism-related condition in
a patient in
need thereof, the cariovascular or lipid or cholesterol metabolism-related
condition being
linked to receptors of the type of receptors.
130
367. The method of claim 366, wherein the cariovascular or lipid or
cholesterol
metabolism-related condition is a cardiovascular disorder.
368. The method of claim 366, wherein the cariovascular or lipid or
cholesterol
metabolism-related condition is hypertriglyceridemia, hypercholesterolemia, or
lipodystrophy due to HIV infection.
369. The method of any one of claims 1-127, wherein the method is used to
address or
treat insufficient preparedness for a future athletic activity.
370. The method of any one of claims 1-127, wherein the method is used to
address an
undesirable mental, neurological or physiological condition in a patient, the
undesirable
mental, neurological or physiological condition being linked to receptors of
the type of
receptor.
371. The method of any one of claims 1-353, wherein the method is used to
address or
treat an undesirable condition linked to the Sirt1 pathway.
372. The method of claim 371, wherein the method is used to address an aging-
related
condition in a patient.
373. The method of claim 371, wherein the method is selected from the group
consisting
of fat metabolism, inflammation, cancer, arthritis, heart disease and
neurodegeneration.
374. The method of any one of claims 371-373, wherein the method is used as a
prophylactic measure against physiological changes caused by aging.
131
