U.S. patent application number 10/642844 was filed with the patent office on 2004-03-04 for methods for treating circadian rhythm disorders.
Invention is credited to Lewy, Alfred J., Sack, Robert L..
Application Number | 20040044064 10/642844 |
Document ID | / |
Family ID | 25282219 |
Filed Date | 2004-03-04 |
United States Patent
Application |
20040044064 |
Kind Code |
A1 |
Lewy, Alfred J. ; et
al. |
March 4, 2004 |
Methods for treating circadian rhythm disorders
Abstract
A method for treating circadian rhythm disorders is described.
The method involves the administration of melatonin, melatonin
agonists or compounds that stimulate endogenous melatonin
production so that the durations of the effective plasma
concentrations of melatonin, melatonin agonists or compounds that
stimulate endogenous melatonin production overlap with onset or
offset of pre-treatment endogenous melatonin production, to provide
a circadian-rhythm phase advance or phase delay, respectively. The
methods of the invention also provide for concentration and/or
duration of the effective plasma concentrations of melatonin,
melatonin agonists or compounds that stimulate endogenous melatonin
production to be greater in the time interval between about 8 hours
before the dim light endogenous melatonin onset (DLMO) to about 4
hours after DLMO than in the time interval from about 4 hours after
DLMO to about 8 hours before DLMO to achieve a circadian-rhythm
phase advance. The methods of the invention also provide for
concentration and/or duration of the effective plasma
concentrations of melatonin, melatonin agonists or compounds that
stimulate endogenous melatonin production to be greater in the time
interval between about 4 hours after DLMO to about 8 hours before
DLMO than in the time interval from about 8 hours before DLMO time
to about 4 hours after DLMO to achieve a circadian-rhythm phase
delay. In addition, the invention provides methods for regulating a
human's exposure to light and dark to prevent or enhance,
respectively, the human's endogenous production of melatonin. The
use of melatonin antagonists, inverse agonists and melatonin
inhibitory compounds such as beta-blockers for achieving a
circadian-rhythm phase-shifting effect (opposite to that of
melatonin administration) are also provided by the invention. The
methods of the invention are illustrated by teachings for use of
these methods for alleviating a variety of circadian rhythm-related
disorders, including jet lag, winter depression, shift work-related
desynchronies and sleep phase disorders.
Inventors: |
Lewy, Alfred J.; (Portland,
OR) ; Sack, Robert L.; (Portland, OR) |
Correspondence
Address: |
McDonnell Boehnen Hulbert & Berghoff
32nd Floor
300 S. Wacker Drive
Chicago
IL
60606
US
|
Family ID: |
25282219 |
Appl. No.: |
10/642844 |
Filed: |
August 18, 2003 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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10642844 |
Aug 18, 2003 |
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08840382 |
Apr 29, 1997 |
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6638963 |
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10642844 |
Aug 18, 2003 |
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08778842 |
Jan 6, 1997 |
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6069164 |
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08778842 |
Jan 6, 1997 |
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08110878 |
Aug 24, 1993 |
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5591768 |
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08110878 |
Aug 24, 1993 |
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08077426 |
Jun 15, 1993 |
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5420152 |
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08077426 |
Jun 15, 1993 |
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07812723 |
Dec 23, 1991 |
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5255776 |
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07812723 |
Dec 23, 1991 |
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07621866 |
Dec 4, 1990 |
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10642844 |
Aug 18, 2003 |
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08779797 |
Jan 7, 1997 |
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08779797 |
Jan 7, 1997 |
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08454545 |
May 30, 1995 |
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5716978 |
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08454545 |
May 30, 1995 |
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08077426 |
Jun 15, 1993 |
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5420152 |
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08077426 |
Jun 15, 1993 |
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07812723 |
Dec 23, 1991 |
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5255776 |
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07812723 |
Dec 23, 1991 |
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07612866 |
Nov 13, 1990 |
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5122242 |
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Current U.S.
Class: |
514/419 |
Current CPC
Class: |
A61K 31/40 20130101;
A61K 31/4045 20130101; A61K 45/06 20130101; A61K 31/40 20130101;
A61K 2300/00 20130101 |
Class at
Publication: |
514/419 |
International
Class: |
A61K 031/405 |
Goverment Interests
[0003] This invention was made with government support under MH
40161 and MH 00703 awarded by the National Institutes of Health.
The government has certain rights in the invention.
Claims
We claim:
1. A method for achieving a circadian rhythm phase-delaying effect
in a human, the method comprising the step of: administering to the
human an amount of melatonin, melatonin agonist or compound that
increases endogenous production of melatonin in the human, wherein
said administration produces in the human a plasma melatonin or
agonist concentration of greater than quiescent melatonin or
equivalent agonist levels at a time that does not overlap with
onset of endogenous melatonin production in the human, and wherein
when melatonin, melatonin agonist or compound that increases
endogenous production of melatonin in the human is administered to
produce plasma melatonin or agonist concentration of greater than
quiescent melatonin or equivalent agonist levels that overlaps
offset of endogenous melatonin production, said greater than
quiescent melatonin or equivalent agonist levels rise after the
melatonin onset and fall before the next melatonin onset.
2. The method of claim 1 wherein melatonin, melatonin agonist or
compound that increases endogenous production of melatonin in the
human is administered to produce plasma melatonin or agonist
concentration of greater than quiescent melatonin or equivalent
agonist levels that rise after about CT 18 and fall before about CT
14.
3. The method of claim 2 wherein melatonin, melatonin agonist or
compound that increases endogenous production of melatonin in the
human is administered to produce plasma melatonin or agonist
concentration of greater than quiescent melatonin or equivalent
agonist levels that rise after about CT 18 and fall before about CT
6.
4. The method of claim 2 wherein melatonin, melatonin agonist or
compound that increases endogenous production of melatonin in the
human is administered to produce plasma melatonin or agonist
concentration of greater than quiescent melatonin or equivalent
agonist levels that rise after about CT 18 and fall before about CT
1.
5. A method according to claims 1, 2, 3 or 4 wherein exogenous
melatonin, melatonin agonist or compound that increases endogenous
production of melatonin in the human is administered to a human in
an immediate-release formulation.
6. A method according to claims 1, 2, 3 or 4 wherein exogenous
melatonin, melatonin agonist or compound that increases endogenous
production of melatonin in the human is administered to a human in
a delayed-release formulation
7. A method according to claims 1, 2, 3 or 4 wherein exogenous
melatonin, melatonin agonist or compound that increases endogenous
production of melatonin in the human is administered to a human in
a sustained-release formulation.
8. A method according to claims 1, 2, 3 or 4 wherein exogenous
melatonin, melatonin agonist or compound that increases endogenous
production of melatonin in the human is administered to a human in
any combination of an immediate-release formulation, a
delayed-release formulation or a sustained-release formulation.
9. A method for achieving a circadian rhythm phase-delaying effect
in a human, the method comprising the step of administering to the
human an amount of melatonin, melatonin agonist or compound that
increases endogenous production of melatonin in the human, wherein
said administration produces in the human a plasma melatonin or
agonist concentration of greater than quiescent melatonin or
equivalent agonist levels during the time interval from about CT 18
to about CT 6 than from the time interval from about CT 6 to about
CT 18.
10. A method according to claim 9 wherein melatonin, melatonin
agonist or compound that increases endogenous production of
melatonin in the human is administered after CT 18 and prior to
about CT 1.
11. A method for alleviating a circadian rhythm disorder in a
human, the method comprising the step of achieving a circadian
phase-delaying effect in the human according to the method of
claims 1, 2, 3 or 4.
12. The method of claim 11 wherein the circadian rhythm disorder is
jet lag.
13. The method of claim 11 wherein the circadian rhythm disorder is
winter depression.
14. The method of claim 11 wherein the circadian rhythm disorder is
a sleep disorder.
15. The method of claim 14 wherein the sleep disorder is
schedule-induced.
16. The method of claims 14 or 15 wherein the sleep disorder is
delayed sleep phase syndrome or advanced sleep phase syndrome.
17. The method of claim 11 wherein the circadian rhythm disorder is
a free-running circadian rhythm disorder.
18. A method for alleviating a circadian rhythm disorder in a
human, the method comprising the step of achieving a circadian
phase-delaying effect in the human according to the method of
claims 9 or 10.
19. The method of claim 18 wherein the circadian rhythm disorder is
jet lag.
20. The method of claim 18 wherein the circadian rhythm disorder is
winter depression.
21. The method of claim 18 wherein the circadian rhythm disorder is
a sleep disorder.
22. The method of claim 21 wherein the sleep disorder is
schedule-induced.
23. The method of claims 21 or 22 wherein the sleep disorder is
delayed sleep phase syndrome or advanced sleep phase syndrome.
24. The method of claim 18 wherein the circadian rhythm disorder is
a free-running circadian rhythm disorder.
Description
[0001] This application is a continuation-in-part of U.S. Ser. No.
08/778,842, filed Jan. 6, 1997, which is a divisional of U.S. Ser.
No. 08/110,878, filed Aug. 24, 1993, now U.S. Pat. No. 5,591,768,
issued Jan. 7, 1997, which is a continuation-in-part of U.S. Ser.
No. 08/077,426, filed Jun. 15, 1993, now U.S. Pat. No. 5,420,152,
issued on May 30, 1995, which is a divisional of U.S. Ser. No.
07/812,723, filed Feb. 25, 1992, now U.S. Pat. No. 5,242,941,
issued Sep. 7, 1993, which is a continuation of U.S. Ser. No.
07/621,866, filed on Dec. 4, 1990 and now abandoned.
[0002] This application is also a continuation-in-part of U.S. Ser.
No. 08/779,797, filed Jan. 7, 1997, which is a continuation of U.S.
Ser. No. 08/454,545, filed May 30, 1995, which is a divisional of
U.S. Ser. No. 08/077,426, filed Jun. 15, 1993, now U.S. Pat. No.
5,420,152, issued on May 30, 1995, which is a divisional of U.S.
Ser. No. 07/812,723, filed Feb. 25, 1992, now U.S. Pat. No.
5,242,941, issued Sep. 7, 1993, which is a continuation application
of U.S. Ser. No. 07/621,866, filed on Dec. 4, 1990 and now
abandoned.
BACKGROUND OF THE INVENTION
[0004] 1. Field of the Invention
[0005] This application relates to circadian rhythms in humans, and
particularly to the synchronization of such human circadian rhythms
with the external environment. Specifically, this invention
describes methods for achieving a chronobiologic (circadian
phase-shifting) effect in humans. The invention provides methods to
specifically advance or delay the phase of certain circadian
rhythms in humans. Specific embodiments of the invention comprise
methods for alleviating the effects of trarsmeridional travel
(i.e., jet lag); methods for alleviating certain circadian phase
disturbance-based psychopathological disorders such as winter
depression (or seasonal affective disorder); methods for achieving
synchrony between a human's wake/sleep cycle or other circadian
rhythms and the human's occupational and other human activity
schedules; and methods for achieving synchrony between a human's
wake/sleep cycle and other circadian rhythms.
[0006] 2. Background of The Related Art
[0007] The phenomenon of circadian rhythms in biology is well
known, and circadian rhythms are exhibited by all eukaryotic plants
and animals, including man. Biological rhythms are periodic
fluctuations in biological properties over time; these include
circadian as well as seasonal variations. Circadian, or
approximately 24 hour, rhythms include the production of biological
molecules such as hormones, the regulation of body temperature, and
behaviors such as wakefulness, sleep and periods of activity.
[0008] In nature, circadian rhythms are closely tied to
environmental cues that impose a 24-hour pattern on many of these
fluctuations. When these cues are absent, most circadian rhythms
have a periodicity different (in humans, usually slightly greater)
than 24 hours. Circadian rhythms that are no longer regulated by
environmental cues are said to be free running. The regulation of
circadian rhythms by signals from the environment is said to
involve entrainment of circadian rhythms. The environmental signals
that affect entrainment have been termed zeitgebers, an example of
which is the light/dark cycle.
[0009] It is thought in this art that the control of circadian
rhythms in mammals is mediated by a portion of the brain called the
superchiasmatic nuclei (SCN). Circadian rhythms are primarily
entrained by the light and dark cycle; light signals are conveyed
by the retina to the SCN, and the pineal gland, which is regulated
by the SCN, produces melatonin (N-acetyl-5-methoxytryptamine).
[0010] Disruption of circadian rhythms can result in a number of
pathophysiological states in humans; one of the most common of
these is jet lag. The use of melatonin to ameliorate the effects of
jet lag has been described in the prior art.
[0011] U.S. Pat. Nos. 4,665,086 and 4,600,723 teach the use of
melatonin to alleviate the symptoms of jet lag. These patents teach
the use of>1 to 10 mg of melatonin, taken at destination
bedtime, and again upon premature awakening in the middle of the
night.
[0012] Gwinner and Benzinger, 1978, J. Comp. Physiol. 126: 123-129
teach that daily injections of melatonin can entrain the
activity/rest cycle in birds.
[0013] Arendt et al., 1984, Neurosci. Lett. 45: 317-325 and Arendt
et al., 1985, CIBA Found. Symp. 117: 266-283 disclose that
melatonin in high doses increases tiredness and the tendency to
sleep in humans.
[0014] Underwood, 1986, J. Pineal Res. 3: 187-196 discloses a phase
response curve for melatonin in the lizard Sceloporus
occidentalis.
[0015] Arendt et al., 1987, Ergonomics 30: 1379-1393 disclose the
administration of melatonin to alleviate jet lag by oral
administration of exogenous melatonin 4 to 6 hours prior to the
human's normal bedtime.
[0016] Mallo et al. 1988, Acta Endocrinol. 119: 474-480 teach that
the administration of 8 mg of melatonin to humans, one hour before
bedtime over a course of four days, results in a slight phase
advance in the melatonin rhythm three days after cessation of the
melatonin treatment but not in other circadian rhythms.
[0017] Armstrong et al., 1989, Experientia 45: 932-938 disclose the
effects of exogenous melatonin administration on the circadian
rhythm of the sleep/wake cycle in rats, and that the effect was
greatest when exogenous melatonin was administered a few hours
before the effective start of the nocturnal activity cycle.
[0018] Petrie et al., 1989, Brit. Med. J. 298: 705-707 teach the
administration of 5 mg of melatonin to humans on a schedule of
three days before flight, during flight, and once a day for three
days after arrival to alleviate jet lag caused by flights from
Auckland, New Zealand to London and back.
[0019] Skene et al., 1989, Sleep '88 (J. Home, ed.), pp. 39-41
teach the use of melatonin to treat jet lag.
[0020] Sack & Lewy, 1989, Amer. Coll. Neuropsychopharm.
Abstract suggest the possibility of achieving a phase advance in a
human using melatonin administered in the evening.
[0021] Samel et al., 1991, J. Biol. Rhythms 6: 235-248 teach the
use of melatonin for the treatment of jet lag using an
administration schedule of melatonin administration at 1800 local
time for 3 days before the time shift, and at 1400 local time for 4
days afterwards.
[0022] Nichelsen et al., 1991, Adv. Pineal Res. 5: 303-306 teach
the administration of 5 mg melatonin at destination bedtime for the
treatment of jet lag resulting from 6, 9 and 11 hour
time-shifts.
[0023] Dahlitz et al., 1991, The Lancet 337: 1121-1124 disclose the
use of melatonin to treat delayed sleep phase disorder.
[0024] Claustrat et al., 1992, Biol. Psychiatry 32: 705-711 teach
the use of melatonin to affect circadian rhythms.
[0025] Sack et al., 1994, Sleep Research 23: 509 disclose melatonin
administration to promote adaptation to shift work.
[0026] Zaidan et al., 1994, Neuroendocrinol. 60: 105-112 describe a
melatonin phase response curve.
[0027] Deacon & Arendt, 1995, Brain Res. 688: 77-85 disclose
dose-dependent phase-shifting effects with melatonin
administration.
[0028] U.S. Pat. No. 5,449,683 issued Sep. 12, 1995 to Wurtnan
teaches the use of low dose melatonin formulations to induce
sleep.
[0029] U.S. Pat. No. 5,498,423, issued Mar. 12, 1996 to Zisapel,
teaches melatonin administration in formulations provided to mimic
a human's endogenous nighttime melatonin profile.
[0030] Similarly, inhibition of endogenous melatonin production
(using, for example, beta-blockers) for affecting human circadian
rhythms have been reported in the prior art.
[0031] Schlager et al., 1993, Soc. Light Treat. Biol. Rhythms
Abstracts 5: 23 teach early morning administration of short-acting
beta-blockers for treatment of winter depression.
[0032] Schlager, 1994, Amer. J. Psych. 151: 1383-1385 teach early
morning administration of short-acting beta-blockers for treatment
of winter depression.
[0033] Schlager et al., 1996, Soc. Light Treat. Biol. Rhythms
Abstracts #15 teach early morning administration of short-acting
beta-blockers for treatment of winter depression.
[0034] The use of light to entrain circadian rhythms is known in
the prior art.
[0035] Lewy et al, 1983, Psychopharmacol. Bull. 19: 523-525
disclose a phase response curve to light in humans and bright light
treatment of delayed sleep phase syndrome.
[0036] Waver et al., 1983, Eur. J. Physiol. 396: 85-87 disclose
light for resetting human temperature and activity rhythms.
[0037] Daan & Lewy, 1984, Psychopharmacol. Bull. 20: 566-568
disclose a phase response curve to light in humans and treatment of
jet lag by scheduled exposure to light.
[0038] Lewy et al, 1985, in Photoperiodism, Melatonin and the
Pineal Gland (Evered et al., eds.), pp. 231-252 disclose bright
light treatment of advanced sleep phase syndrome.
[0039] Czeisler et al., 1986, Science 233: 667-671 disclose light
for resetting the circadian rhythm pacemaker.
[0040] Lewy et al, 1987, Science 235:352-354 disclose circadian
phase-shifting and antidepressant effects of light treatment
[0041] Eastman, 1987, Temporal Disorder in Human Oscillatory
Systems, (Rensing et al., eds.) discloses light to promote
adaptation to shift work.
[0042] Honma & Honma, 1988, Jap. J. Psychiatry Neurol. 42:
167-168 disclose a light phase response curve in humans.
[0043] Wever, 1989, J. Biol. Rhythms 4: 161-186 disclose a light
phase response curve in humans.
[0044] Czeisler et al., 1989, Science 244: 1328-1333 disclose a
light phase response curve in humans.
[0045] Hoban et al, 1989, Chronobiol. Intl. 6: 347-353 disclose the
use of bright light treatment upon awakening to entrain a single
sighted subject's circadian rhythm.
[0046] Minors et al., 1991, Neurosci. Lett. 133: 36-40 disclose a
light phase response curve in humans.
[0047] U.S. Pat. No. 5,163,426, issued Nov. 17, 1992 to Czeisler et
al., discloses the use of bright light to affect circadian
rhythms.
[0048] U.S. Pat. No. 5,167,228, issued Dec. 1, 1992 to Czeisler et
al., discloses the use of bright light to affect circadian
rhythms.
[0049] U.S. Pat. No. 5,176,133, issued Jan. 5, 1993 to Czeisler et
al., discloses the use of bright light to affect circadian
rhythms.
[0050] U.S. Pat. No. 5,304,212, issued Apr. 19, 1994 to Czeisler et
al., discloses the use of bright light to affect circadian
rhythms.
[0051] Eastman et al., 1994, Sleep 17: 535-543 disclose light
exposure regulatory regimens for promoting adaptation to shift
work.
[0052] McArthur et al, 1996, Sleep 19: 544-553 disclose the use of
melatonin to entrain human circadian rhythms.
[0053] U.S. Pat. No. 5,503,637, issued Apr. 2, 1996 to Kyricos et
al., disclose an apparatus for delivering bright light to a human
to affect circadian rhythms.
[0054] U.S. Pat. No. 5,545,192, issued Aug. 13, 1996 to Czeisler et
al., disclose the use of bright light to affect circadian
rhythms.
[0055] Entrainment and regulation of circadian rhythms have been
demonstrated in a number of animal species. The ability to effect
an actual change in the phase of circadian rhythms would be useful
for the alleviation of a number of circadian-rhythm related
disorders.
[0056] U.S. patent Ser. No. 5,242,941, issued Sep. 7, 1993 and U.S.
Pat. No. 5,420,152, issued May 30, 1995, both issued to the present
inventors, were the first to disclose a phase response curve for
melatonin in humans. These references taught that an appropriate
time to administer melatonin to induce a change in phase of human
circadian rhythms is related to the time of dim light melatonin
onset (DLMO), a robust marker of a human's circadian rhythms.
Contrary to the teachings of the prior art (that melatonin was
simply associated with darkness, which came to be thought of as
being equivalent to sleep in diurnal animals), the teachings of
these patents established that the circadian rhythm of endogenous
melatonin production was tightly coupled to the endogenous
circadian pacemaker that regulates the timing of a variety of other
human circadian rhythms (such as core body temperature, cortisol
and sleep propensity), and that affecting the phase of the human
melatonin circadian rhythm by administration of exogenous melatonin
could effect both phase advances and phase delays in other human
circadian rhythms. These patents disclosed that the magnitude and
direction (Le., phase advance or phase delay) of the desired
circadian rhythm phase shift was dependent on the time of melatonin
administration. Contrary to the established teachings of the prior
art, these patents prescribed administration of relatively
non-soporific (<1 mg) dosages of melatonin at times that usually
were not equivalent to destination bedtime, based on the human
melatonin phase response curve (PRC). The teachings of these
patents are hereby expressly incorporated by reference.
[0057] U.S. Pat. No. 5,591,768, issued Jan. 7, 1997 to the present
inventors, disclosed methods of administering exogenous melatonin
at different clock times over a course of melatonin treatment,
wherein melatonin administration was kept at a constant time
relative to the dim light melatonin onset (DLMO) time. In this
patent, the present inventors disclosed the use of administration
regimes holding the time of melatonin administration constant
relative to DLMO time for achieving both phase advances and phase
delays of the melatonin phase response curve, for alleviating
circadian rhythm disorders including jet lag, winter depression,
shift work desynchronies, and sleep disorders. The teachings of
this patent are hereby expressly incorporated by reference.
[0058] The human melatonin PRC described in U.S. patent Ser. Nos.
5,242,941 and 5,420,152 suggested that exogenous melatonin would be
most effective when administered during the light period, to
compete with light as a "substitute" for darkness. The human
melatonin PRC clearly shows that melatonin acts like darkness on
the endogenous circadian pacemaker(s) in humans. The circadian
rhythm of melatonin production has an active phase of about 12
hours (levels reaching from a few picograms per mL of plasma to as
great as several hundred picograms per mL, depending on the
individual) and a quiescent phase of about 12 hours (levels falling
to about 10 pg/mL or lower, depending on the individual and
sensitivity of the melatonin assay). In entrained, sighted
individuals, melatonin is produced only during nighttime darkness
and not during daytime darkness, suggesting that melatonin may act
by helping the endogenous circadian pacemaker to discriminate
between the nighttime dark period and sporadic episodes of daytime
darkness (including daytime sleep). Melatonin in combination with
dim light or darkness thus might be a more effective darkness
zeitgeber than darkness alone in the absence of melatonin. Aside
from its effect on causing the human to perceive darkness, sleep
alone has been found to have little, if any, chronobiologic effect
in humans; however, it is possible that sleep may have a slight
effect in potentiating the phase-shifting effects of melatonin and
darkness.
SUMMARY OF THE INVENTION
[0059] This invention relates to a method for achieving a
chronobiologic (phase-shifting) effect in a human by regulation of
a human's circadian rhythms. Specifically, the circadian
phase-shifting effect is achieved by the administration of
exogenous melatonin. The methods of the invention produce phase
shifting of circadian rhythms by administration of exogenous
melatonin, wherein the term "melatonin" is intended to encompass
melatonin itself and other circadian rhythm phase-shifting
compounds that increase endogenous melatonin levels or act on
melatonin receptors, the term "melatonin levels" is intended to
encompass levels, particularly plasma concentration levels, of
melatonin itself and melatonin agonists, and the term "quiescent
melatonin levels" is intended to encompass melatonin itself and
equivalent agonists, as all of these terms are described herein
(see the Detailed Description of Preferred Embodiments). Further,
the methods of the invention relate to the timing of melatonin
administration to the human. The methods described herein are used
to advance or delay the phase of circadian rhythms in a human. This
effect is advantageously achieved by administering exogenous
melatonin to the human at an appropriate time relative to the
human's endogenous melatonin onset and offset times. In this way,
the present invention is able to alleviate jet lag and other
circadian rhythm disorders of both the phase-delay and the
phase-advance types.
[0060] In one aspect of the invention is provided a method for
achieving a circadian rhythm phase-shifting effect in a human, the
method comprising administering to the human an amount of
melatonin, said administration producing in the human a plasma
melatonin concentration of greater than quiescent melatonin levels.
The timing of plasma melatonin concentrations greater than
quiescent melatonin levels overlaps with either the onset of
endogenous melatonin production in the human (to cause a phase
advance) or the offset of endogenous melatonin production in the
human (to cause a phase delay). Thus, in one embodiment of the
invention is provided a method for causing a circadian rhythm
phase-shifting effect that is a phase advance, wherein the time of
plasma melatonin concentration of greater than quiescent melatonin
levels overlaps with the onset of endogenous melatonin production
in the human. In this embodiment, melatonin is administered to the
human in an immediate-release formulation before about circadian
time (CT) 14, preferably after about CT 6, and levels continue past
the time of endogenous melatonin onset (CT 14 is the time of an
individual's dim light endogenous melatonin onset, termed DLMO,
which is defined and described in detail herein). Alternatively,
exogenous melatonin is administered to a human in a delayed-release
formulation at a time wherein plasma melatonin concentration in the
human is increased to greater than quiescent levels before about CT
14, preferably after about CT 6. Alternatively, exogenous melatonin
is administered to a human in a sustained-release formulation
before about CT 14, preferably in a formulation having a duration
of less than about 12 hours, and preferably after about CT 6 to
continue past the time of endogenous melatonin onset. According to
the methods of the invention, the duration of the exogenous
melatonin pulse, as defined herein, is sufficient to overlap the
endogenous melatonin onset time for any of these different types of
administered formulations, and preferably does not overlap the
endogenous melatonin offset time.
[0061] In another embodiment, the invention provides a method for
causing a circadian rhythm phase-shifting effect that is a phase
delay, wherein the time of plasma melatonin concentration of
greater than quiescent melatonin levels overlaps with the offset of
endogenous melatonin production in the human. In a preferred
embodiment, exogenous melatonin is administered to a human in an
immediate-release formulation before about CT 1, preferably after
about CT 18. Alternatively, exogenous melatonin is administered to
a human in a delayed-release melatonin formulation at a time
wherein plasma melatonin concentration in the human is increased to
greater than quiescent levels before about CT 1, preferably after
about CT 18. Alternatively, exogenous melatonin is administered in
a sustained-release formulation before about CT 1, preferably in a
formulation having a duration of less than about 19 hours, and
preferably at about CT 18, wherein the plasma melatonin
concentration returns to quiescent levels before the next night's
endogenous melatonin onset. According to the methods of the
invention, the duration of the exogenous melatonin pulse, as
defined herein, is sufficient to overlap the endogenous melatonin
offset time (typically, from CT 0 to CT 1) for any of these
different types of administered formulations and preferably does
not overlap the endogenous melatonin onset time.
[0062] In another aspect, the invention provides a method for
achieving a circadian rhythm phase-shifting effect in a human, the
method comprising administering to the human an amount of melatonin
wherein said administration produces in the human a plasma
melatonin concentration of greater than quiescent melatonin levels
for a duration that coincides at least in part with either the
phase advance zone (about CT 6 to about CT 18) or phase delay zone
(about CT 18 to about CT 6) of the human melatonin phase response
curve. In a first embodiment of this aspect of the invention, the
circadian rhythm phase-shifting effect is a phase advance and
exogenous melatonin is administered in a formulation having a
duration to provide a period of plasma melatonin concentration
greater than quiescent melatonin levels within the interval from
about CT 6 to about CT 18. In a second embodiment of this aspect of
the invention, the circadian rhythm phase-shifting effect is a
phase delay and exogenous melatonin is administered in a
formulation having a duration to provide a period of plasma
melatonin concentration greater than quiescent levels within the
interval from about CT 18 to about CT 6. Melatonin administration
for achieving a phase advance advantageously is performed using a
melatonin formulation having a duration of elevated plasma
melatonin concentration that provides maximum stimulation of the
phase-advance portion of the phase response curve (about CT 6 to
about CT 18) while avoiding stimulation of the phase-delay portion
of the phase response curve (about CT 18 to about CT 6), that is,
having a maximum duration of about 12 hours. Melatonin
administration for achieving a phase delay advantageously is
performed using a melatonin formulation having a duration of
elevated plasma melatonin concentration that provides maximum
stimulation of the phase-delay portion of the phase response curve
(about CT 18 to about CT 6) while avoiding stimulation of the
phase-advance portion of the phase response curve (about CT 6 to
about CT 18). However, it is also advantageous both to stimulate
the maximum amount of the phase-delay portion of the phase response
curve, and to provide for the longest duration of elevated plasma
melatonin concentration after the endogenous melatonin offset (at
about CT 1) without overlapping the time of endogenous melatonin
onset. Thus, for achieving a phase delay, melatonin is
advantageously administered having a maximum duration of about 19
hours (i.e., from about CT 18 to about CT 13). For phase advances,
exogenous melatonin administration produces in the human a plasma
melatonin concentration of greater than quiescent melatonin levels
for a time or in a concentration during a time interval from about
CT 6 to about CT 18 that is greater than that produced during the
time interval from about CT 18 to about CT 6. For phase delays,
exogenous melatonin administration produces in the human a plasma
melatonin concentration of greater than quiescent melatonin levels
for a time or in a concentration during a time interval from about
CT 18 to about CT 6 that is greater than that produced during the
time interval from about CT 6 to about CT 18.
[0063] The invention also provides a method for achieving a
circadian rhythm phase-shifting effect in a human, the method
comprising regulating exposure of the human to light, preferably
sufficiently bright light to suppress endogenous melatonin
production. In one embodiment of this aspect of the invention, the
phase-shifting effect is a phase delay, the method comprising
exposing the human to light for a time from about CT 6 to about CT
18. In a preferred embodiment, the human is subjected to light
exposure at a time from about CT 14 to about CT 18. In another
embodiment, the phase-shifting effect is a phase advance, and the
method comprises subjecting the human to light exposure at a time
from about CT 18 to about CT 6. In a preferred embodiment, the
human is subjected to light exposure at a time from about CT 18 to
about CT 1.
[0064] The invention also provides a method for achieving a
circadian rhythm phase-shifting effect in a human, the method
comprising regulating exposure of the human to light, wherein the
human is subjected to darkness or dim light, or by limiting light
exposure, for example, by prescribing the use of dark or
red-colored goggles or other means to prevent a human from exposure
to a light stimulus. In one embodiment of this aspect of the
invention, the phase-shifting effect is a phase advance, the method
comprising subjecting the human to darkness or dim light from about
CT 6 to about CT 18. In a preferred embodiment, the human is
subjected to darkness or dim light from about CT 14 to about CT 18.
In another embodiment of this aspect, the invention provides a
method for achieving a circadian rhythm phase delay, the method
comprising regulating exposure of the human to darkness or dim
light from about CT 18 to about CT 6. In a preferred embodiment,
the human is subjected to darkness or dim light from about CT 18 to
about CT 1.
[0065] Also contemplated as components of the methods of the
instant invention are embodiments wherein melatonin administration
is accompanied, either at times coincident with melatonin
administration times by reducing exposure to artificial or natural
light (i.e., providing darkness), or at appropriate times other
than melatonin administration times, by exposure of a human to
light, either artificial or naturally-occurring. Appropriate
combinations of exogenous melatonin administration, dim light or
bright light treatments are provided by this invention, as
described more fully in the Examples below.
[0066] In another aspect of the invention is provided a method for
achieving a circadian rhythm phase-shifting effect in a human, the
method comprising administering to the human an amount of a
melatonin antagonist or inverse agonist. In these embodiments of
the methods of the invention, melatonin antagonist or inverse
agonist is administered at a time to produce preferred stimulation
of either the advance or delay zone of the melatonin PRC, or to
provide an overlap between the time of plasma concentration levels
of the melatonin antagonist or inverse agonist either the onset of
endogenous melatonin production in the human (to cause a phase
delay) or the offset of endogenous melatonin production in the
human (to cause a phase advance).
[0067] Thus, in one embodiment of this aspect of the invention is
provided a method for causing a circadian rhythm phase-shifting
effect that is a phase delay, wherein the time of plasma
concentration of the melatonin antagonist or inverse agonist
overlaps with the onset of endogenous melatonin production in the
human. In this embodiment, melatonin is administered to the human
in an immediate-release formulation before about circadian time
(CT) 14, preferably after about CT 6, and that levels continue past
the time of endogenous melatonin onset. Alternatively, a melatonin
antagonist or inverse agonists is administered to a human in a
delayed-release formulation before about CT 1, preferably after
about CT 6. Alternatively, melatonin antagonists or inverse
agonists are administered to a human in a sustained-release
formulation before about CT 14, preferably in a formulation having
a duration of less than about 12 hours, and preferably after about
CT 6 to continue past the time of endogenous melatonin offset.
According to the methods of the invention, the duration of the
pulse of melatonin antagonist or inverse agonist, as defined
herein, is sufficient to overlap the endogenous melatonin onset
time for any of these different types of administered
formulations.
[0068] In another embodiment, the invention provides a method for
causing a circadian rhythm phase-shifting effect that is a phase
advance, wherein the time of plasma concentration of the melatonin
antagonist or inverse agonist overlaps with the offset of
endogenous melatonin production in the human. In a preferred
embodiment, a melatonin antagonist or inverse agonist is
administered to a human in an immediate-release formulation before
about CT 1, preferably after about CT 18. Alternatively, melatonin
antagonists or inverse agonists are administered to a human in a
delayed-release melatonin formulation at a time before about CT 1,
preferably after about CT 18. Alternatively, melatonin antagonists
or inverse agonists are administered in a sustained-release
formulation before about CT 1, preferably in a formulation having a
duration of less than about 19 hours, and preferably after about CT
18, wherein the plasma concentration levels of melatonin antagonist
or inverse agonist decrease to pre-treatment levels before the next
night's endogenous melatonin onset. According to the methods of the
invention, the duration of the exogenous pulse of melatonin
antagonist or inverse agonist, as defined herein, is sufficient to
overlap the endogenous melatonin offset time (typically, from CT 0
to CT 1) for any of these different types of administered
formulations and preferably does not overlap the endogenous
melatonin onset time (DLMO).
[0069] In another embodiment of this aspect of the present
invention, melatonin antagonist or inverse agonist is administered
at a time wherein said administration produces in the human a
plasma concentration of melatonin antagonist or inverse agonist for
a time or in a concentration during a time interval from about CT 6
to about CT 18 that is greater than that produced during the time
interval from about CT 18 to about CT 6, to provide a phase delay.
For a phase advance, melatonin antagonist or inverse agonist is
administered at a time wherein said administration produces in the
human a plasma concentration of melatonin antagonist or inverse
agonist for a time or in a concentration during a time interval
from about CT 18 to about CT 6 that is greater than that produced
during the time interval from about CT 6 to about CT 18, to produce
a phase advance.
[0070] In another embodiment, the invention provides a method for
achieving a circadian rhythm phase-shifting effect in a human, the
method comprising administering to the human an amount of a
compound that decreases endogenous production of melatonin in the
human wherein said administration reduces endogenous plasma
melatonin concentration in the human to a plasma concentration for
a duration of time that is co-incident with a portion of the
profile of endogenous melatonin production. In one embodiment of
the method of the invention, the circadian rhythm phase-shifting
effect is a phase advance and the duration of the effect of
administration of a compound that decreases endogenous production
of melatonin in the human on plasma melatonin concentration is from
about CT 18 to about CT 1. In another embodiment, the circadian
rhythm phase-shifting effect is a phase delay and the duration of
the effect of administration a compound that decreases endogenous
production of melatonin in the human on plasma melatonin
concentration is from about CT 14 to about CT 18. In preferred
embodiments, the administered melatonin reducing compound is a
beta-blocker.
[0071] The invention also provides methods for administering
melatonin to a human without causing a circadian rhythm
phase-shifting effect. In this aspect, the invention provides a
method of administering melatonin to a human without causing a
phase shift in the human's circadian rhythms. The inventive methods
comprise administering melatonin to a human wherein said
administration produces in the human a plasma melatonin
concentration of greater than quiescent melatonin levels wherein
the duration of elevated plasma concentration greater than
quiescent levels overlaps equally with both the onset time and
offset time of endogenous melatonin production in the human. In an
alternative embodiment of this aspect of the invention, melatonin
is administered wherein said administration produces in the human a
plasma melatonin concentration of greater than quiescent melatonin
levels wherein the duration of elevated plasma concentration
coincides with equal portions of the phase advance and phase delay
zones of the human's phase response curve.
[0072] Thus, in one embodiment of this aspect of the invention is
provided a method comprising the step of administering to the human
melatonin wherein said administration produces in the human a
plasma melatonin concentration of greater than quiescent melatonin
levels for a time wherein the rise of exogenous melatonin is about
as many hours earlier than the onset as the fall of exogenous
melatonin is later than the offset of the human's pre-treatment
endogenous melatonin profile. In another embodiment, the invention
provides a method comprising administering to the human melatonin
wherein said administration produces in the human a plasma
melatonin concentration of greater than quiescent melatonin levels
for a time wherein the time of plasma melatonin concentration
levels of greater than quiescent melatonin levels is co-incident
with an equal portion of the phase advance and the phase delay
zones of the individual's melatonin phase response curve.
[0073] Methods for administering melatonin antagonists, inverse
agonists and compounds that reduce endogenous melatonin production
in a human that do not produce a phase shift are also provided by
the invention. In one embodiment of this aspect of the invention,
the method comprises administering to the human a melatonin
antagonist, inverse agonist or a compound that reduces melatonin
production in a human, wherein said administration produces a
plasma concentration of melatonin antagonist, inverse agonist or a
compound that reduces melatonin production in a human for a time
co-incident with equal portions of the phase advance and phase
delay zones of the individual's melatonin phase response curve. In
another embodiment, the method comprises administering to the human
a melatonin antagonist, inverse agonist or a compound that reduces
melatonin production in a human, wherein said administration
produces a plasma concentration of melatonin antagonist, inverse
agonist or a compound that reduces melatonin production in a human
for a time wherein the rise of plasma concentration of melatonin
antagonist, inverse agonist or a compound that reduces melatonin
production in a human is about as many hours earlier than the onset
as the fall of plasma concentration of melatonin antagonist,
inverse agonist or a compound that reduces melatonin production in
a human is later than the offset of the human's pre-treatment
endogenous melatonin profile.
[0074] The methods of the invention are advantageously provided to
alleviate a circadian rhythm-associated disorder in a human. In
preferred embodiments, the circadian rhythm-associated disorder is
jet lag, winter depression, shift-work related desynchronies or
sleep disorders.
[0075] Specific preferred embodiments of the present invention will
become evident from the following more detailed description of
certain preferred embodiments and the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0076] FIG. 1 illustrates circadian rhythm phase shifts in the
melatonin PRC for 9 subjects who participated in melatonin phase
response curve trials as described in Example 2.
[0077] FIG. 2 illustrates circadian rhythm phase shifts in the
melatonin PRC for 5 subjects who participated in melatonin phase
response curve trials as described in Example 3;
[0078] FIGS. 3 and 4 illustrate the relationship between the degree
of phase advance and duration (FIG. 3) and half-life (FIG. 4) of
exogenous melatonin administered as disclosed in Example 4. FIGS. 5
and 6 illustrate the relationship between the degree of phase
advance and duration (FIG. 5) and half-life (FIG. 6) of exogenous
melatonin administered as disclosed in Example 5.
[0079] FIG. 7 describes the changes in depression ratings in
patients with winter depression in response to melatonin treatment
compared to placebo, as disclosed in Example 11. FIG. 8 describes
the changes in depression ratings in patients with winter
depression in response to melatonin or light treatment compared to
placebo, as disclosed in Example 11.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0080] The methods of this invention utilize enhancement and
reduction of stimulation of the human melatonin phase response
curve to produce a circadian-rhythm phase shift in a human. The
methods of this invention prescribe particular exogenous melatonin
administration and duration times during a course of exogenous
melatonin treatment to effect a circadian rhythm phase shift.
Exogenous melatonin administration times are prescribed according
to the invention relative to an internal circadian rhythm marker,
the DLMO time, rather than external markers such as destination
bedtime (although administration times can be given as clock times
that relate to known or estimated DLMO times). The invention
thereby provides methods for achieving circadian rhythm
phase-shifting effects that result in the effective treatment of a
variety of circadian rhythm phase disturbances, including jet lag,
winter depression, sleep disorders, shift-work and other human
activity schedule-related disorders and desynchronies with external
zeitgebers. The present invention contemplates the administration
of various doses of melatonin which promote quantitative shifts in
an individual's endogenous circadian pacemaker. The administration
of sufficient doses of melatonin is capable of shifting the
endogenous circadian pacemaker, as well as the melatonin PRC, by an
appropriate degree. A linear dose effect has been found as
described herein and in U.S. Pat. Nos. 5,242,941 and 5,420,152,
incorporated by reference, at melatonin dosages from about 0.125 mg
to about 0.5 mg melatonin. The amount of melatonin administered to
a human subject should be sufficient to achieve the desired
circadian rhythm phase-shifting effect.
[0081] In a preferred embodiment of this invention, a dosage of
about 0.01 mg to about 100 mg, more preferably about 0.1 mg to
about 10 mg, most preferably about 0.1 mg to about 1 mg, of
exogenous melatonin is used to effect the desired change in phase
of the circadian rhythm of endogenous melatonin production. For the
purposes of this invention, the term "exogenously administered
melatonin" encompasses various formulations of melatonin, melatonin
agonists (that is, compounds that mimic melatonin's actions) and
compounds that raise endogenous melatonin levels. Therefore,
whenever reference is made to increasing plasma melatonin levels
due to administration of exogenous melatonin, this refers also to
increasing plasma melatonin levels due to administration of a
melatonin stimulant and increasing equivalent agonist levels due to
administration of a melatonin agonist. In the latter case, when
plasma levels of melatonin are referred to following a melatonin
agonist, these melatonin levels are meant to be equivalent to
levels of the melatonin agonist.
[0082] Pharmaceutical quality melatonin is commercially available.
Since melatonin appears to be absorbed across almost all tissues,
many routes of administration are possible. These include but are
not limited to submucosal, sublingual, intranasal, ocular
cul-de-sac, rectal, transdermal, buccal, intravenous,
intramuscular, and subcutaneous methods of administration. A
variety of administration means, including but not limited to
capsules, tablets, suppositories, repositories, injections,
transdermal or transbuccal patches or any reservoir capable of
containing and dispensing melatonin, are also useful. In a
preferred embodiment of this invention, melatonin is administered
orally.
[0083] It may be advantageous to administer melatonin in
immediate-release formulations, in formulations wherein the
melatonin is continuously released physiologically for a set time
(sustained-release formulations), or in formulations wherein the
physiological release of melatonin is delayed (delayed-release
formulations), or in combinations thereof. The present invention
encompasses the use of such melatonin formulations in the methods
of the instant invention.
[0084] The present invention contemplates the use of melatonin
precursors, agonists and other compounds which mimic melatonin
activity, in place of melatonin (N-acetyl-5-hydroxytryptamine)
itself, as well as compounds that compete with melatonin at the
melatonin receptor (melatonin antagonists) and compounds that
stimulate melatonin receptors to have an effect opposite to that of
melatonin (melatonin inverse agonists), in addition to drugs
(melatonin blockers or melatonin stimulants) and interventions
(such as exposure to light or darkness) that lower or raise,
respectively, endogenous melatonin levels. For the purposes of this
invention, the use of the term "melatonin" will also be understood
to encompass all such melatonin agonists, precursors and other
compounds that mimic melatonin activity, as well as compounds that
increase endogenous melatonin production in the human or otherwise
potentiate or enhance the physiological activity of melatonin in a
human.
[0085] Further, the methods of the invention relate to the timing
of the administration of the dosage of melatonin and these other
agents to the human. The timing of these agents in the human as
described results in a specific phase shift (phase advance or phase
delay) in the human's circadian rhythms.
[0086] The present invention is based on the melatonin phase
response curve (PRC; see U.S. patent Ser. No. 5,242,941 and Example
2 below). The human melatonin PRC, shown in FIG. 1, indicates the
presence of a time interval for each individual during which
administration of exogenous melatonin results in clear and
unequivocal phase-shifting responses. Within this interval, the
time of administration of melatonin is related to the magnitude of
the resulting phase shift of the PRC. The human melatonin PRC
indicates the presence of time intervals for each individual during
which administration of exogenous melatonin results in clear and
unequivocal phase-shifting responses of the phase-advance and
phase-delay types.
[0087] Melatonin administration as disclosed herein is achieved
using melatonin formulations that increase plasma melatonin levels
above quiescent levels present in a human during the day. For the
purposes of this invention, the term "quiescent levels" and
"quiescent melatonin levels" used with regard to endogenous
melatonin plasma concentrations is intended to describe plasma
melatonin levels that range from about 1 to about 10 pg/mL,
depending on the individual and on the sensitivity of the melatonin
assay, and which typically occur during the day in humans.
[0088] The existence of the DLMO provides for rendering the human
melatonin phase response curve in terms of circadian time
(designated CT) as well as clock time. Circadian time can be
determined, for example, relative to at least two events: under
entrained (steady-state) conditions, the first sufficiently bright
light exposure after awakening, designated as CT 0; and the DLMO
time, which is a physiologically-determi- ned event that varies
among individuals but typically occurs about 14 hours (CT 14) after
first sufficiently bright light exposure after awakening. It will
be understood that for most individuals, CT 0 is equivalent to
wake-up time, but that some people awaken to darkness and do not
receive sufficient light exposure until some time after awakening,
which is CT 0 for these individuals.
[0089] In preferred embodiments of this invention, phase advances
or phase delays in circadian rhythms can be effected by
administration of an amount of exogenous melatonin based on any one
of the following measures of the human's circadian rhythms: the
individual's melatonin phase response curve, either actually
measured or predicted; the individual's actual or estimated DLMO
time, relative to other markers such as the individual's wake-up
time (taken to be CT 0); or other circadian markers (such body core
temperature, sleep onset times, and cortisol production) that can
reasonably predict the phase relationships of the DLMO or the
endogenous circadian pacemaker. Circadian time (CT) can be
translated to clock times for ease of consumer or other use of the
methods of the invention.
[0090] A modification of the method of Lewy and Markey (1978,
Science 201: 741-3) is advantageously used to determine the time of
onset of the patient's endogenous melatonin production, and can
also be used to establish the individual's melatonin PRC. The
preferred use of this method is taught in Example 1.
[0091] DLMO times are expected to vary from person to person. The
most convenient method of estimating circadian times are relative
to "sleep offset," defined as CT 0 and equal to the time of first
sufficiently bright light exposure upon awakening. DLMO typically
occurs 14 hours after such early morning light exposure, i.e. at CT
14. For example, for an individual who awakens at 7 a.m., DLMO time
is typically 9 p.m. Thus, if the actual DLMO time is not determined
as disclosed in Example 1, it can be estimated to be at about 9
p.m. for an individual who awakens at about 7 a.m, or 14 hours
after the clock time of first sufficiently bright light exposure
after awakening. Administration times given as circadian time can
then be converted into clock times accordingly.
[0092] Determination of circadian time is done optimally using the
DLMO time. However, in some individuals who have very low melatonin
production (encompassing less than about 10% of the population),
the DLMO will occur at slightly later times than CT 14, so that
determination of the entire melatonin curve may be preferable in
these low melatonin producers. Alternatively, DLMO time can be
calculated as the time when a percent (e.g., about 25%) of peak
endogenous production has been achieved, and the estimate of the
DLMO's circadian time adjusted accordingly.
[0093] Markers for circadian time other than DLMO are also useful,
for example sleep onset (bedtime), and in some cases these markers
are more convenient than the DLMO time. There are also other
physiological markers that may be used, including but not limited
to the core body temperature minimum or the rising limb of the
cortisol circadian rhythm. Preferred markers are markers that are
tightly coupled to the endogenous circadian pacemaker (such as the
DLMO), whereas other, less preferred markers such as the sleep
rhythm (which may be influenced by social cues and other
homeostatic factors) are somewhat less tightly coupled (although
the sleep propensity rhythm is tightly coupled).
[0094] For the purposes of this invention, the increase in plasma
melatonin or melatonin agonist concentration in a human resulting
from administration of exogenous melatonin, melatonin agonist or
compound used to stimulate endogenous melatonin production is
termed the melatonin pulse; the time of the beginning of the pulse
is termed the melatonin rise: and the time of the end of the pulse
is termed the melatonin fall. These terms are used to distinguish
between the increase in plasma melatonin concentrations in a human
resulting from pre-treatment endogenous production of melatonin,
herein termed the melatonin p the time of the beginning of the
profile is termed the melatonin on and the time of the end of the
profile is termed the pre-treatment endogenous offset. The
threshold levels used to discern these times are typically about 10
pg/mL. In some individuals, specifically those termed "very low
secretors," this threshold is decreased to about 1 pg/mL (or even
less in some individuals). It is recognized that, as assay
methodology improves, this lower threshold may be used more
frequently, and could be even lower than these thresholds. For the
purposes of this invention, melatonin onset and offset times are
determined relative to plasma melatonin concentration levels of
about 1-10 pg/mL; this range encompasses daytime (quiescent)
melatonin levels in virtually all individuals.
[0095] The present invention provides methods for achieving a
circadian rhythm phase-shifting effect whereby exogenous melatonin
is administered co-incident with at least a portion of the phase
advance or phase delay zone of the melatonin phase response curve
to provide a phase advance or a phase delay, respectively. This
invention provides for exogenous melatonin having a duration of
preferably less than about 12 hours to be administered from about
CT 6 to about CT 18 to achieve a phase advance, or from about CT 18
to about CT 6 to achieve a phase delay. Administration using this
protocol has as one basis the stimulation of the greatest extent of
the "area under the curve" (AUC) of the phase advance or phase
delay zone of the melatonin PRC, while avoiding stimulation of the
other zone of the PRC to achieve a circadian rhythm phase-shifting
effect in one direction (phase advance) or the other (phase delay).
In these embodiments of the methods of the invention, for phase
advances, exogenous melatonin administration produces in the human
a plasma melatonin concentration of greater than quiescent
melatonin levels for a time or in a concentration during a time
interval from about CT 6 to about CT 18 that is greater than that
produced during the time interval from about CT 18 to about CT 6.
For phase delays, exogenous melatonin administration produces in
the human a plasma melatonin concentration of greater than
quiescent melatonin levels for a time or in a concentration during
a time interval from about CT 18 to about CT 6 that is greater than
that produced during the time interval from about CT 6 to about CT
18.
[0096] The invention also provides methods for achieving a
circadian rhythm phase-shifting effect comprising the step of
elevating plasma melatonin concentration above quiescent melatonin
levels at a time and for a duration that overlaps with the
individual human's onset or offset of endogenous melatonin
production. For a phase advance, exogenous melatonin is
administered at a time and in a formulation having a duration
sufficient to provide for overlap of the elevated plasma melatonin
concentration caused by administration of exogenous melatonin with
the onset of increased plasma melatonin concentration caused by
endogenous melatonin production. For most individuals, the time of
onset of endogenous melatonin onset occurs at about CT 14 or
typically at about 9 p.m., 14 hours after the first
sufficiently-bright light exposure received by the human upon
awakening. For different melatonin formulations, administration of
melatonin before about CT 14 is advantageous for producing a phase
advance. For example, immediate-release formulations are preferably
administered from about CT 6 to the onset of endogenous melatonin
production, whereas sustained-release formulations and delayed
release formulations are administered to raise plasma melatonin
concentration levels above quiescent melatonin levels preferably
from about CT 6 to about CT 18. It will be recognized by those with
skill in the art that alternative times of administration are also
encompassed by the methods of the present invention, provided such
alternative administration schedules produce elevated plasma
melatonin concentration levels that overlap with the onset of
endogenous melatonin production, to produce a phase advance.
[0097] For a phase delay, exogenous melatonin is administered at a
time and in a formulation having a duration sufficient to provide
for overlap of the elevated plasma melatonin concentration caused
by administration of exogenous melatonin with the offset of
increased plasma melatonin concentration caused by endogenous
melatonin production. Endogenous melatonin offset occurs at about
CT 1, which is about one hour after an individual's first morning
sufficiently-bright light exposure (which occurs at awakening for
individuals who awaken after daybreak), and typically corresponds
to clock time of about 8 a.m. For different melatonin formulations,
administration of melatonin before about CT 1 is advantageous for
producing a phase delay. For example, immediate-release
formulations are preferably administered from about CT 18 to the
offset of endogenous melatonin production, whereas
sustained-release formulations and delayed-release formulations are
preferably administered to raise plasma melatonin concentration
levels above quiescent melatonin levels from about CT 18 to about
CT 6. It will be recognized by those with skill in the art that
alternative times of administration are also encompassed by the
methods of the present invention, provided such alternative
administration schedules produce elevated plasma melatonin
concentration levels that overlap with the offset of endogenous
melatonin production to produce a phase delay.
[0098] Since the beginning of increased plasma melatonin
concentrations defines the rise of the exogenous melatonin pulse,
while the end of in creased plasma melatonin concentrations defines
the fall of the exogenous melatonin pulse, the time between the
rise and fall defines the duration of the pulse of increased plasma
melatonin concentration due to exogenous melatonin administration.
The duration of the pulse is expected to vary depending on the
formulation of melatonin administered to the individual.
Administration of immediate-release melatonin formulations (as
disclosed in U.S. Pat. No. 5,242,941, incorporated by reference) is
characterized by a rapid increase in plasma melatonin
concentration, of up to several thousand-fold higher than typical
endogenous melatonin plasma concentrations depending on the size of
the total dose administered, followed by a gradual (compared with
the rate of increase) clearance of elevated plasma melatonin levels
to quiescent levels (i.e., defined herein as being less than about
1 to about 10 pg/mL). Sustained-release melatonin formulations (as
disclosed in co-owned and co-pending U.S. Ser. No. 08/480,558,
incorporated by reference) produce an elevated plasma melatonin
concentration (i.e., defined herein as being greater than about 1
to about 10 pg/mL) over a longer time course, ranging from about 3
to about 19 hours in duration. Delayed-release formulations display
the kinetics and profile of immediate-release formulations, but
include a time lag or delay between administration time and the
time of the exogenous melatonin rise. Formulations comprising
mixtures and combinations of formulations having these plasma
melatonin profiles are understood in the art and provide for
flexibility and variety in melatonin administration regimes. Of
particular importance in this regard is the use of sustained- or
delayed-release formulations that provide for the rise of exogenous
melatonin plasma concentrations at times later than administration
times which would be inconvenient or counter-productive to address
directly (such as causing a melatonin pulse during an individual's
sleep phase to maximally stimulate one zone of the melatonin PRC
while minimally stimulating the other; see below).
[0099] The magnitude of the phase-shifting effect caused by
exogenous melatonin administration, according to the methods of the
invention, depends on the difference between the time of the
exogenous rise and the time of the endogenous onset (for a phase
advance) or the difference between the time of the endogenous
offset and the time of the exogenous fall (for a phase delay).
Also, preferably the exogenous fall overlaps the endogenous onset
for a phase advance, and the exogenous rise overlaps the endogenous
offset for a phase delay. However, melatonin pulses wherein both
the rise and the fall precede the endogenous melatonin onset, or
wherein both the rise and the fall occur within the endogenous
melatonin profile, also produce circadian rhythm phase-shifting
effects (phase advances or phase delays, respectively), albeit less
efficiently than administered pulses that overlap the endogenous
onset or endogenous offset. In these embodiments of the invention,
the magnitude, extent and direction (phase advance or phase delay)
of the achieved phase-shifting effect is dependent on the
difference between the midpoint of the plasma melatonin
concentration duration of the exogenous pulse of melatonin
administration and the midpoint of the plasma melatonin
concentration duration of the endogenous profile of melatonin
production.
[0100] The magnitude of the melatonin phase shift also depends on
the extent of exogenous melatonin stimulation of each zone of the
melatonin phase response curve (PRC). Phase advances of the
greatest magnitude are produced by stimulation of the maximum
portion of the phase-advance zone of the melatonin PRC, which
extends from about CT 6 to about CT 18. Phase delays of the
greatest magnitude are produced by stimulation of the maximum
portion of the phase-delay zone of the melatonin PRC, which extends
from about CT 18 to about CT 6. In addition, the magnitude of the
achieved phase-shifting effect is diminished to the extent that the
opposite zone of the melatonin PRC is stimulated (i.e., exogenous
melatonin stimulation between about CT 18 and about CT 6 can
diminish a phase advance and exogenous melatonin stimulation
between about CT 6 and about CT 18 can diminish a phase delay).
Thus, circadian rhythm phase-shifting is optimally achieved by
stimulation of the appropriate zone of the melatonin PRC wherein
stimulation of the other zone of the melatonin PRC is avoided. This
appears to be important for achieving phase advances, so that
administration of exogenous melatonin in a formulation having a
maximum duration of greater than 12 hours is less advantageous that
administration of formulations having a duration of 12 hours or
less, that are administered to coincide with only the phase-advance
zone of the melatonin PRC. However, at least in the case of phase
delays in at least some individuals, stimulation of the greatest
extent of the phase delay portion of the melatonin PRC can be
accompanied by further stimulation of the phase advance portion of
the PRC between about CT 6 and about CT 13, because such an
exogenous melatonin pulse will provide both the greatest
stimulation of the area under the curve of the delay portion of the
melatonin PRC and the greatest difference between the endogenous
offset and the exogenous fall, without overlap of endogenous
melatonin onset. Thus, the negative effects on circadian rhythm
phase-shifting produced by stimulation of the opposite (i.e.,
phase-advance portion of the melatonin PRC) is offset by the
positive effects on circadian rhythm phase-shifting produced by
increasing the magnitude of the greatest difference between the
endogenous offset and the exogenous fall. However, even in this
situation, for optimal production of phase delays there should be
greater stimulation of the delay zone than the advance zone of the
melatonin PRC.
[0101] The invention also provides methods for administering
melatonin without producing a circadian rhythm phase-shifting
effect. It will be understood by those with skill in the art that,
as a consequence of the existence of the melatonin PRC (first
disclosed in U.S. patent Ser. No. 5,242,941, issued Sep. 7, 1993
and incorporated herein by reference), almost any administration of
exogenous melatonin will potentially cause a phase shift. Melatonin
administration performed in ignorance of such effects on an
individual's PRC runs the risk of causing inappropriate phase
shifts, which may act contra to the other physiological effects
intended to be produced by said melatonin administration. Thus, it
is evident from the present disclosure and the teachings of U.S.
Pat. No. 5,242,941 that an individual's melatonin PRC must be
understood and taken into account whenever exogenous melatonin is
administered to a human, even if a phase shift is to be minimized
or avoided.
[0102] These considerations become especially important in the
treatment of certain circadian rhythm-related pathological
disorders. For example, because of the simultaneous existence
(co-morbidity) of insomnia not related to phase disturbances and
phase-related sleep problems, melatonin pulses may have to be
carefully crafted to stimulate one zone of the melatonin PRC and to
avoid stimulation of the other zone, as well as to take advantage
of any soporific side effects associated with administration of
melatonin.
[0103] In embodiments of the invention providing methods of
administering melatonin without producing phase-shifting effects,
exogenous melatonin is administered to provide an interval between
the exogenous rise and the endogenous onset that is equal to the
interval between the endogenous offset and the exogenous fall.
(This is equivalent to providing the midpoint of the exogenous
pulse to be about 12 hours out of phase with the midpoint of the
endogenous profile.) Alternatively, the invention provides
melatonin administration methods that avoid phase-shifting effects
by stimulating the phase-advance and phase-delay zones of the
melatonin PRC equally, with administration of exogenous melatonin
having a duration that overlaps equal portions of the two zones of
the melatonin PRC. In alternative embodiments the invention also
provides methods for administering melatonin antagonists, inverse
agonists or compounds that reduce endogenous melatonin production
without producing phase-shifting effects. In these embodiments of
the invention, melatonin antagonists or inverse agonists are
administered to provide an interval between the exogenous rise and
the endogenous onset that is equal to the interval between the
endogenous offset and the exogenous fall. Alternatively, the
invention provides methods for administering melatonin antagonists
or inverse agonists that avoid phase-shifting effects by
stimulating the phase-advance and phase-delay zones of the
melatonin PRC equally, with administration of melatonin antagonists
or inverse agonists having a duration that overlaps equal portions
of these two zones of the melatonin PRC.
[0104] The invention also provides methods for achieving a
circadian rhythm phase shift wherein exposure (or lack of exposure)
to sufficiently-bright light is used to affect the duration of a
human's endogenous melatonin production profile. In these
embodiments of the methods of the invention, exposure to light is
provided to suppress endogenous melatonin production, so that
exposure to light during the time when endogenous melatonin
production would otherwise occur during the phase-advance zone of
the melatonin PRC (about CT 14 to about CT 18) will produce a phase
delay, and exposure to light during the time when endogenous
melatonin production would otherwise occur during the phase-delay
zone of the melatonin PRC (about CT 18 to about CT 1) will produce
a phase advance. Comparison with the melatonin PRC reveals that
light produces a phase response curve similar in shape but 12 hours
out of phase with the melatonin PRC. Exposure to light coincident
with the phase-advance zone of the melatonin PRC, particularly from
about CT 14 to about CT 18 where endogenous melatonin production
would otherwise occur, will delay an individual's endogenous
melatonin onset time by reducing endogenous melatonin production
during the advance zone of the melatonin PRC, thus causing a phase
delay. Similarly, exposure to light coincident with the phase-delay
zone of the PRC, particularly from about CT 18 to about CT 1 where
endogenous melatonin production would otherwise occur, will advance
an individual's endogenous melatonin offset time and result in a
phase advance. The use of compounds that reduce endogenous
production of melatonin (e.g., beta-blockers, as described below)
between part or all of the interval from about CT 14 to about CT 1
can be substituted for light suppression of endogenous melatonin
production.
[0105] Conversely, lack of exposure to light (equivalent to
exposure to dim light or darkness) will reduce suppression of
endogenous melatonin production by ambient light and have some of
the same effects and be subject to the same provisions for
effecting circadian rhythm phase shifting as disclosed above for
exogenous melatonin administration. For example, exposure to
darkness during the phase-advance zone of the melatonin PRC,
particularly between about CT 14 and about CT 18 will reduce
suppression by light of endogenous melatonin production during the
advance zone of the melatonin PRC and will shift an individual's
melatonin onset time earlier, thereby resulting in a phase advance.
Similarly, exposure to darkness during the phase-delay zone of the
melatonin PRC, particularly from about CT 18 to about CT 1, will
reduce suppression by light of endogenous melatonin production
during the delay zone of the melatonin PRC and will shift an
individual's endogenous melatonin offset to a later time, thereby
resulting in a phase delay. Alternatively, other means of reducing
bright light exposure, such as wearing dark or red-tinted goggles
or other eye accouterment, are used to produce a circadian rhythm
phase-shifting effect (as disclosed in U.S. Pat. No. 5,591,768,
incorporated by reference). Exposure to darkness is also provided
by the expedient of the individual taking a nap during the
appropriate zone of the melatonin PRC to achieve the desired
circadian rhythm phase-shifting effect.
[0106] Melatonin agonists or melatonin antagonists (and inverse
agonists) are also provided wherein administration mimics, or
opposes, respectively, the action of melatonin on the melatonin PRC
to achieve the desired circadian rhythm phase-shifting effect.
Melatonin blockers or stimulants also mimic the effects of bright
light or darkness (or dim light), respectively, in their effects on
endogenous melatonin production. The phase-shifting effects of
melatonin inverse agonists, melatonin agonists and melatonin
blockers can be predicted according to the melatonin PRC, and in
the case of melatonin blockers, also according to how the
post-treatment onset and offset of endogenous melatonin production
relate to the pre-treatment onset and offset.
[0107] In a preferred embodiment, beta-blockers are administered to
an individual to inhibit endogenous melatonin production and
thereby mimic the effects of light on endogenous melatonin
production. Preferably, beta-blockers are administered having a
duration that overlaps either the onset or offset of endogenous
melatonin production, wherein the change in endogenous melatonin
onset or offset determines the extent of the phase shift produced:
a later onset will cause a phase delay, and an earlier offset will
cause a phase advance. Additionally, beta-blockers are preferably
administered to coincide with a portion of the appropriate zone of
the melatonin PRC to achieve a circadian rhythm phase-shifting
effect. For a phase advance, administration of beta-blockers from
about CT 18 to about CT 1 reduces endogenous melatonin production
in the delay zone of the melatonin PRC as well as shifts the offset
of endogenous melatonin production to an earlier time, thereby
resulting in a phase advance. For a phase delay, administration of
beta-blockers from about CT 14 to about CT 18 reduces endogenous
melatonin production in the advance zone of the melatonin PRC as
well as shifts the individual's endogenous melatonin onset to a
later time, resulting in a phase delay. Thus, beta-blockers are
administered according to the methods of the invention having a
duration appropriate for overlap of endogenous melatonin onset or
offset and to suppress endogenous melatonin production during the
appropriate zone of the melatonin PRC.
[0108] Thus, to obtain a circadian rhythm phase-shifting effect
according to the methods of this invention, melatonin
administration is accomplished so that there is an overlap either
between the rise in post-treatment melatonin plasma concentration
levels and the offset of pre-treatment endogenous melatonin
production, or between the fall in post-treatment levels and the
onset of pretreatment levels. In either event (and also when
overlap occurs in both cases or occurs in neither case), the change
in the onset/rise compared to the change in the offset/fall
predicts the magnitude and direction of the resulting phase shift.
An equal change in the onset/rise compared with the offset/fall is
useful for avoiding a circadian rhythm phase shift, for example,
when melatonin is administered for a reason other than phase
shifting). These teachings apply to the administration of exogenous
melatonin, melatonin agonists and light exposure, and to compounds
that affect (enhance of diminish) endogenous melatonin production
in a human, as well as melatonin antagonists and inverse agonists,
which effectively "reduce" plasma melatonin levels by blocking the
action of melatonin on melatonin receptors or by inducing the
"inverse" response at such receptors. The invention also
encompasses methods that stimulate one zone (i.e., phase advance or
phase delay) of the melatonin PRC more than the other, and
preferably stimulate one zone rather than the other, to produce a
phase shift, while stimulating both zones equally when
administering melatonin, melatonin agonists, melatonin antagonists,
melatonin inverse agonists, compounds that endogenous melatonin
production in a human, or light, to avoid a phase-shifting
effect.
[0109] The present invention may be used in, but is not limited to,
the following situations to achieve chronobiologic effects and/or
to alleviate circadian rhythm phase disorders: jet lag; shift work;
people who have a maladaptation to work and off-work schedules;
submariners, or persons confined for research, exploration or
industrial purposes below the seas; miners, explorers, spelunkers,
researchers or those confined beneath the Earth; psychiatric
patients; insomniacs; the comatose, or those who need to be
maintained in a state of unconsciousness for medical, psychiatric
or other reasons; medical residents, nurses, firemen, policemen or
those whose duties require alertness and wakefulness at evening or
nighttime hours, or those deprived of sleep for various periods
because of their duties or responsibilities; the infantry, or other
members of the armed forces whose duties require extreme levels of
alertness and wakefulness, and who may be sleep deprived in the
performance of these duties; astronauts in orbit around the Earth,
on missions in space to the Earth's moon or to the planets or out
of the known solar system, or in training for such missions; the
blind or sight-impaired or all those whose ability to distinguish
differences in light and dark may be permanently or temporarily
impaired; residents of the far North or Antarctica, or all those
who live in a climate or climates that possess abnormal amounts of
light or darkness; those suffering from seasonal affective
disorder, winter depression, or other forms of depression; infants,
particularly newborns; the aged; Alzheimer's disease patients, or
those suffering from other forms of dementia; the sick, or those
who require dosages of medication at appropriate times in the
circadian cycle; animal breeders, for use in controlling circadian
time; and for ameliorating the phase-disrupting effects of changing
from Standard to Daylight Savings Time or vice versa.
[0110] Five types of insomnia can also be helped by melatonin
administration. One, termed pure insomnia, is not particularly
related to a circadian phase disturbance, and melatonin is useful
for its soporific qualities. Two insomnias are known to be
circadian rhythm-related insomnias; advanced sleep phase syndrome
(ASPS) and delayed sleep phase syndrome (DSPS). There are also two
types of mixed insomnias, termed pure insomnia plus ASPS and pure
insomnia plus DSPS. Since most people have intrinsic circadian
periods greater than 24 hours (which explains why so many people
have at least some difficulty falling asleep quickly initially and
waking up easily and alert), an agent that causes a phase advance
acts to re-entrain circadian rhythms to the 24 hour light/dark
cycle.
[0111] Melatonin Administration Under Medical Supervision
[0112] The present invention provides methods useful in the
treatment any of the above-listed conditions, under direct medical
supervision, wherein melatonin administration times are chosen
after determination of an individuals actual DLMO time. In certain
instances, an individual's PRC must also be specifically
determined, for example, in those patients where use of melatonin
precursors, stimulants, analogs, agonists, inverse agonists,
antagonists, or melatonin blockers require a more precise
determination of dose and time of exogenous administration.
Examples of such instances include individuals whose response to
melatonin treatment, or absorption or metabolism of melatonin or
melatonin agonists, antagonists or precursors may vary from the
normal response, thereby necessitating medical supervision.
[0113] A certain portion of the human population falls outside of
what is considered the "normal" human characteristics of drug
absorption, or have circadian rhythms with unusual characteristics.
These individuals may require a more accurate determination of the
individual melatonin PRC before attempting intervention. Other
individuals who may be suffering from pathological or clinical
circadian rhythm phase disorders may also benefit from a more
accurate determination of the melatonin PRC or at least the DLMO
before intervention. In a controlled setting, under medical
supervision, a more precise and specific intervention of the
melatonin PRC or of just the baseline DLMO can be accomplished
using the methods of the present invention to effect predictable
phase advances or delays. In certain individuals, the endogenous
circadian pacemaker (or "body clock") may in some circumstances
(such as the result of melatonin or light/dark cycle induced phase
shifts) shift faster than the DLMO. In such cases, the rate of
change in the melatonin PRC may need to be determined directly for
optimal scheduling of melatonin administration or light exposure,
although estimations are possible here as well.
[0114] Under medical supervision, a subject can have the DLMO time
determined carefully by sampling physiological levels of melatonin
in blood, saliva or other biological fluids. The concentration of
melatonin can be determined analytically using methods including
but not limited to gas chromatography-mass spectrometry (GC-MS),
radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA)
methods. The advantage of medical supervision is to more accurately
and exactly determine an individual's DLMO time and establish their
melatonin PRC. This information then enables specific and precise
intervention by exogenous melatonin administration for adjusting s
human's circadian rhythms in a predictable manner.
[0115] Melatonin Administration By The Individual
[0116] In another embodiment of the invention, melatonin
administration can be performed directly by an individual without
medical supervision. For such uses, times of exogenous melatonin
administration can be described, for example in a table,
instructing the individual to take melatonin at specific times
based upon normal bedtime and waking time and the magnitude and
direction of the desired phase shift. For example, the use of the
methods herein described to alleviate the effects of jet lag can
advantageously be enabled by an article of manufacture comprising
melatonin in a consumer-accessible formulation, accompanied by
charts or tables setting out proper clock times of exogenous
melatonin administration based on the number of time zones crossed
in travel and the direction of travel, and also based either on
characteristically "normal" human DLMO times or with reference to
any other indicia of an individual's actual DLMO time (such as the
individual's actual wake-up time). In other specific examples of
embodiments of the invention for treating jet lag, melatonin may be
administered in timed-release formulations that are geared to
release melatonin in conjunction with the number and direction of
time zones crossed, releasing the melatonin at the proper times.
Such articles of manufacture and melatonin formulations are
expressly within the scope of the instant invention. Analogous
articles of manufacture, formulations and methods of administration
for treating other circadian rhythm phase disorders are also
provided by and within
[0117] A. Kit for Determining DLMO.
[0118] For many individuals a less precise determination of their
DLMO time will enable them to use the methods provided by this
invention to effect a desired circadian rhythm phase shift based on
an estimate of their DLMO time. A convenient means for allowing an
individual to adjust the DLMO in a predictable manner and without
medical supervision would involve the use of a simple home assay
kit. This assay kit would allow the individual to determine his own
melatonin onset or DLMO time by sampling biological fluids at short
intervals during the course of part of a normal day.
[0119] 1. Dip Stick for Saliva
[0120] In one embodiment, the amount of melatonin or melatonin
metabolite in the individual's saliva could be assayed simply by
applying a saliva sample to an applicator stick designed to react
with melatonin or melatonin metabolite in a concentration-dependent
fashion. The individual could compare the assay sticks contacted
with saliva over a period of time and use an interpreting means
(such as a color comparison strip) to determine the approximate
DLMO time. Once an individual had determined the DLMO time, tables
or other instruction means based on the DLMO time and providing a
schedule of exogenous melatonin administration times for achieving
a desired phase shift could be used to inform the individual when
and how much melatonin to take to achieve the desired phase
shift.
[0121] 2. Blood Drop Test
[0122] In another embodiment, an individual could use a drop of
blood to assay for the physiological concentration of melatonin or
melatonin metabolite, similar to methods currently in use for
determining blood levels of sugar or cholesterol. This assay would
result in a quantitatively more accurate determination of the
individual's DLMO time compared with the previously-described dip
stick method and would be useful for applications of the methods of
the invention wherein more accurate estimates of the DLMO time are
required.
[0123] Alternatively, in certain instances it may be advantageous
to apply these approaches seriatim, i.e., wherein DLMO times are
estimated using awakening as a circadian marker, and in cases where
this estimate proves unsatisfactory or sub-optimal, DLMO times
determined more precisely. The nighttime melatonin profile
(including DLMO time) can be obtained by testing blood, urine,
saliva or other body fluid for the presence of melatonin or
physiological or metabolized products thereof.
[0124] The methods of this invention encompass melatonin
administration times based upon an individual's PRC and DLMO time,
whether actually determined or estimated. Administration times are
prescribed relative to the DLMO time; however, the DLMO time will,
by definition, change as a circadian rhythm phase shift is
accomplished by exogenous melatonin administration and an
individual's melatonin PRC is readjusted (accompanied by
resynchronization of the individual's circadian rhythms with the
external environment). Thus, exogenous melatonin administration
times are, in preferred embodiments, also adjusted to provide a
constant relationship between administration time and DLMO.
[0125] Melatonin can also be administered in combination with
scheduling bright light administration, ordinary-intensity light
exposure, or exposure to dim-light or darkness (or even sleep). In
one embodiment of this aspect of the invention, melatonin
administration using the methods disclosed herein is accompanied by
having an individual wear dark or red goggles at the time of
melatonin administration, to provide for the additive effects of
the combination of melatonin treatment plus darkness. In another
embodiment of this aspect, the individual wears dark goggles at
times including times other than the time of melatonin
administration to avoid the occurrence of a conflicting external
zeitgeber in opposition to the phase shift promoted by the
exogenous melatonin administration protocol. In another embodiment,
light can be used to suppress endogenous melatonin production when
this would occur at the "wrong" time, i.e., at a time according to
the melatonin PRC which would be antagonistic to the desired phase
shift.
[0126] Undesirable endogenous melatonin production can also be
suppressed pharmacologically by melatonin blockers using a number
of pharmaceutical agents, including but not limited to
alpha-2-noradrenergic agonists, beta-adrenergic receptor blockers
and benzodiazepines. It may also be desirable to suppress all or a
part of the endogenous melatonin profile, for example, to cause
receptor supersensitivity; partial suppression creates a new onset
or offset and reduces endogenous melatonin from stimulating the
undesirable part of the melatonin PRC or eliminates potentiating
effects of a competing melatonin, melatonin-like or darkness
(sleep) signal. One example of this embodiment is the use of
atenolol plus a very low dose of melatonin (0.125 mg) in the
treatment of winter depression (as described in U.S. Pat. No.
5,591,768, incorporated by reference). Atenolol is given at about
CT 14 and low-dose melatonin at about CT 8. Atenolol blocks
endogenous melatonin production that would otherwise primarily
occur during the delay zone (which promotes a phase advance), and
it also induces supersensitivity to the melatonin administered at
about CT 8. It is also noted that patients taking such drugs for
other clinical reasons can be expected to have circadian rhythm
side effects, so that it is advantageous to work a compensatory
adjustment in their melatonin levels to avoid unwanted phase
shifts.
[0127] Certain other drugs, such as melatonin stimulants (for
example, tricyclic antidepressants, noradrenergic and
serotoninergic re-uptake blockers, MAO inhibitors and
alpha-2-adrenergic antagonists) can raise endogenous melatonin
levels, particularly between about CT 14 and about CT 1. This side
effect will also affect an individual patient's "biological clock"
in ways predicted by the melatonin PRC.
[0128] Melatonin precursors such as tryptophan,
5-hydroxytryptophan, serotonin and N-acetylserotonin may also raise
endogenous melatonin levels and affect circadian rhythms, either
via their conversion to melatonin, or by the direct action of these
compounds on melatonin receptors. Such influences are predictable
using the melatonin PRC, adjusted to account for absorption time,
metabolic conversion rates, etc.
[0129] The invention also contemplates the co-administration of
sedative-hypnotics, or soporific doses of melatonin (>1 mg) for
use in circumstances in which the soporific compounds are
administered along with lower doses of melatonin given primarily
during wake times.
[0130] As mentioned above, the phase-shifting effects of compounds
that act opposite to melatonin (antagonists, inverse agonists,
blockers) can be analyzed and predicted by the melatonin PRC. In
general, however, the phase-shifting effects of these compounds are
more complex than those of melatonin because these effects depend
on whether a particular compound acts directly on melatonin
receptors to compete with melatonin binding (defined as an
antagonist), or acts to reduce endogenous melatonin production
(defined as a melatonin blocker) or acts to cause an effect
opposite to melatonin (defined as an inverse agonist).
[0131] Melatonin Administration: Formulations
[0132] A. Fixed-Dose Melatonin Formulations
[0133] In the simplest formulations, melatonin is provided as
fixed-dose pharmaceutical compositions. Such compositions and means
for making such compositions are well known in the art. Fixed-dose
formulations provide a predictable phase shift in a "normal"
individual when administered using the methods of the invention
herein disclosed. Clock time for melatonin administration depends
on the magnitude and direction of the desired shift, and the DLMO
time of the individual.
[0134] 1. Based on an Individual's Actual DLMO Time
[0135] An accurately-determined DLMO time for an individual can be
determined by medical assay or by the home assay methods disclosed
above. The administration times appropriate for obtaining the
desired phase shift are then predicted by the melatonin PRC. The
times and dosages of exogenous melatonin administration provided by
the present invention may be used to achieve the desired phase
shift.
[0136] 2. Based on an Individual's Estimated DLMO Time
[0137] In many instances, the magnitude of the preferred phase
shift, or the amount of an individual's desire for the phase shift
{i.e., whether phase shifting is medically necessary (e.g., in
winter depression patients) or less seriously (e.g., for jet lag)},
may permit the administration of melatonin based upon an estimated
DLMO time. This can be done by using the phase position of an
individual's typical wake-up and sleep-onset times as being about
CT 0 and about CT 16, respectively. Using exogenous melatonin
administration schedules based on such rough estimates of the DLMO
time allow reasonably good intervention for most people. Such
interventions can still encompass most of either the estimated
advance or delay zone of the melatonin PRC without overlapping with
the other zone of the PRC that predicts a phase-shifting effect
opposite to the desired effect. Methods using estimated DLMO times
are particularly applicable for alleviating circadian rhythm phase
disturbances caused by transmeridional travel, shift work and other
manmade circadian rhythm desynchronizations of human circadian
rhythms. Immediately after a change in sleep/wake time, the DLMO is
at about the same clock time as before the change. It then often
shifts by about 1-3 hours per day, and after several days is again
at about 14 hours after an individual's typical wake-up time of the
new schedule.
[0138] B. Timed-Release Melatonin Formulations
[0139] Melatonin formulations can be designed to administer the
dose of melatonin slowly over a period of time at a fixed rate,
quickly at a specific time after the taking of the formulation, or
at any other combination of release times and rates. Such
formulations can be made by those with skill in the pharmaceutical
arts.
[0140] 1. That Shift Release Time Over the Period of
Administration.
[0141] Formulations of melatonin can be designed which can be taken
at the same time each day, but which will release melatonin at
different times and rates. These formulations can be selected so
that the timing of physiological activity of administered melatonin
coincides with the times predicted by the melatonin PRC for
achieving a desired phase-shifting effect, even though the clock
time at which the individual takes melatonin does not change during
the course of treatment. In one embodiment, such melatonin
formulations could be dispensed in a kit much like birth control
pills are currently dispensed, with specific formulations being
administered in sequence to achieve the daily shift of exogenous
melatonin administration times without requiring the individual to
vary daily administration times.
[0142] 2. That are of Fixed Time of Release but can Vary in
Dosage
[0143] The linear relationship between phase shift and melatonin
dose has been demonstrated (see Example 6U.S. Pat. No. 5,591,768).
This suggests that formulations of melatonin that release varying
doses of melatonin may be useful; methods for making such
formulations are known in the art. The use of different dose
formulations can also be used in combination over the period of
administration. Such an administration format would allow phase
shifting of circadian rhythms, including the melatonin PRC, in
individuals having unique requirements, for example due to work
schedule, disease, personal reaction to melatonin, life style, or
other factors. Use of such a formulation would enable the
individual to have gradually increasing or decreasing melatonin
levels over time.
[0144] 3. That Shift Release Time and Released Dosage
[0145] Melatonin formulations that release different doses at
different release times may also be useful. Such formulations would
permit the melatonin dose and time of physiological action to be
varied, while still being convenient to use. Use of such
formulations would enable administration of sustained low levels of
melatonin to achieve the desired phase shift, while avoiding the
soporific side effects of large does of melatonin during desired
hours of alertness. Similarly, sustained low-level release of
melatonin during desired hours of alertness can be followed, or
preceded by release of higher levels of melatonin during desired
sleep times to enhance both soporific and indirect (sleep and
darkness-mediated) phase-shifting effects.
[0146] The following Examples describe certain specific embodiments
of the invention. However, many additional embodiments not
described herein nevertheless fall within the spirit and scope of
the present invention and claims.
EXAMPLE 1
Detection of Melatonin Levels in Human Plasma Using Gas
Chromatography-Mass Spectrometry
[0147] Prior to collection of human blood, subjects were kept in
dim light for about 5 hours (usually between 6 p.m. and II p.m.).
An intravenous line or heparin lock was inserted in a forearm vein
and 5 mL of blood drawn every 30 minutes between 7 p.m. and II p.m.
The blood samples were centrifuged for 5 minutes at 1000 g and
4.degree. C., and the plasma aspirated into a silanized glass or
plastic tube. Samples were assayed immediately or frozen for later
analysis. Saliva samples can alternatively be collected and
analyzed To a 1 mL aliquot of such plasma was added 50 picograms of
N-acetyl-5-methoxy(.alpha.,.alpha.,.beta.,.beta-
.-D.sub.4)tryptamine as a chromatographic control. An equal volume
of normal saline was added and the mixture gently shaken with 8
volumes of petroleum ether. The organic phase was removed, and
melatonin and the added
N-acetyl-5-methoxy(.alpha.,.alpha.,.beta.,.beta.-D.sub.4)tryptamine
control extracted from the aqueous phase with 8 volumes of
chloroform. The aqueous phase was then discarded, and the
chloroform evaporated to dryness.
[0148] The dried extract containing melatonin and the added
N-acetyl-5-methoxy(.alpha.,.alpha.,.beta.,.beta.-D.sub.4)tryptamine
control was dissolved in 50 .mu.L ethyl acetate. The melatonin
contained in the plasma samples and the added
N-acetyl-5-methoxy(.alpha.,.alpha.,.b-
eta.,.beta.-D.sub.4)tryptamine control were then derivatized by the
addition of 50 .mu.L of pentafluoroproprionic acid anhydride and
reacted at 70.degree. C. for 10 minutes. These reaction products
were then evaporated to dryness under nitrogen. The dried extract
was partitioned between 0.5 mL acetonitrile and 1 mL hexane by
vigorous mixing followed by centrifugation and removal of the
hexane layer. This partitioning step was repeated twice more,
except that the hexane was not removed after the final
partitioning. The derivatives are stable and can be stored at
-20.degree. C. for several weeks.
[0149] The amount of melatonin present in each sample was
determined by gas chromatographic-mass spectrometric analysis.
Before injection onto the GC column, the dried derivatives were
dissolved in 10 .mu.L iso-octane. 2 .mu.L of this volume were
applied to a 30 m.times.25 .mu.m fused silica capillary column
{0.15 micron film thickness with a 5 m retention gap (Rtx 225,
Restek Corp., Bellefonte, Pa.)}. The oven (HP 5890, Series 2) was
programmed from 85.degree. C. to 240.degree. C. with helium as
carrier gas (constant flow) and methane used as make-up gas
(ionizer, 2.0 torr). Derivatized melatonin and the added
N-acetyl-5-methoxy(.alpha.,.alpha.,.beta.,.beta.-D.sub.4)tryptamine
derivatized control were found to elute from the column after 10-14
minutes.
[0150] Mass spectrographic analysis of the column eluant was then
performed. Mass spectra were recorded using a Hewlett Packard 5989A
mass spectrometer with an ETP Scientific electron multiplier using
HP Chemstation software. The relative signals of melatonin and the
added
N-acetyl-5-methoxy(.alpha.,.alpha.,.beta.,.beta.-D.sub.4)tryptamine
control were detected at m/e (mass/charge) ratios of 320 and 323,
respectively. The amount of melatonin present in any unknown sample
can be determined by comparison of the ratio of the intensities of
these signals to a standard curve, prepared as described using
known amounts of melatonin and added
N-acetyl-5-methoxy(.alpha.,.alpha.,.beta.,.beta.-D.su-
b.4)tryptamine control.
EXAMPLE 2
[0151] Melatonin was administered to nine subjects as two doses of
0.25 mg, two hours apart, thereby simulating a sustained-release
(SR) formulation. Subjects were administered melatonin by capsule
for four days with the following regimen: placebo capsules were
given for the first two days and melatonin capsules were given
during the last four days, followed by a day during which the dim
light melatonin onset (DLMO) was determined. The DLMO was used
because it is an excellent marker for circadian phase position. The
week before this administration regime, each subject's baseline
DLMO was assessed after a six-day course of treatment using only
placebo capsules. Phase shifts were calculated by subtracting the
post-treatment DLMO from the pre-treatment DLMO.
[0152] The results of these studies are shown in FIG. 1. FIG. 1
illustrates phase shifts (double-plotted) for nine subjects who
participated in a total of 30 trials. The circadian time of
administration is referenced to the time of the first capsule. In
these studies, maximal phase advances were found to occur around CT
7.5 (see FIG. 1). The data clearly support the conclusion that the
earlier melatonin is administered in the afternoon and evening, the
greater the degree of the resulting phase advance. However, if
melatonin is administered too early (ie., before about CT 7.5), the
extent of induced phase advances diminish in magnitude or, for very
early administration times, phase delays occur. The phase-advancing
effect of exogenous melatonin administration was found to depend on
the initial time of ingesting the capsule. This results in a phase
relationship between the exogenous rise and the endogenous onset,
characterized in that--within certain limits--the earlier the rise
occurs relative to the onset, the greater the phase advance. These
results provided the first evidence of a phase response curve for
melatonin in humans.
EXAMPLE 3
[0153] Melatonin was administered to five subjects as a single 0.5
mg (or immediate-release (IR)) dose. Subjects were administered
placebo capsules for the first week of the study. For the second
week, subjects were given placebo capsules for two days followed by
four days of melatonin administration. Dim light melatonin onset
(DLMO) times were determined at the end of each week. Phase shifts
were calculated from a comparison of the post-treatment DLMO to the
pre-treatment DLMO. Subjects participated in a series of twelve
trials in which melatonin was administered at different times of
the day and night, resulting in individual phase response curves
(PRCs) for exogenous melatonin.
[0154] The results of these studies are shown in FIG. 2,
illustrating phase shifts (double-plotted) for five subjects (a
total of twelve trials each). The results of these studies
indicated that the circadian time for maximal phase advances was
about CT 11. In this study, the same total dose of melatonin was
administered as in the study described in Example 2. In this
example, however, the earlier melatonin was administered prior to
CT 11, the less the magnitude of the induced phase advance. Phase
delays were found to begin at about the same time as found in
Example 2 (i.e., at about CT 6).
[0155] This result was unexpected, because the IR dose results in a
higher maximum physiological concentration of melatonin in the
subject's bloodstream (C.sub.max). This apparent discrepancy in the
results of Examples 2 and 3 is explained by recognizing that the
single IR dose has a shorter duration than the same total dose
administered as a split dose in Example 2. Duration is understood
to mean the amount of time exogenous melatonin administration
causes or results in plasma melatonin concentration levels to
exceed quiescent levels (which, in these individuals, was less than
about 10 pg/mL). Because the IR dose is a shorter duration dosage
form, these results suggest that the phase relationship between the
fall of the exogenous melatonin pulse and the onset of the
endogenous melatonin profile is one determinant of the magnitude of
the induced phase shift. (Another determinant is the phase
relationship between the exogenous rise and the endogenous onset,
as described in U.S. Ser. No. 5,242,941, incorporated by
reference). These results indicated that the fall of exogenous
melatonin should overlap (i.e., occur later than) the onset of
endogenous melatonin production. The consistent teachings of both
these Examples is that the earlier the afternoon rise of exogenous
melatonin relative to the endogenous onset, the greater the phase
advance observed.
[0156] There are a number of similarities between FIGS. 2 and 3.
One of the most prominent similarities is that the crossover points
between advance and delay responses, and between delay and advance
responses, are about CT 18 and about CT 6, respectively. These
crossover points divide the melatonin PRC in half. This division
makes possible a method of using melatonin pulses for achieving a
circadian rhythm phase-shifting effect wherein the duration of the
exogenous melatonin pulse is about 12 hours, provided the pulse is
localized to one half of the melatonin PRC or the other. Such an
exogenous pulse stimulates one zone of the PRC and not the other in
order to optimally cause a phase shift. This approach is termed the
"area under the curve" (AUC) strategy. For optimizing phase
shifting using the AUC strategy, the duration of the melatonin
pulse is confined to these 12-hour intervals. For enhancing the
magnitude of a phase shift, a dose of 12-hours duration is taken at
the beginning of the appropriate interval, to stimulate the maximal
portion of the appropriate AUC while avoiding as much as possible
stimulating the other, inappropriate AUC of the melatonin PRC.
Thus, in order to optimally cause a phase delay, melatonin is
administered between about CT 18 and about CT 6. In order to cause
a phase advance, melatonin is administered between about CT 6 and
about CT 18. Based on the average DLMO time of 2100 (9 o'clock
p.m.), these circadian times translate to clock times as follows.
In order to cause a phase advance, melatonin is administered
between about 1 p.m. and 1 a.m. In order to cause a phase delay,
melatonin is administered between about 1 a.m. and about 1 p.m.
According to the AUC strategy, the duration of the exogenous
melatonin administered within these time periods should not be
longer than the portion of the appropriate AUC remaining after
melatonin is administered.
EXAMPLE 4
[0157] Melatonin was administered to five subjects as a single 0.5
mg IR dose. Subjects were administered placebo capsules for the
first week of the study. For the second week, subjects were given
placebo capsules for two days followed by four days of melatonin
administration. DLMOs were determined at the end of each week Phase
shifts were calculated from the change from the pretreatment DLMO
to the post-treatment DLMO. Subjects participated in a series of
twelve trials in which melatonin was administered at different
times of the day and night, resulting in individual PRCs for
exogenous melatonin. On one occasion, subjects were given 0.5 mg
melatonin during the day under normal lighting conditions while
plasma samples were drawn to assess pharmacokinetics of melatonin.
Results of the pharmacokinetics were analyzed according to duration
and half-life, and how they affected the magnitude of phase
advances.
[0158] The results of these experiments are shown in FIGS. 3 and 4.
FIG. 3 illustrates the relationship between the magnitude of the
greatest phase advance observed for each subject versus the
duration of the exogenous melatonin pulse. FIG. 4 illustrates the
relationship between the magnitude of the greatest phase advance
for each subject plotted against the half-life of exogenous
melatonin. As is shown in the Figures, it was found that the
greater the duration (FIG. 3) and the greater the half-life (FIG.
4) of exogenous melatonin, the greater the phase advance obtained.
These results further supported the conclusion that, for achieving
a maximal phase advance, exogenous melatonin is administered
sufficiently early in the afternoon (as described by the melatonin
PRC), and is of sufficient duration or half-life to permit the
exogenous melatonin fall to overlap with the endogenous onset.
These results also indicated that stimulation by exogenous
melatonin of a greater extent of the AUC of the advance zone of the
melatonin PRC caused a greater phase advance shift
EXAMPLE 5
[0159] In this study, melatonin was administered to five subjects
as a single 0.5 mg IR dose. Subjects were administered placebo
capsules for the first week of the study. For the second week,
subjects were given placebo capsules for two days followed by four
days of melatonin administration. DLMOs were determined at the end
of each week. Phase shifts were calculated from the change in the
pre-treatment DLMO to the post-treatment DLMO. Subjects
participated in a series of twelve trials in which melatonin was
administered at different times of the day and night, resulting in
individual PRCs to exogenous melatonin. On one occasion, subjects
were given 0.5 mg melatonin during the day under normal lighting
conditions while plasma samples were drawn to assess
pharmacokinetics of melatonin. Results of the pharmacokinetics were
analyzed according to duration and half-life, and how they affected
the magnitude of phase delays.
[0160] The results of these experiments are shown in FIGS. 5 and 6.
FIG. 5 shows the relationship between the magnitude of the phase
delay for each subject versus the duration of the exogenous
melatonin pulse. FIG. 6 illustrates the relationship between the
magnitude of the phase delay for each subject plotted against the
half-life of exogenous melatonin. As is shown in these Figures, the
greater the duration (FIG. 5) and the greater the half-life (FIG.
6) of exogenous melatonin, the greater the phase delay
obtained.
[0161] These results extended the experimental results obtained in
Example 4 with regard to phase advances to apply to phase delays.
These results provided experimental evidence to support the
conclusion that, for achieving a maximal phase delay, exogenous
melatonin is administered during the delay zone of the PRC, and it
has sufficient duration or half-life so that the exogenous
melatonin rise overlaps with the endogenous offset. Thus, these
results led to the conclusion that--within certain limits--the
later the exogenous fall, the greater the phase delay obtained.
These results also indicated that stimulation by exogenous
melatonin of a greater extent of the AUC of the delay zone of the
melatonin PRC caused a greater phase-delay shift.
EXAMPLE 6
[0162] The results obtained in Examples 2 through 5 were used to
construct empirical tables of preferred melatonin administration
times useful for maximizing the magnitude and extent of phase
shifts obtained by exogenous melatonin administration (Tables 1 and
2). The right-hand column of Table 1 relates to maximizing a
circadian phase-delaying effect by providing that the fall of
exogenous plasma melatonin concentration occurs as late as
possible, but before the next's night's onset. The middle column of
Table 1 relates to achieving a circadian phase-shifting effect by
stimulating the maximal extent of the area under the curve (AUC) of
the delay zone of the melatonin PRC and avoiding as much as
possible stimulating the advance zone of the melatonin PRC.
Therefore, for an individual having an endogenous melatonin offset
occurring at about CT 1, melatonin is optimally administered no
later than at about CT 0, so that the rise overlaps (that is,
occurs before) the offset. For this or any other preferred or
desirable administration time for an exogenous melatonin dose, the
duration of the exogenous melatonin pulse can be adjusted in order
to optimize the magnitude of the phase delay. For administration at
about CT 0, the duration of the melatonin dose is less than about
13 hours to avoid overlap of the fall of the exogenous dose with
the onset of endogenous melatonin in the individual the next night.
For individuals having an earlier endogenous offset (i.e., earlier
than about CT 1, caused, for example, by early morning light
exposure), exogenous melatonin is administered earlier than about
CT 0. In this instance, the duration of the exogenous melatonin
pulse can advantageously be longer than about 12 hours, provided
the fall of the exogenous dose does not overlap the onset of the
individual's endogenous melatonin production.
[0163] Alternatively, stimulating the maximal portion of the delay
zone of the AUC of the melatonin PRC is useful for achieving a
phase delay by an administration regime provided in the middle
column of Table 1 for various immediate-release, sustained-release
and combined immediate/sustained-release formulations. For example,
melatonin can be administered at about CT 23 having a duration of
less than or equal to about 7 hours, to avoid stimulation of the
phase-advance zone of the melatonin PRC at about CT 6. A melatonin
dose administered at about CT 23 and having a duration of up to 14
hours would be appropriate if a phase delay was achieved by the
latest possible fall (while avoiding overlap with the endogenous
onset).
[0164] Table 1 can also be used to calculate the proper
administration time for an exogenous dose of any known (or
predicted) duration. In this way, the circadian administration time
can be optimized for any particular immediate- or sustained-release
dose (or mixtures thereof). For example, a dose of melatonin having
a 9-hour duration and administered to produce a phase delay is not
administered after about CT 4 to avoid overlap with endogenous
melatonin onset. Similarly, such a dose is not administered after
about CT 21 to avoid stimulating the phase-advance zone of the AUC
(i.e., from about CT 6 to about CT 18). In addition, melatonin is
advantageously administered before about CT 0 so that the exogenous
rise occurs prior to the endogenous offset. It is also advantageous
to administer melatonin to produce plasma melatonin concentrations
higher than endogenous levels during the interval when endogenous
melatonin is produced.
[0165] The results obtained in Examples 2-5 were also used to
construct a Table of times useful for maximizing the magnitude and
extent of phase advances (Table 2). This Table begins at CT 6,
since it is generally unwise to administer melatonin before this
time to produce a phase advance. The middle column of this Table
teaches overlap of the exogenous melatonin fall with endogenous
melatonin onset for maximizing phase advances. The right-hand
column teaches administering melatonin having a generally longer
duration so that the maximal portion of the phase-advance zone of
the area under the curve (AUC) is stimulated. The duration of
plasma melatonin concentration taught in the right hand column of
Table 2 are optimal, whereas the duration prescribed in the middle
column of the Table is minimal. For any preferred or desirable
administration time for an exogenous melatonin dose, the duration
of the exogenous melatonin pulse can be adjusted in order to
optimize the magnitude of the phase advance. For example, melatonin
administered at about CT 10 advantageously has a duration of no
less than about 4 hours and optimally about 8 hours.
[0166] Table 2 can also be used to calculate the proper
administration time for an exogenous dose of known (or predicted)
duration. Using the middle column of the Table, for example, a
melatonin dose having a duration of about 7 hours is administered
no earlier than about CT 7 (to overlap the endogenous onset at
about CT 14). Similarly, a melatonin dose having a duration of
about 3 hours is administered no earlier than about CT 11. In
general, melatonin is administered at a time appropriate to ensure
overlap between the exogenous fall and the endogenous onset,
assuming the melatonin onset occurs at CT 14. In this way, the
circadian administration time can be optimized for any particular
IR or SR dose (or mixtures thereof) providing for overlap of the
exogenous fall and the endogenous onset. Alternatively, the
right-hand column of the Table is used to direct stimulation of the
maximal portion of the AUC of the phase-advance zone of the
melatonin PRC. For example, a dose having a duration of about 7
hours is optimally administered at about CT 7 rather than about CT
11, so as to stimulate the maximal portion of the of the
phase-advance zone of the melatonin PRC, as well as to overlap the
onset of endogenous melatonin production and to provide the
earliest rise in exogenous melatonin levels.
EXAMPLE 7
[0167] Melatonin is often taken as a soporific agent. Frequently, a
phase advance is also desired (i.e., the sleep phase is desired
earlier than the individual's circadian rhythms dictate, due, for
example, to transmeridional travel to the east). Melatonin's
soporific effectiveness is thus two-fold: a phase advance in the
sleep propensity rhythm can decrease sleep latency, and a direct
effect on sleep (often requiring a higher dose than required by the
circadian rhythm phase shift) may also be produced by melatonin
administration. Additionally, sleep can also help reset an
individual's body clock by superimposing darkness upon the
light/dark cycle. (Under any of these circumstances, however, a
phase delay should be avoided.) However, in the event that
melatonin causes instantaneous phase shifts, proper administration
of melatonin can result in a phase advance in the sleep propensity
rhythm (induced by giving melatonin in the beginning of the night),
and in addition melatonin can be used to promote sleep maintenance
by causing a phase delay in the sleep propensity rhythm by
melatonin administration later in the night that stimulates the
delay zone of the melatonin PRC. (Of course, melatonin stimulation
of the delay zone should be avoided after sleep onset if the
individual is having trouble awakening at the desired time.) This
pattern of effect on sleep propensity and circadian rhythm phase
shifting is advantageously achieved using a melatonin formulation
comprising a sustained-release formulation, or alternatively, a
combination of an immediate-release and a sustained- or
delayed-release formulation.
[0168] If phase delays are to be avoided or minimized, the
exogenous fall should be earlier than the endogenous offset, as
well as to reduce stimulation of the AUC of the phase-delay zone of
the melatonin PRC. Table 3 is constructed to optimize exogenous
melatonin pulse duration to avoid the delay zone of the PRC. The
middle column indicates the maximal duration of exogenous melatonin
concentrations if the AUC strategy is not used (although, for phase
advances, the fall should always precede the offset), whereas the
right-hand column of the Table indicates the exogenous melatonin
duration if the AUC strategy is used. If melatonin is taken at
about CT 15, for example, and a phase delay is to be avoided,
melatonin duration is not more than about nine hours to avoid a
fall later than the offset, and is less than about three hours to
avoid stimulation of the phase-delay zone of the melatonin PRC.
When taking melatonin for its soporific effect, phase delays are
avoided by not administering melatonin after about CT 17 (and at
this time only if it has a one-hour duration), if the AUC strategy
is used. Also, for some individuals who can benefit from
melatonin's soporific effects, melatonin should be taken as early
as possible so as to enhance phase delays; these include elderly
people with sleep maintenance insomnia, early morning awakening and
other signs of abnormally phase-advanced circadian rhythms.
[0169] Sleep-time use of sedative-hypnotics and soporific (>1
mg) doses of melatonin can also be used alone or in combination
with phase-shifting doses (s 1 mg) when direct soporific effects
are needed in addition to the phase-shifting effects of low-dose
daytime administration of melatonin.
EXAMPLE 8
[0170] Melatonin can also be administered to avoid a phase shift
(for example, when melatonin is used specifically as a soporific).
To achieve this result, melatonin is administered at preferred
times and durations so that the rise of exogenous melatonin is the
same number of hours earlier than the onset as the fall is later
than the offset (as shown in Table 4). Table 4 assumes that the
endogenous onset is about CT 14 and the offset is about CT 1,
although it should be recognized that ambient light exposure will
shorten the melatonin duration somewhat, delaying the onset and
advancing the offset. Alternatively, melatonin is given at a time
that provides stimulation of equal parts of the advance and delay
zones of the melatonin PRC.
EXAMPLE 9
Jet Lag
[0171] The present invention and the teachings of U.S. Pat. Nos.
5,242,941 and 5,591,768 provide methods for the treatment of jet
lag using melatonin administration. These teachings of this Example
are primarily based on the area under the curve and overlap
strategies and can be modified according to the teachings of the
previous Examples. Table 5 provides preferred times for using light
exposure to suppress endogenous melatonin production, when such
endogenous melatonin production would otherwise cause a phase shift
contrary to the direction of the desired phase shift. Table 5
teaches that light suppression of endogenous melatonin production
will enhance a phase delay when exposure occurs between about CT 14
and about CT 18, and will enhance a phase advance when exposure
occurs between about CT 18 and CT 1. These are also the preferred
times when it would be advantageous to administer melatonin
blockers. Table 5 also teaches times when additional hours of light
exposure would benefit the desired phase shift on the first day of
arrival and for subsequent days, whereby light exposure stimulates
the light PRC. The Table describes two 12-hour intervals for light
exposure, about CT 18 to about CT 6 for causing a phase delay and
about CT 6 to about CT 18 for causing a phase advance. These are
also the times that would be advantageous for administering
melatonin inverse agonists and melatonin antagonists to achieve the
phase shifts as indicated in the Table.
[0172] In addition, avoiding light exposure can reduce light
suppression of endogenous melatonin production and thereby increase
melatonin stimulation of the melatonin PRC. If appropriately timed,
such endogenous melatonin stimulation will help with a desired
phase shift. The present invention provides the use of avoiding
light exposure for achieving a circadian rhythm phase shift. Table
6 provides an illustration of how avoiding light exposure on the
first day after arrival and for subsequent days is used to affect
circadian rhythm phase shifting for treating jet lag. The Table
discloses preferred times that are particularly important for
reducing light exposure to minimize light suppression of endogenous
melatonin production and facilitate the desired phase shift. The
Table also indicates the 12-hour intervals of each day when light
exposure is reduced on the first day of arrival and for subsequent
days that facilitates the desired phase shift by reducing
stimulation of the light PRC. These 12-hour intervals of reduced
light response (about CT 18 to about CT 6 for enhancing phase
delays and about CT 6 to about CT 18 for enhancing phase advances)
are also the times that are advantageously used for administration
of exogenous melatonin, melatonin agonists and melatonin
stimulants.
[0173] It will be understood that, in using these and other Tables
herein which teach clock time administrations for shifting the body
clock, the body clock can shift up to about 3-4 hours per day. To
be conservative (that is, to avoid scheduling phase-shifting agents
at the "wrong" time), the columns of these and other Tables change
by one hour per day. However, an individual, particularly with
treatment as disclosed by the invention, can shift more than one
hour per day. The rate of phase-shifting for an individual can be
simply monitored by using DLMO time (determined physiologically as
described herein) or some other reliable circadian marker, to
estimate how fast the circadian pacemaker is phase shifted over the
course of treatment. Accordingly, an individual can "skip" the
instructions on any given day and use the invention's instructions
for the following day, or the day after that, etc. That is, instead
of following instructions for Day 2 after arrival, one can follow
them for Day 3, Day 4 or Day 5, depending on how fast one is phase
shifting. For example, if one is shifting at the rate of two hours
per day, then instructions for Day 3 should be substituted for Day
2 and instructions for Day 5 should be substituted for Day 3. If
one is shifting faster, then instructions for Day 4 should be
substituted for Day 2, etc. It will also be understood that Day 0
refers to the schedule before or during the day of travel.
Individuals can monitor the rate of their phase shifting either by
using the services of a physician or other clinical worker, or by
using the "self-administered" tests (e.g., a melatonin dip-stick)
as described above. However, one can usually assume that, if
treated, phase shifting is going to occur at a rate of at least 2
hours per day.
[0174] One way to avoid bright light exposure is to sleep during
the day ("taking a nap"). This behavior influences endogenous
melatonin production by changing the pattern of light exposure
experienced by a human and therefore influences the times and
duration of endogenous melatonin production (because a nap will
cause the biological clock to experience a dark pulse). Times of
nap-taking are therefore important when considering circadian
rhythm phase-shifting effects in a human. A tendency to nap is
common in individuals experiencing transmeridional travel. Nap
times are preferred when light exposure should be avoided or
reduced, most particularly when the appropriate zone (advance or
delay) of the melatonin PRC is advantageously stimulated by
reducing light suppression of endogenous melatonin production.
Table 6 indicates the times when napping advantageously has this
effect on the endogenous melatonin PRC, as well as times when
napping reduces stimulation of the light PRC by ambient light.
Similarly, naps are to be avoided at certain times according to
Table 5, particularly during times when it is desirable that
endogenous melatonin production stimulates the appropriate zone of
the melatonin PRC and most particularly when ambient light
stimulates the appropriate zone of the light PRC. Of course, there
may be other reasons to sleep that need to be taken into account.
However, if an individual feels the need to sleep, Table 6
indicates the preferred times (to avoid stimulation by light of the
light PRC) and most preferred times (to stimulate the melatonin
PRC) to sleep.
[0175] Application of these teachings to alleviating the symptoms
of jet lag are as follows. For a traveler going to Continental
Europe from Portland, Oreg. (nine time zones to the east), a phase
advance of 9 hours is required to re-entrain the traveler to local
time and alleviate the symptoms of jet lag. For this traveler,
light exposure {particularly bright artificial light or sunlight
(which is brighter than indoor light)} preferably occurs between
about 10 a.m. and about 10 p.m. Destination Time (DT). Light is
particularly avoided in the morning before about 10 a.m. DT for the
first day after arrival. This is the time when endogenous melatonin
should not be suppressed by light, so that the absence of light
(i.e., darkness) may facilitate (directly and indirectly)
endogenous melatonin stimulation of the appropriate zone of the AUC
of the melatonin PRC. (Indirect facilitation of melatonin's
phase-shifting effects refers to simultaneous administration of
darkness and melatonin having a mutually potentiating effect.) In
other words, naps are preferably taken before about 10 a.m. DT and
light exposure preferably occurs between about 10 a.m. and 10 p.m.
DT. In addition, naps or prolonged darkness should be avoided
between about 10 a.m. and 10 p.m. DT, and particularly between
about 10 a.m. and 5 p.m. DT, because stimulation by endogenous
metatonin at this time would stimulate the wrong zone of the
melatonin PRC (the delay zone), and would thus work contrary to the
desired 9-hour phase advance. Naps taken before about 10 a.m. are
preferred, since this is also the time when light exposure should
be avoided, and darkness at this time permits endogenous melatonin
production to stimulate the appropriate (advance) zone of the
melatonin PRC, thereby enhancing the desired 9-hour phase advance
needed to adjust to the new time zone. For this traveler, napping
after about 5 p.m. DT would be less likely to counteract the
desired phase shift (since endogenous melatonin production will end
at or before about this time). {However, it will be recognized that
such evening naps might make it more difficult to fall asleep that
night, and that light exposure between about 5 p.m. and about 10
p.m. may be helpful to enhance a phase advance by stimulating the
appropriate (advance) zone of the light PRC.} For shorter trips to
the east, or on subsequent days, these times are preferably moved
earlier, as shown in more detail in Tables 5 and 6.
[0176] Tables 5 and 6 can also be used for prescribing times of
bright light exposure and bright light avoidance for travelers
making transmeridional trips to the west. For example, after the
return trip to Portland (nine time zones to the west, requiring a
9-hour phase delay to re-entrain the traveler to local time and
alleviate the symptoms of jet lag), Table 5 describes the times of
nap avoidance and Table 6 describes the times of nap desirability.
On the first day of arrival, naps should occur after about 4 p.m.
DT, since light exposure is particularly undesirable before this
time (with the same proviso as above that an evening nap might
reduce sleep drive later in the night). Light exposure is avoided
in general between about 4 p.m. and 4 a.m. DT for such a traveler.
Naps are particularly avoided between about noon and about 4 p.m.
DT, and light exposure is particularly desirable at this time, in
order to suppress endogenous melatonin production. Light exposure
is generally desirable for this traveler between about 4 a.m. and 4
p.m. DT. These times are shifted later for shorter trips and on
subsequent days. Table 5 indicates the preferred times (to
stimulate the light PRC) and most preferred times (to avoid
stimulation of the melatonin PRC) to avoid sleep. These times need
to be considered along with other considerations of sleep need and
desirability, when scheduling sleep and nap times.
[0177] Alternatively, if naps are not taken at the appropriate
times, light exposure may be reduced by the use of goggles, as
previously described (see U.S. Pat. No. 5,591,768, incorporated by
reference). The preferred times for obtaining light (Table 5) and
avoiding light (Table 6) regarding the effects of light on
endogenous melatonin production are also the times of the most
sensitive (robust) parts of the light PRC. Avoiding light exposure
at certain times after travel is important for avoiding
re-entrainment by partition, that is, shifting the body clock in
the opposite direction as traveled (which often results in the
sleep/wake cycle shifting in one direction and the other circadian
rhythms shifting in the other direction). Avoiding and obtaining
light exposure may also be important for suppressing endogenous
melatonin production.
[0178] Selective reduction of endogenous melatonin production
during either the advance zone or the delay zone of the melatonin
PRC is also achieved by the use of beta-blockers (or other
pharmacological agents that reduce endogenous melatonin production
or otherwise limit binding of melatonin to melatonin receptors).
Preferred administration times for using beta-blockers to effect
circadian rhythm phase shifting are provided in Table 7. For
example, when traveling east nine time zones, a beta-blocker having
a duration of about 7 hours is advantageously taken at about 10
a.m. DT upon the first day of arrival, thereby reducing endogenous
melatonin production until about 5 p.m. DT. Timing of beta-blocker
administration is earlier than about 10 a.m. for shorter trips (and
on subsequent days) when traveling east, as shown in Table 7. For
earlier administration times (which may prove inconvenient), a
delayed-release (DR) form can be taken at bedtime rather than in
the middle of the night to avoid interference with sleep. For
travel nine time zones to the west, beta-blockers are taken at
about 11 a.m. DT upon arrival. This time should be later for
shorter trips, and on subsequent days (see Table 7). For traveling
west, beta-blockers of four-hour duration are useful and can also
be taken according to Table 7. This Table assumes no delay in the
onset of action. This Table can be appropriately modified if the
duration of action of the beta-blocker is different than seven
hours (for eastward travel) or four hours (for westward travel) or
if the onset of melatonin activity is not immediate. When going
east, durations greater than 7 hours are acceptable; however, the
duration should not be so great that it inhibits endogenous
melatonin production in the beginning of the next night (this would
reduce endogenous melatonin stimulation of the advance zone of the
melatonin PRC), unless complete inhibition of endogenous melatonin
production is desired. (inhibition of the entire endogenous
melatonin profile in some individuals might enhance phase shifting
in either direction.) For facilitating phase advances,
beta-blockers of longer duration are not necessary and should be
taken earlier, ending at about CT 18; they should not be taken
earlier than about CT 6, except with a DR formulation, unless
complete inhibition of endogenous melatonin production is desired.
When going west (requiring a phase delay), durations of greater
than 4 hours are acceptable: for every hour of duration greater
than 4 hours, the beta-blocker should be administered one hour
earlier than is suggested in Table 7, or an appropriate DR
formulation should be used. For facilitating phase delays,
beta-blockers should ideally be about 4 hours in duration. However,
administration should not occur when endogenous melatonin might
stimulate the delay zone of the melatonin PRC, unless complete
inhibition of endogenous melatonin production is desired.
Beta-blockers can be taken for a few days before travel and during
the day of travel; these times are indicated in Table 7 in the rows
designated 0 time zones and are given in Embarkation Time
(E.T.).
[0179] Table 9 illustrates preferred melatonin administration
duration times when taking more than about 1 mg at bedtime for
alleviating jet lag according to the melatonin PRC. For example,
for travel nine time zones to the east (requiring a phase advance),
melatonin administration is disadvantageous prior to about 10 p.m.
DT. A DR formulation may be necessary if one goes to bed earlier
than 10 p.m. DT, which is very common on the plane or after a night
of relative sleep deprivation on the plane. The duration of
exogenously-administered melatonin should be at least nine hours to
permit overlap of the fall with the onset and to maximize the
extent of phase-shifting. However, melatonin duration should not be
more than 12 hours, in order to avoid stimulating the delay zone of
the melatonin PRC, unless the soporific effect during sleep times
is more desirable. (Providing the latest possible fall before the
next night's endogenous melatonin onset requires a longer
duration.) As the melatonin PRC shifts on subsequent days, the
dosage is reduced, or the duration shortened in other ways to avoid
stimulation of the delay zone or to produce a fall later than the
endogenous melatonin offset. Melatonin administration in the middle
of the night (about 0.5-3 mg, preferably achieved using DR
formulations) can be used to help sleep maintenance, but should not
be taken after about 5 a.m. D.T. (see Table 8 for preferred
administration times), unless the soporific effect during sleep
times is more desirable. (Providing the latest possible fall before
the next night's endogenous melatonin onset requires a longer
duration.) This time should be moved earlier, on subsequent days
and for shorter trips to the east.
[0180] For an individual traveling nine time zones to the west
(which requires a phase delay of nine hours to re-synchronize the
traveler to local time), melatonin administration at a dosage of 3
mg in an immediate-release dosage form (or a dose of this order of
magnitude) taken at bedtime will coincidentally be helpful in
causing both sleep as well as having a phase-shifting effect on the
delay zone. For this administration regime, the exogenous melatonin
rise precedes, and the fall occurs later than, the endogenous
melatonin offset. For subsequent days, a set of SR formulations
having increasingly longer durations are useful for facilitating
the required phase delay (see Table 9). After a few days,
formulations having longer durations (to selectively stimulate more
of the delay zone of the melatonin PRC) advantageously are used to
counter any inadvertent phase advance occurring if melatonin is
taken too early during the advance zone of the melatonin PRC (i.e.,
before the endogenous melatonin onset), and also by causing a later
fall. Alternatively, an administration regimen of low-dose SR
melatonin formulation (e.g., having a 12-hour duration) taken at
increasingly later times or combined with a DR formulation (see
Table 10 for preferred administration times) can be used to effect
the required phase delay using a bedtime administration protocol to
produce a fall later than the endogenous offset. Also, melatonin
duration may be higher if the soporific effect during sleep times
is more desirable.
[0181] However, for travel less than three time zones west, bedtime
administration is the wrong time, unless a very long SR formulation
is taken that can cause a more potent phase delay by extending the
new offset, or a low-dose (non-soporific) melatonin formulation is
taken having a 12 hour duration and administered with a 1-3 hour DR
component (see Table 10).
[0182] Melatonin administration before or on the day of travel can
also be advantageous in some circumstances, and the desirability of
administering low-dose and high-dose formulations depends in part
on whether one intends to sleep on the plane and can take melatonin
at a time given as the zero time in Table 6. However, under most
circumstances melatonin administration is disadvantageous prior to
1 a.m. ET when going west or after 1 a.m. ET when going east,
unless the soporific effect during sleep times is more desirable.
To enhance a phase advance (required for eastward travel),
melatonin is taken to stimulate the advance zone of the melatonin
PRC (between about CT 6 and about CT 18), and to enhance a phase
delay (required for westward travel), melatonin is taken to
stimulate the delay zone of the melatonin PRC (between about CT 18
and about CT 6 or longer for some individuals). In addition,
melatonin administration is advantageously accompanied by
concomitant darkness for several hours. Melatonin agonists and
stimulants can also be taken before travel at the same times as
described for melatonin. Melatonin inverse agonists or melatonin
antagonists are taken to stimulate the opposite zone, as described
for melatonin, of the melatonin PRC (see Table 5). Table 5 also
indicates when to take a melatonin blocker to suppress endogenous
melatonin production. Light and dark can also be used as described
before travel, but may interfere with sleep and wakefulness (see
the row for 0 time zones in Tables 5 and 6).
[0183] Dosage forms comprising about 0.5 mg to about 3 mg of
melatonin (or a dose of these orders of magnitude) are
advantageously used for effecting phase shifting for alleviating
the symptoms of jet lag, as described in U.S. Pat. Nos. 5,242,941
and 5,591,768 (incorporated by reference). However, melatonin is
taken no earlier than certain times, depending on the number of
time zones crossed and the number of days after arrival (see Table
11 for preferred administration times), unless the soporific effect
during sleep times is more desirable. For example, after traveling
nine time zones to the west (requiring a phase delay), a 0.5 mg
dose of melatonin is taken no earlier than about 4 p.m. DT, with
later administration times prescribed for subsequent days. When
traveling east, the approximate dose of 0.5 mg of melatonin can be
taken in the middle of the night, following a low-to-moderate dose
IR formulation, if one awakens after sleep onset. However,
middle-of-the-night melatonin administration is not taken so late
at night that it will stimulate the inappropriate zone of the
melatonin PRC (for example, after about 5 a.m. DT the first day
following a trip through nine time zones to the west; see Table
8).
[0184] A complication arises if an air traveler has not completely
adjusted to the new time zone, especially when such a traveler
returns to the embarkation point or other destination before
complete synchrony has been achieved with local time of the first
destination. This situation is illustrated as follows. If an
individual has traveled 8 time zones to the east and stayed four
days without using any schedule of light exposure or avoidance and
without using any exogenous melatonin administration to speed
adjustment, this individual will typically have shifted about 4
hours (instead of the 8 required for complete adjustment to the new
time zone), since it takes at least about one day to shift about
one hour without using any special techniques to enhance phase
shifting. Upon returning to the west, this individual will need to
adjust only 4 hours back to the original circadian phase. In this
case, the Tables and teachings of the present invention are used by
applying the schedule for a westward time zone difference of 4
hours, even though the traveler has crossed through 8 time
zones.
[0185] Another way to treat such partial phase shifts is to
consider the teachings of Tables 5-11 in terms of circadian time.
These Tables are based on the assumption that CT 14 is about 9 p.m.
for most people. For individuals who have not completely adjusted
to a new time zone, however, this will not be the case. For
example, an individual who has only half adjusted to an 8 hour trip
to the east will typically have a DLMO at about 1 a.m. For example,
in Table 5, when returning 8 time zones to the west, light exposure
is obtained between about 9 a.m. and about 9 p.m. on Day 1 (since 1
a.m. is 4 hours later than 9 p.m., the times in the Table should be
adjusted to be about 4 hours later). This adjustment can be made
because, according to Table 5, in order to obtain a phase delay the
light PRC is stimulated between about CT 6 and about CT 18 and
endogenous melatonin stimulation of the melatonin PRC is suppressed
by light exposure between about CT 14 and about CT 18. Table 5 was
constructed using an algorithm for obtaining a phase delay by
administering a melatonin antagonist or melatonin inverse agonist
between about CT 6 and about CT 18 (which is also the time interval
when light exposure will enhance a phase delay according to the
light PRC), as well as by administering a compound that blocks
endogenous melatonin production between about CT 14 and about CT
18; this is also the time interval when light exposure will enhance
a phase delay, in part by suppressing endogenous melatonin
production. Table 5 was also constructed using an algorithm for
obtaining a phase advance by administering a melatonin antagonist
or melatonin inverse agonist between about CT 18 and about CT 6
(which is also the time interval when light exposure will enhance a
phase advance according to the light PRC), as well as by
administering a compound that blocks endogenous melatonin
production between about CT 18 and about CT 1; this is also the
time when light exposure will enhance a phase advance, in part by
suppressing endogenous melatonin production. Table 6 was
constructed using an algorithm for obtaining a phase advance by
administering melatonin, a melatonin agonist or a compound that
stimulates endogenous melatonin production between about CT 6 and
about CT 18, which is also the time interval when avoiding light
exposure will enhance a phase advance according to the light PRC
(from about CT 14 to about CT 18 is also the time interval when
avoiding light exposure will enhance a phase advance by reducing
suppression of endogenous melatonin production by light). Table 6
was also constructed using an algorithm for obtaining a phase delay
by administering melatonin, a melatonin agonist or a compound that
stimulates endogenous melatonin production between about CT 18 and
about CT 6 (which is also the time interval when avoiding light
exposure will enhance a phase delay according to the light PRC;
from about CT 18 to about CT 1 is also the time interval when
avoiding light exposure will enhance a phase delay by reducing
suppression of endogenous melatonin production by light).
[0186] As disclosed above, beta-blocker administration can also be
used to affect re-synchronization of circadian rhythms following
transmeridional travel, as shown in Table 7. A beta-blocker is
administered to block endogenous melatonin production between about
CT 14 and about CT 18 to facilitate a phase delay, and between
about CT 18 and about CT 1 to facilitate a phase advance. For Table
8, phase advances are enhanced by providing that
middle-of-the-night melatonin not be administered after about CT
18, for enhancing a phase advance. Table 9 was constructed on the
assumption that when melatonin is taken at bedtime (about 9 p.m.),
it is advantageous to delay melatonin activity until after about CT
18 when traveling west (and to avoid melatonin activity between
about CT 6 and about CT 18, which would stimulate a disadvantageous
phase advance), and to ensure that melatonin activity ceases before
about CT 18 when traveling east (and to provide melatonin
stimulation of the greatest extent of the area under the curve
between about CT 6 and about CT 18).
[0187] In Table 10, melatonin activity is maximal between about CT
18 and CT 6 to achieve a phase delay, and melatonin activity occurs
between about CT 6 and about CT 18 to achieve a phase advance.
Table 11 is provided for a melatonin formulation having a duration
of about 5 hours, wherein, to achieve a phase delay, melatonin is
administered no earlier than about CT 18. It will be understood
that the algorithmic bases of these Tables are adjusted to account
for incomplete circadian phase adjustments following air travel,
and for individuals whose DLMO times are not 9 p.m.
[0188] In addition, it will be recognized that there are
circumstances when it is desirable to achieve a phase shift after
transmeridional travel whereby the phase shift is opposite to that
of the direction of travel, i.e., when one would rather advance
than delay, or (more likely) delay rather than advance. This
non-intuitive principle is particularly pronounced with regard to
phase delays. For example, a phase delay of 14 hours is generally
preferable to a phase advance of 10 hours after eastward travel
across ten time zones. The methods and teachings of this invention
can be used to achieve a phase delay rather than a phase advance in
such circumstances. Finally, melatonin, melatonin agonists,
antagonists, inverse agonists and compounds that enhance or
diminish endogenous melatonin production can be advantageously
combined with a sedative/hypnotic of appropriate pharmacological
activity and duration or a high-dose melatonin formulation (>1
mg) to be administered at a time whereby sleep loss is reduced
during adjustment to the destination time zone.
EXAMPLE 10
[0189] Human Sleep Phase Disorders
[0190] Delayed sleep phase syndrome (DSPS) is characterized by
difficulty falling asleep and difficulty waking up in the morning.
In general, individuals suffering from DSPS need to have their
circadian rhythms, including the melatonin circadian rhythm,
gradually shifted earlier (i.e., phase advanced) by about 2-6
hours. DSPS can be treated with morning light exposure. According
to the melatonin PRC, this magnitude of phase advance requires
melatonin administration between about CT 6 and about CT 11.
Assuming awakening at about 10 a.m. (which would equal about CT 0),
exogenous melatonin would be administered between about 4 p.m. and
about 9 p.m. According to the invention disclosed in U.S. Pat. No.
5,591,768 (incorporated by reference), the clock time of
administration is shifted earlier each day, on the order of about
15-30 minutes, to keep the phase relationship between the time of
administration and DLMO constant. The instant invention teaches
that the fall of exogenous melatonin is timed to overlap the onset
of endogenous melatonin and continues through the advance zone of
the melatonin PRC. In an individual who awakens at about 10 a.m.,
endogenous melatonin onset typically occurs at about midnight. In
order for the fall to overlap this onset, therefore, the duration
of the exogenous melatonin pulse (administered at about 6 p.m.) is
at least about six hours; however, to stimulate all of the advance
zone of the melatonin PRC, the duration extends to about 4 a.m. and
is be no more than about ten hours in duration, to avoid
stimulation of any part of the delay zone of the AUC of the
melatonin PRC. These times are shifted earlier on successive days
until the desired sleep time is reached, at a rate dependent on how
fast the individual is advancing their circadian rhythms (usually
15-30 minutes per day) a preferred formulation provides a low dose
of melatonin for the first few hours after administration followed
by rising melatonin levels (about six-fold) at about CT 15 to take
advantage of any direct soporific effect of melatonin (since CT 16
typically corresponds to bed-time). A melatonin formulation can be
combined with a short-acting sedative/hypnotic medication to treat
patients with DSPS. Also, in view of the fact that every American
experiences a transient DSPS when adjusting to Daylight Savings
Time, the methods of this invention encompass methods for
alleviating these acute circadian rhythm phase disorders associated
with changing from Standard Time to Daylight Savings Time.
[0191] Advanced sleep phase syndrome (ASPS) is characterized by
difficulty staying awake in the evening and difficulty maintaining
sleep in the morning. ASPS can be treated with evening light
exposure. According to the melatonin PRC as taught by U.S. Pat. No.
5,591,768, exogenous melatonin is administered immediately upon
awakening (i.e., at about CT 0) to cause a phase delay that does
not require awakening during the night to take the formulation.
Alternatively, a DR formulation is administered that is formulated
to increase melatonin levels at about CT 18 and continue through
about CT 6 (to stimulate the AUC of the delay zone of the melatonin
PRC and to avoid stimulating the advance zone of the melatonin PRC)
or through about CT 13 (to produce the latest time of exogenous
melatonin fall that does not overlap the onset of endogenous
melatonin the next night). Additionally, administration times are
shifted later each day, by about 15-30 minutes, as awakening times
gradually shift to later clock times according to the teachings of
U.S. Pat. No. 5,591,768. The instant invention teaches that
melatonin is administered before about CT 1 and that the duration
of elevated plasma melatonin concentration administered at about CT
1 is at least about five hours, in order to have exogenous
melatonin production be continuous with the endogenous melatonin
profile and to stimulate the remaining AUC of the delay zone of the
melatonin PRC. Using another strategy, exogenous melatonin duration
is advantageously about 13 hours (taken at about CT 0) to
selectively stimulate the maximal portion of the AUC of the delay
zone of the melatonin PRC and to provide a maximally delayed fall
that does not overlap the next night's endogenous onset. Low-dose
melatonin administration is important to avoid daytime sleepiness
for administration times affecting plasma melatonin concentrations
during an individual's day in view of these considerations, a
sustained-release formulation is preferred for treating ASPS.
Longer-acting sedative/hypnotics or short-acting sedative/hypnotics
with a delayed-release component can be taken with melatonin in the
treatment of ASPS. Also, in view of the fact that every American
experiences a transient ASPS when adjusting to Standard Time from
Daylight Savings Time, the methods of this invention encompass
methods for alleviating these acute circadian rhythm phase
disorders associated with changing from Daylight Savings Time to
Standard Time. Melatonin agonists and stimulants can be substituted
for melatonin, accompanied by reduced light exposure; melatonin
antagonists and inverse agonists can be given during the opposite
zone of the melatonin PRC as recommended for melatonin, accompanied
by light exposure; and melatonin blockers can be given during the
opposite zone of the melatonin PRC as recommended for melatonin,
accompanied by light exposure, that also coincides with the
endogenous melatonin profile, as described in Example 9.
[0192] Mixed ASPS/DSPS sleep disorders are characterized by those
individuals who have trouble falling asleep and staying asleep.
These individuals are advantageously administered exogenous
melatonin so that the exogenous rise precedes the endogenous onset
and melatonin stimulates the AUC of the advance zone of the
melatonin PRC, having plasma melatonin concentration levels
increase at about CT 15 to induce sleep, and then providing high
plasma melatonin levels until desired wake-up time (stimulating the
AUC of the delay zone of the melatonin PRC) to delay sleep
propensity, and providing a drop-off in levels as quickly as
possible slightly before or around sleep offset.
EXAMPLE 11
[0193] Winter Depression
[0194] Winter depression can be treated by achieving a circadian
rhythm phase shift using exogenous melatonin administration. In
winter depression, most patients are thought to be abnormally phase
delayed when depressed in the winter. According to the melatonin
PRC as taught by U.S. Pat. No. 5,242,941, exogenous melatonin is
administered in the afternoon or early evening, in order to provide
a corrective phase advance. According to the teachings of U.S. Pat.
No. 5,591,768, administration clock times are shifted earlier by
about one hour after about one week of treatment, in order to
stimulate the same point on the melatonin PRC after the melatonin
PRC has shifted as a result of exogenous melatonin treatment; in
this way, the phase relationship between melatonin administration
and the melatonin PRC is maintained. In addition, it has been
determined that individuals with winter depression are extremely
sensitive to the soporific effects of melatonin. Consequently, the
lowest possible dose (about 0.025 to about 0.25 mg) is
administered. Only a sustained-release formulation (or repeated
administration of low-dose immediate release formulations) can
provide a sufficiently long duration of a such dose of melatonin so
that the exogenous melatonin fall is later than the endogenous
melatonin onset (at about CT 14). Thus, in order to treat winter
depression by causing an optimal phase advance, the lowest possible
dose is used with extremely careful timing of its rise and fall, so
that the rise occurs as early as about CT 6 or about CT 8, the fall
overlaps the endogenous onset, and the maximal portion of the AUC
of the advance zone of the melatonin PRC is stimulated (the end of
which is as late as about CT 18), while stimulation of the delay
zone of the melatonin PRC is avoided. Such low-dose SR formulations
preferably have a duration of about 11-12 hours.
[0195] Patients with winter depression were treated with either
melatonin (N=5) or placebo (N=5). All subjects were screened prior
to being admitted into the study and met the following criteria: 1)
the DSM-IV criteria (American Psychiatric Association, 1994) for
moderate to severe major depressive disorder (without psychotic
episodes) or bipolar disorder (depressed or not otherwise
specified) with a winter type seasonal pattern; 2) scored.ltoreq.20
on the Structured Interview Guide for the Hamilton Depression
Rating Scale-Seasonal Affective Disorder Version (SIGH-SAD)
(Williams et al., 1994, Structured Interview Guide for the Hamilton
Depression Scale-Seasonal Effective Disorder Version (SIGH-SAD)
N.Y.: New York State Psychiatric Institute) with Hamilton
Depression Scale (HAM-D) (Hamilton, 1967, Brit J. Soc. Clin.
Psychol. 6: 278-296).ltoreq.10 and an a typical score.ltoreq.5
(Terman et al., 1990, Neuropsychopharmacol. 2: 1-22); 3) reported
that a depression developed during the fall or winter and remitted
the following spring for at least the two preceding years; 4) were
in good physical health; 5) were not suicidal; 6) were not using
psychotropic medications for the prior four weeks or other
medications that interfered with endogenous melatonin production;
7) did not have other serious psychiatric, medical illnesses or
sleep disorders; and 8) were not working a night shift
schedule.
[0196] Prior to inclusion in the study, subjects were interviewed
by a physician and also completed a health and sleep screening
questionnaire. Written informed consent was obtained for all
participants.
[0197] The study was a three-week, parallel-group design,
consisting of a pre-treatment assessment followed by three
treatment weeks. Subjects were randomly assigned to either a
melatonin or placebo group and were counterbalanced based on their
initial depression scores (SIGH-SAD) and their reported awakening
times. Each group received melatonin or placebo in two daily
capsules at about CT 8 and about CT 12, estimated from each
subject's initial reported awakening time (about CT 0). The dose of
melatonin was 0.125 mg per capsule.
[0198] For behavioral ratings, subjects were initially interviewed
face-to-face using the 29-item Structured Interview Guide for the
Hamilton Depression Rating Scale--Seasonal Affective Disorder
version (SIGH-SAD). Two subsequent interviews were done weekly by
telephone and the third and final interview was conducted in
person. All interviews were conducted by a researcher blind to
treatment conditions.
[0199] For the three-week period, subjects completed a Likert daily
rating form and a daily sleep diary. To specifically assess fatigue
associated with the capsule, subjects also completed a Profile of
Mood States (POMS) 30 minutes after ingestion of each capsule. In
addition, pre-study and weekly expectations questionnaires were
completed.
[0200] Ten patients (9 females) with winter depression were
admitted into the study. The mean age of the melatonin group was 37
(SD=13.6; range: 22-58) and the placebo group was 32.2 (SD=8.6;
range: 22-42). The mean pre-treatment SIGH-SAD score for the
placebo group was 29.4; the melatonin group mean was 29.2. The
initial reported mean wake up time for the placebo group was 7:12
AM; the melatonin group mean was 7:20 AM. Two subjects in the
melatonin group dropped out of the study after the second week of
treatment, because of interfering school constraints. Therefore,
the sample size for the third week was too small to be included in
the analyses, although it should be mentioned that the means for
the third treatment week were identical to those of the first two
treatment weeks (mean changes in depression ratings occurred during
the first week of treatment and remained constant through the end
of the study).
[0201] A two-way repeated measures ANOVA using treatment group
(melatonin and placebo) as a grouping factor and week
(pre-treatment and at Week 2) as the repeated measure showed a main
effect for week (p<0.0001) and a significant (week*group)
interaction (p=0.049). a one-tailed, unpaired t-test for SIGH-SAD
scores after two weeks of capsules revealed a significant
difference (p=0.05) between the melatonin and placebo groups (see
FIG. 7). Unpaired t-tests for change scores from pre-treatment to
Weeks One and Two showed significant differences between the groups
(p<0.05). These scores were 15.4 in Week 1 for the group
administered melatonin (Standard Error of the Mean=2.18) and 8.4
for the group administered placebo (S.E.M.=2.04). For Week 2 of
treatment, the scores were 16.8 for the melatonin group
(S.E.M.=1.5) and 9.2 for the placebo group (S.E.M.=2.91). By
classifying subjects into non-responders and responders using the
criteria of 39% or greater decrease in SIGH-SAD ratings to a score
of 21 or less, there was only one responder in the placebo group,
whereas all five subjects responded to melatonin (p=0.048, Fisher's
Exact test).
[0202] These data indicate that melatonin can be used to treat
winter depression. Remarkably, this melatonin regimen seems to be
as effective by some, if not all measures, as morning light
exposure, the current treatment of choice. (The treatment of choice
for winter depression has been morning bright light exposure which
causes a corrective phase advance.) In the present study, the
melatonin dose was lowered to minimize soporific side effects that
can be interpreted by the patient as symptoms of their disease.
Normally, such a low dose is not expected to cause much of a phase
advance. However, by giving the first dose at about CT 8 the
phase-advancing properties of melatonin are enhanced according to
our invention, provided that its duration was continuous with the
endogenous melatonin onset. Such durations were achieved by a
second immediate release melatonin administration given at about CT
12. The two doses also provide for near-maximal stimulation of the
AUC of the advance zone of the melatonin PRC. For perhaps both of
these reasons, an appropriate phase advance can be reasonably
expected using this regimen. In addition, soporific side effects
are avoided using this low dosage form. These data clearly indicate
that the optimal melatonin treatment for winter depression is
administration of the lowest possible dose in a SR formulation,
beginning shortly after about CT 6 and extending to between about
CT 14 and about CT 18, provided that the administered dose at the
same time avoids soporific side effects before bedtime. The same
treatment regimen can be applied to the treatment of any
phase-delay disorder, including but not limited to subsyndromal
winter depression and delayed sleep phase syndrome, even in its
mildest form in which an individual has trouble falling asleep and
waking up alert at the desired time. Melatonin can be given alone,
in combination with morning bright light exposure and in
combination with a melatonin blocker, such as a beta-blocker, to
reduce endogenous melatonin production throughout the night or
primarily during the delay zone of the melatonin PRC. Melatonin
agonists and stimulants can be substituted for melatonin,
accompanied by reduced light exposure; melatonin antagonists and
inverse agonists can be given during the opposite zone of the
melatonin PRC as recommended for melatonin, accompanied by light
exposure, as described in Example 9.
EXAMPLE 12
[0203] Shift Work
[0204] Shift work produces circadian rhythm phase disorders in
workers required to periodically change working hours. For workers
changing to a later shift (for example, from a day shift (8 a.m. to
4 p.m.) to an evening shift (4 p.m. to 12 a.m.)), the invention
disclosed in U.S. Pat. No. 5,242,941 describes melatonin
administration on the delay zone of the melatonin PRC (i.e.,
between about CT 18 and CT 6). According to the teachings of U.S.
Pat. No. 5,591,768, delay-specific administration of exogenous
melatonin is performed at a later clock time on each day over a
course of treatment (typically, about 4-6 days, the number of days
during the work week). According to the instant invention,
exogenous melatonin is administered at about CT 18 (about 1 a.m.),
in order to selectively stimulate most of the delay zone. Melatonin
can also be given at this time, advantageously before shifting the
sleep/wake schedule (appearing in Row Day 0). Melatonin
formulations administered at about CT 18 preferably have a duration
of about 12 hours, in order to stimulate all of the delay zone. For
some individuals, the latest possible fall may be more effective in
causing a phase delay than avoiding stimulating any portion of the
AUC of the advance zone of the melatonin PRC (as long as the fall
ends before that night's onset). In this case, the duration of
increased exogenous melatonin plasma concentration is optimally
longer, about 19 hours. Whatever time of administration is chosen,
however, the exogenous melatonin rise precedes and the fall occurs
after the endogenous melatonin offset to create a circadian rhythm
phase-delaying effect. An optimal modality for administering
melatonin under these circumstances is a SR formulation, so that a
lower dose can be used to avoid sleepiness until about 9 a.m. (when
night workers usually go to bed). In addition, over the last few
days of a treatment period, DR formulations having a delay of up to
about 4 hours can be administered, allowing the capsule to be taken
no later than bedtime, i.e., around 9 a.m. (see Table 12 for
preferred administration times).
[0205] To be conservative (that is, to avoid scheduling
phase-shifting agents at the "wrong" time), the columns of these
and other Tables change by one hour per day. However, an
individual, particularly with treatment as disclosed by the
invention, can shift more than one hour per day. The rate of
phase-shifting for an individual can be simply monitored by using
DLMO time (determined physiologically as described herein) or some
other reliable circadian marker, to estimate how fast the circadian
pacemaker is phase shifted over the course of treatment.
Accordingly, for some individuals who shift more quickly than
average, the suggested administration time for Day 3 can be
substituted for Day 2, Day 5 for Day 3, etc. For those individuals
who shift even more quickly, Day 4 and be substituted for Day 2,
Day 6 for Day 3, etc. Individuals can monitor the rate of their
phase shifting either by using the services of a physician or other
clinical worker, or by using the "self-administered" tests (e.g., a
melatonin dip-stick) as described above. However, one can usually
assume that, if treated, phase shifting is going to occur at a rate
of at least 1-2 hours per day.
[0206] For treatment embodiments comprising beta-blockers (or any
pharmacologic means of reducing melatonin production or blocking
SCN melatonin receptors), the drugs are taken at about 9 p.m., and
then at successively later clock times until about 9 a.m., and are
taken only in formulations having a duration of less than about
four hours (see Table 13 for preferred administration times).
Beta-blockers having durations longer than about 4 hours can be
used according to modification of the instructions comprising the
Tables. For example, a beta-blocker with a 12-hour duration and
used for delaying to the night-work schedule is taken on Day 1 at
about 1 p.m. to avoid reducing endogenous melatonin production on
any part of the delay zone of the melatonin PRC, while still
reducing endogenous melatonin stimulation of the advance zone of
the melatonin PRC. Of course, this means that the beta-blocker is
also taken when, at least in part, no endogenous melatonin
production is occurring; therefore, a four-hour duration is
preferable. However, beta-blockade should not occur when endogenous
melatonin might stimulate the delay zone of the melatonin PRC
unless complete inhibition of endogenous melatonin production is
desired. For facilitating phase delays, beta-blocker formulations
having shorter duration times are advantageously administered at
earlier times, to end at about CT 18; however, they should not be
taken earlier than about CT 6, except for DR formulations, unless
complete inhibition of endogenous melatonin production is desired
(which might enhance phase shifting).
[0207] Alternatively, shift workers can advance the phase of their
circadian rhythms to the nighttime work schedule. To do this, the
instant invention teaches administration of exogenous melatonin in
a sustained-release formulation having about a 12-hour duration and
an administration time of about 9 a.m. (bedtime). However for the
first few days of treatment, a delayed-release/sustained-release
formulation is given in which levels substantially rise four hours
after bedtime administration on the first day, with decreasing
delays on subsequent days. After this initial delayed-release
regimen, a SR formulation should be taken at successively earlier
administration clock times (see Table 14 for preferred
administration times). Treatment regimes using beta-blockers
(having a seven-hour duration) prescribe drugs administration at 1
a.m. and then at successively earlier administration clock times.
At the endpoint of treatment, beta-blockers are taken at about 9
a.m. (bedtime) with the delayed-release interval decreasing from
about 7 to about 5 hours (see Table 15 for preferred administration
times). The delayed-release interval is needed to avoid getting up
during the daytime sleep period. For facilitating phase advances,
beta-blockers ideally have about seven hours duration, unless
complete inhibition of melatonin endogenous is desired (which might
enhance phase shifting).
[0208] When shifting back to the off-work week, a phase advance is
sometimes preferred. According to the melatonin PRC taught in U.S.
Pat. No. 5,242,941, this can be achieved by exogenous melatonin
administration at about 1 a.m., assuming that the circadian rhythms
have completely adapted to the 12-hour phase shift during the
previous week. Consequently, a DR formulation would be essential,
because taking melatonin at bedtime might stimulate part of the
delay zone of the melatonin PRC (contrary to the desired phase
advance). Preferred administration times for a delayed-release
formulation set to release melatonin four hours after the final
administration, in order to stimulate the advance zone of the
melatonin PRC, are shown in Table 16.
[0209] Sustained-release formulations are also preferred to provide
low melatonin plasma levels at the end 0.10 of the pulse to avoid
the soporific effects of melatonin. After a few days of treatment,
the SR formulation would not need the DR component and would be
taken at times successively earlier. Beta-blockers can be taken at
1 p.m. and then successively earlier (see Table 17 for preferred
administration times), preferably having a duration of about 7
hours. For the last few days, beta-blocker are taken having a DR
component, set to produce a substantial rise in beta-blocker levels
at about 9 hours after administration and then having decreasing
delayed-release intervals on subsequent days, ending with a delayed
administration time of about 5 hours on Day 12. This regime is
constructed to avoid the need to wake up to take a formulation
(which would interfere with sleep). Beta-blocker formulations
preferably have a duration of less than about 12 hours, unless
complete inhibition of endogenous melatonin production is desired.
Some shift workers prefer to delay to the off-work week. These
workers take a 12-hour SR melatonin formulation at about 1 p.m. on
the first day and then successively later. For the last few days of
the treatment regime, preferred melatonin administration times are
held constant at about 9 p.m. with successively longer DR
components, until melatonin is administered having about a 3 hour
delayed-release interval on Day 12 (see Table 18 for preferred
administration times). This is done to avoid having to wake up to
take a formulation (which would interfere with sleep).
Beta-blockers of at least about 7 but not more than about 12 hours
duration should be taken at about 9 a.m. and then successively
later until about 9 p.m. on Day 12, or the last day of
administration if resetting is completed sooner (see Table 19 for
preferred administration times). Beta-blockers should never be
taken with a duration of more than 12 hours, unless complete
inhibition of endogenous melatonin production is desired.
[0210] For shift workers who have not adjusted completely or for
some other reason do not start the work week or off-work week with
a baseline DLMO of 9 p.m., the teachings of Tables 12-19 are
modified or the appropriate algorithm for each Table used to
determine the appropriate melatonin administration time. If the
worker has not completely shifted 12 hours by the end of the work
week, one would start on the appropriate row of the appropriate
Table (the same thinking applies to the shift worker who has not
completely adjusted to the off-work schedule when using the work
week Tables). For Tables 12 and 18, melatonin having an about
12-hour duration is administered to cause elevated plasma melatonin
concentrations between about CT 18 and about CT 6 to achieve a
phase delay. For Tables 14 and 16, melatonin having an about
12-hour duration is administered to cause elevated plasma melatonin
concentrations between about CT 6 and about CT 18 to achieve a
phase advance. For Tables 13 and 19 beta-blocker levels are
elevated between about CT 14 and about CT 18 for facilitating a
phase delay. For Tables 15 and 17, beta-blockers should be active
between about CT 18 and about CT 1 for facilitating a phase
advance. Melatonin agonists and stimulants can be substituted0for
melatonin, accompanied by reduced light exposure; melatonin
antagonists and inverse agonists can be given during the opposite
zone of the melatonin PRC as recommended for melatonin, accompanied
by light exposure, as described in Example 9.
EXAMPLE 13
[0211] Many infants, most totally blind people, and a few sighted
adults have free-running circadian rhythms that are not entrained
to the light/dark cycle. These individuals therefore would benefit
from the applications of the methods of this invention to entrain
their free-running circadian rhythms to about a 24 hour period.
[0212] Most free-running people have an intrinsic circadian period
of slightly more than 24 hours. For these people, a small daily
phase advance is required to entrain their intrinsic circadian
period to about 24 hours. Entrainment of sighted people can be
accomplished using appropriately-timed bright exposure. Exogenous
melatonin administration is used in a method provided by the
invention wherein melatonin, a melatonin agonist or a compound that
stimulates endogenous production of melatonin in a human is
administered at a time and for a duration of plasma melatonin or
agonist concentration greater than quiescent melatonin or
equivalent agonist plasma concentration wherein the time overlaps
with the endogenous melatonin onset and preferably does not overlap
endogenous melatonin offset. Exogenous melatonin agonist or a
compound that stimulates endogenous production of melatonin in a
human is also effectively administered wherein a greater portion of
the advance zone of the melatonin PRC (from about CT 6 to about CT
18) is stimulated than the delay zone of the melatonin PRC (from
about CT 18 to about CT 6). For the blind, melatonin administration
is required daily (or almost daily) to maintain entrainment of
their intrinsically free-running circadian rhythms. For sighted
people, melatonin administration can be supplemented with increased
light exposure scheduled to occur during a greater portion of the
time interval between about CT 18 to about CT 6 (particularly from
about CT 18 to about CT 1) than the time interval from about CT 6
to about CT 18 (particularly between about CT 14 and about CT 18).
For both sighted and blind people, melatonin antagonists or inverse
agonists can be administered instead of, or even in addition to,
exogenous melatonin at times described for light exposure. For both
sighted and blind people, compounds that block endogenous melatonin
production can be administered instead of or along with the other
phase-shifting agents disclosed herein, most preferably during the
time interval from about CT 14 to about CT 18, or to coincide with
the entire endogenous melatonin profile (about CT 14 to about CT
1).
[0213] Some free-running individuals have intrinsic circadian
periods that are slightly less than 24 hours. These people require
a phase delay to entrain their intrinsic circadian period to about
24 hours. Exogenous melatonin administration is used in a method
provided by the invention wherein melatonin, a melatonin agonist or
a compound that stimulates endogenous production of melatonin in a
human is administered at a time and for a duration of plasma
melatonin or agonist concentration greater than quiescent melatonin
or equivalent agonist plasma concentration wherein the time
overlaps with the endogenous melatonin offset and preferably does
not overlap endogenous melatonin onset. Exogenous melatonin agonist
or a compound that stimulates endogenous production of melatonin in
a human is also effectively administered wherein a greater portion
of the delay zone of the melatonin PRC (from about CT 18 to about
CT 6) is stimulated than the advance zone of the melatonin PRC
(from about CT 6 to about CT 18). For the blind, melatonin
administration is required daily (or almost daily) to maintain
entrainment of their intrinsically free-running circadian rhythms.
For sighted people, melatonin administration can be supplemented
with increased light exposure scheduled to occur during a greater
portion of the time interval between about CT 6 to about CT 18
(particularly from about CT 14 to about CT 18) than the time
interval from about CT 18 to about CT 6 (particularly between about
CT 18 and about CT 1). For both sighted and blind people, melatonin
antagonists or inverse agonists can be administered instead of, or
even in addition to, exogenous melatonin at times described for
light exposure. For both sighted and blind people, compounds that
block endogenous melatonin production can be administered instead
of or along with the other phase-shifting agents disclosed herein,
most preferably or to coincide with the entire endogenous melatonin
profile also co-incident with the melatonin profile (about CT 14 to
about CT 1).
[0214] It should be understood that the foregoing disclosure
emphasizes certain specific embodiments of the invention and that
all modifications or alternatives equivalent thereto are within the
spirit and scope of the invention as set forth in the appended
claims.
1TABLE 1 To Produce a Phase Delay If AUC Important, If AUC not
Important, CT of Duration of Exogenous Duration of Exogenous
Administration Pulse of at Least About: Pulse of at Least About: 18
.ltoreq.12 hrs .ltoreq.19 hrs 19 .ltoreq.11 hrs .ltoreq.18 hrs 20
.ltoreq.10 hrs .ltoreq.17 hrs 21 .ltoreq.9 hrs .ltoreq.16 hrs 22
.ltoreq.8 hrs .ltoreq.15 hrs 23 .ltoreq.7 hrs .ltoreq.14 hrs 0
.ltoreq.6 hrs .ltoreq.13 hrs 1 .ltoreq.5 hrs .ltoreq.12 hrs 2
.ltoreq.4 hrs .ltoreq.11 hrs 3 .ltoreq.3 hrs .ltoreq.10 hrs 4
.ltoreq.2 hrs .ltoreq.9 hrs 5 .ltoreq.1 hrs .ltoreq.8 hrs
[0215]
2TABLE 2 To Produce a Phase Advance Duration of Optimal Duration of
CT of Exogenous Pulse of Exogenous Pulse of Administration at Least
About: About 6 8 hrs 12 hrs 7 7 hrs 11 hrs 8 6 hrs 10 hrs 9 5 hrs 9
hrs 10 4 hrs 8 hrs 11 3 hrs 7 hrs 12 2 hrs 6 hrs 13 1 hr 5 hrs 14
-- 4 hrs 15 -- 3 hrs 16 -- 2 hrs 17 -- 1 hr
[0216]
3TABLE 3 Melatonin used as a soporific, to avoid phase delays
Maximal Duration of Maximal Duration of Exogenous Pulse, if
Exogenous Pulse, if AUC not Important, AUC Important, At CT Should
be About: Should be About: 12 <12 hrs <6 hrs 13 <11 hrs
<5 hrs (DLMO) 14 <10 hrs <4 hrs 15 <9 hrs <3 hrs
(Bedtime) 16 <8 hrs <2 hrs 17 <7 hrs <1 hr 18 Avoid
Avoid 19 Avoid Avoid
[0217]
4TABLE 4 To Avoid a Phase Shift CT of Duration of Exogenous
Administration Pulse 13 .congruent. 13 hrs 12 .congruent. 14 hrs 11
.congruent. 15 hrs 10 .congruent. 16 hrs 9 .congruent. 17 hrs 8
.congruent. 18 hrs 7 .congruent. 19 hrs
[0218]
5TABLE 5 When to Obtain Light Exposure for Stimulating the Light
PRC (and when to take a Melatonin Antagonist or Inverse Agonist);
and when to obtain light exposure for avoiding (or reducing)
Stimulating of the Melatonin PRC by Suppressing Endogenous
Melatonin Productions (and when to take a Compound that Blocks
Endogenous Production of Melatonin). (Row 0 is in Embarkation Time;
all others are in Destination Time.) Light Time Exposure Zones to:
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 .Arrow-up
bold. 15 Stim. 10 pm- 11 pm- M-N 1 am-1 pm 2 am-2 pm 3 am-3 pm 4
am-4 pm 5 am-5 pm Light PRC: 10 am 11 am Avoid Stim. 9 am-1 pm 7
am-11 am 8 am-N 9 am-1 pm 10 am-2 pm 11 am-3 pm N-4 pm 1 pm-5 pm
Mel. PRC: .Arrow-up bold. 14 Stim. 11 pm- M-N 1 am-1 pm 2 am-2 pm 3
am-3 pm 4 am-4 pm 5 am-5 pm 6 am-6 pm Light PRC: 11 am Avoid Stim.
7 am-11 am 8 am-N 9 am-1 pm 10 am-2 pm 11 am-3 pm N-4 pm 1 pm-5 pm
2 pm-6 pm Mel. PRC: .Arrow-up bold. 13 Stim. M-N 1 am-1 pm 2 am-2
pm 3 am-3 pm 4 am-4 pm 5 am-5 pm 6 am-6 pm 7 am-7 pm Light PRC:
Avoid Stim. 8 am-N 9 am-1 pm 10 am-2 pm 11 am-3 pm N-4 pm 1 pm-5 pm
2 pm-6 pm 3 pm-7 pm Mel. PRC: .Arrow-up bold. 12 Stim. 1 am-1 pm 2
am-2 pm 3 am-3 pm 4 am-4 pm 5 am-5 pm 6 am-6 pm 7 am-7 pm 8 am-8 pm
Light PRC: Avoid Stim. 9 am-1 pm 10 am-2 pm 11 am-3 pm N-4 pm 1
pm-5 pm 2 pm-6 pm 3 pm-7 pm 4 pm-8 pm Mel. PRC: .Arrow-up bold. 11
Stim. 2 am-2 pm 3 am-3 pm 4 am-4 pm 5 am-5 pm 6 am-6 pm 7 am-7 pm 8
am-8 pm 9 am-9 pm Light PRC: Avoid Stim. 10 am-2 pm 11 am-3 pm N-4
pm 1 pm-5 pm 2 pm-6 pm 3 pm-7 pm 4 pm-8 pm 5 pm-9 pm Mel. PRC:
.Arrow-up bold. 10 Stim. 3 am-3 pm 4 am-4 pm 5 am-5 pm 6 am-6 pm 7
am-7 pm 8 am-8 pm 9 am-9 pm 10 am- Light PRC: 10 pm Avoid Stim. 11
am-3 pm N-4 pm 1 pm-5 pm 2 pm-6 pm 3 pm-7 pm 4 pm-8 pm 5 pm-9 pm 6
pm-10 pm Mel. PRC: .Arrow-up bold. 9 Stim. 4 am-4 pm 5 am-5 pm 6
am-6 pm 7 am-7 pm 8 am-8 pm 9 am-9 pm 10 am- 11 am- Light PRC: 10
pm 11 pm Avoid Stim. N-4 pm 1 pm-5 pm 2 pm-6 pm 3 pm-7 pm 4 pm-8 pm
5 pm-9 pm 6 pm-10 pm 7 pm-11 pm Mel. PRC: .Arrow-up bold. 8 Stim. 5
am-5 pm 6 am-6 pm 7 am-7 pm 8 am-8 pm 9 am-9 pm 10 am- 11 am- N-M
Light PRC: 10 pm 11 pm Avoid Stim. 1 pm-5 pm 2 pm-6 pm 3 pm-7 pm 4
pm-8 pm 5 pm-9 pm 6 pm-10 pm 7 pm-11 pm 8 pm-M Mel. PRC: .Arrow-up
bold. 7 Stim. 6 am-6 pm 7 am-7 pm 8 am-8 pm 9 am-9 pm 0 am-10 pm 11
am- N-M 1 pm-1 am Light PRC: 11 pm Avoid Stim. 2 pm-6 pm 3 pm-7 pm
4 pm-8 pm 5 pm-9 pm 6 pm-10 pm 7 pm-11 pm 8 pm-M 9 pm-1 am Mel.
PRC: .Arrow-up bold. 6 Stim. 7 am-7 pm 8 am-8 pm 9 am-9 pm 10 am-
11 am- N-M 1 pm-1 am Light PRC: 10 pm 10 pm Avoid Stim. 3 pm-7 pm 4
pm-8 pm 5 pm-9 pm 6 pm-10 pm 7 pm-11 pm 8 pm-M 9 pm-1 am Mel. PRC:
.Arrow-up bold. 5 Stim. 8 am-8 pm 9 am-9 pm 10 am- 11 am- N-M 1
pm-1 am Light PRC: 10 pm 11 pm Avoid Stim. 4 pm-8 pm 5 pm-9 pm 6
pm-10 pm 7 pm-11 pm 8 pm-M 9 pm-1 am Mel. PRC: .Arrow-up bold. 4
Stim. 9 am-9 pm 10 am- 11 am- N-M 1 pm-1 am Light PRC: 10 pm 11 pm
Avoid Stim. 5 pm-9 pm 6 pm-10 pm 7 pm-11 pm 8 pm-M 9 pm-1 am Mel.
PRC: .Arrow-up bold. 3 Stim. 10 am- 11 am- N-M 1 pm-1 am Light PRC:
10 pm 11 pm Avoid Stim. 6 pm-10 pm 7 pm-11 pm 8 pm-M 9 pm-1 am Mel.
PRC: .Arrow-up bold. 2 Stim. 11 am- N-M 1 pm-1 am Light PRC: 11 pm
Avoid Stim. 7 pm-11 pm 8 pm-M 9 pm-1 am Mel. PRC: .Arrow-up bold. 1
Stim. N-M 1 pm-1 am Light PRC: Avoid Stim. 8 pm-M 9 pm-1 am Mel.
PRC: West 0 Stim. 1 pm-1 am Light PRC: Avoid Stim. 9 pm-1 am Mel.
PRC: East 0 Stim. 1 am-1 pm Light PRC: Avoid Stim. 1 am-8 am Mel.
PRC: .dwnarw. 1 Stim. 2 am-2 pm 1 am-1 pm Light PRC: Avoid Stim. 2
am-9 am 1 am-8 am Mel. PRC: .dwnarw. 2 Stim. 3 am-3 pm 2 am-2 pm 1
am-1 pm Light PRC: Avoid Stim. 3 am-10 am 2 am-9 am 1 am-8 am Mel.
PRC: .dwnarw. 3 Stim. 4 am-4 pm 3 am-3 pm 2 am-2 pm 1 am-1 pm Light
PRC: Avoid Stim. 4 am-11 am 3 am-10 am 2 am-9 am 1 am-8 am Mel.
PRC: .dwnarw. 4 Stim. 5 am-5 pm 4 am-4 pm 3 am-3 pm 2 am-2 pm 1
am-1 pm Light PRC: Avoid Stim. 5 am-N 4 am-11 am 3 am-10 am 2 am-9
am 1 am-8 am Mel. PRC: .dwnarw. 5 Stim. 6 am-6 pm 5 am-5 pm 4 am-4
pm 3 am-3 pm 2 am-2 pm 1 am-1 pm Light PRC: Avoid Stim. 6 am-1 pm 5
am-N 4 am-11 am 3 am-10 am 2 am-9 am 1 am-8 am Mel. PRC: .dwnarw. 6
Stim. 7 am-7 pm 6 am-6 pm 5 am-5 pm 4 am-4 pm 3 am-3 pm 2 am-2 pm 1
am-1 pm Light PRC: Avoid Stim. 7 am-2 pm 6 am-1 pm 5 am-N 4 am-11
am 3 am-10 am 2 am-9 am 1 am-8 am Mel. PRC: .dwnarw. 7 Stim. 8 am-8
pm 7 am-7 pm 6 am-6 pm 5 am-5 pm 4 am-4 pm 3 am-3 pm 2 am-2 pm 1
am-1 pm Light PRC: Avoid Stim. 8 am-3 pm 7 am-2 pm 6 am-1 pm 5 am-N
4 am-11 am 3 am-10 am 2 am-9 am 1 am-8 am Mel. PRC: .dwnarw. 8
Stim. 9 am-9 pm 8 am-8 pm 7 am-7 pm 6 am-6 pm 5 am-5 pm 4 am-4 pm 3
am-3 pm 2 am-2 pm Light PRC: Avoid Stim. 9 am-4 pm 8 am-3 pm 7 am-2
pm 6 am-1 pm 5 am-N 4 am-11 am 3 am-10 am 2 am-9 am Mel. PRC:
.dwnarw. 9 Stim. 10 am- 9 am-9 pm 8 am-8 pm 7 am-7 pm 6 am-6 pm 5
am-5 pm 4 am-4 pm 3 am-3 pm Light PRC: 10 pm Avoid Stim. 10 am-5 pm
9 am-4 pm 8 am-3 pm 7 am-2 pm 6 am-1 pm 5 am-N 4 am-11 am 3 am-10
am Mel. PRC: .dwnarw. 10 Stim. 11 am- 10 am- 9 am-9 pm 8 am-8 pm 7
am-7 pm 6 am-6 pm 5 am-5 pm 4 am-4 pm Light PRC: 11 pm 10 pm Avoid
Stim. 11 am-6 pm 10 am-5 pm 9 am-4 pm 8 am-3 pm 7 am-2 pm 6 am-1 pm
5 am-N 4 am-11 am Mel. PRC: .dwnarw. 11 Stim. N-M 11 am- 10 am- 9
am-9 pm 8 am-8 pm 7 am-7 pm 6 am-6 pm 5 am-5 pm Light PRC: 11 pm 10
pm Avoid Stim. N-7 pm 11 am-6 pm 10 am-5 pm 9 am-4 pm 8 am-3 pm 7
am-2 pm 6 am-1 pm 5 am-N Mel. PRC: .dwnarw. 12 Stim. 1 pm-1 am N-M
11 am- 10 am- 9 am-9 pm 8 am-8 pm 7 am-7 pm 6 am-6 pm Light PRC: 11
pm 10 pm Avoid Stim. 1 pm-8 pm N-7 pm 11 am-6 pm 10 am-5 pm 9 am-4
pm 8 am-3 pm 7 am-2 pm 6 am-1 pm Mel. PRC: .dwnarw. 13 Stim. 2 pm-2
am 1 pm-1 am N-M 11 am- 10 am- 9 am-9 pm 8 am-8 pm 7 am-7 pm Light
PRC: 11 pm 10 pm Avoid Stim. 2 pm-9 pm 1 pm-8 pm N-7 pm 11 am-6 pm
10 am-5 pm 9 am-4 pm 8 am-3 pm 7 am-2 pm Mel. PRC: .dwnarw. 14
Stim. 3 pm-3 am 2 pm-2 am 1 pm-1 am N-M 11 am- 10 am- 9 am-9 pm 8
am-8 pm Light PRC: 11 pm 10 pm Avoid Stim. 3 pm-10 pm 2 pm-9 pm 1
pm-8 pm N-7 pm 11 am-6 pm 10 am-5 pm 9 am-4 pm 8 am-3 pm Mel. PRC:
.dwnarw. 15 Stim. 4 pm-4 am 3 pm-3 am 2 pm-2 am 1 pm-1 am N-M 11
am- 10 am- 9 am-9 pm Light PRC: 11 pm 10 pm Avoid Stim. 4 pm-11 pm
3 pm-10 pm 2 pm-9 pm 1 pm-8 pm N-7 pm 11 am-6 pm 10 am-5 pm 9 am-4
pm Mel. PRC: Light Time Exposure Zones to: Day 10 Day 11 Day 12 Day
13 Day 14 Day 15 Day 16 .Arrow-up bold. 15 6 am-6 pm 7 am-7 pm 8
am-8 pm 9 am-9 pm 10 am-10 pm 11 am-11 pm N-M 1 pm-1 am 2 pm-6 pm 3
pm-7 pm 4 pm-8 pm 5 pm-9 pm 6 pm-10 pm 7 pm-11 pm 8 pm-M 9 pm-1 am
.Arrow-up bold. 14 7 am-7 pm 8 am-8 pm 9 am-9 pm 10 am-10 pm 11
am-11 pm N-M 1 pm-1 am 3 pm-7 pm 4 pm-8 pm 5 pm-9 pm 6 pm-10 pm 7
pm-11 pm 8 pm-M 9 pm-1 am .Arrow-up bold. 13 8 am-8 pm 9 am-9 pm 10
am-10 pm 11 am-11 pm N-M 1 pm-1 am 4 pm-8 pm 5 pm-9 pm 6 pm-10 pm 7
pm-11 pm 8 pm-M 9 pm-1 am .Arrow-up bold. 12 9 am-9 pm 10 am-10 pm
11 am-11 pm N-M 1 pm-1 am 5 pm-9 pm 6 pm-10 pm 7 pm-11 pm 8 pm-M 9
pm-1 am .Arrow-up bold. 11 10 am-10 pm 11 am-11 pm N-M 1 pm-1 am 6
pm-10 pm 7 pm-11 pm 8 pm-M 9 pm-1 am .Arrow-up bold. 10 11 am-11 pm
N-M 1 pm-1 am 7 pm-11 pm 8 pm-M 9 pm-1 am .Arrow-up bold. 9 N-M 1
pm-1 am 8 pm-M 9 pm-1 am .Arrow-up bold. 8 1 pm-1 am 9 pm-1 am
.Arrow-up bold. 7 .Arrow-up bold. 6 .Arrow-up bold. 5 .Arrow-up
bold. 4 .Arrow-up bold. 3 .Arrow-up bold. 2 .Arrow-up bold. 1 West
0 East 0 .dwnarw. 1 .dwnarw. 2 .dwnarw. 3 .dwnarw. 4 .dwnarw. 5
.dwnarw. 6 .dwnarw. 7 .dwnarw. 8 1 am-1 pm 1 am-8 am .dwnarw. 9 2
am-2 pm 1 am-1 pm 2 am-9 am 1 am-8 am .dwnarw. 10 3 am-3 pm 2 am-2
pm 1 am-1 pm 3 am-10 am 2 am-9 am 1 am-8 am .dwnarw. 11 4 am-4 pm 3
am-3 pm 2 am-2 pm 1 am-1 pm 4 am-11 am 3 am-10 am 2 am-9 am 1 am-8
am .dwnarw. 12 5 am-5 pm 4 am-4 pm 3 am-3 pm 2 am-2 pm 1 am-1 pm 5
am-N 4 am-11 am 3 am-10 am 2 am-9 am 1 am-8 am .dwnarw. 13 6 am-6
pm 5 am-5 pm 4 am-4 pm 3 am-3 pm 2 am-2 pm 1 am-1 pm 6 am-1 pm 5
am-N 4 am-11 am 3 am-10 am 2 am-9 am 1 am-8 am .dwnarw. 14 7 am-7
pm 6 am-6 pm 5 am-5 pm 4 am-4 pm 3 am-3 pm 2 am-2 pm 1 am-1 pm 7
am-2 pm 6 am-1 pm 5 am-N 4 am-11 am 3 am-10 am 2 am-9 am 1 am-8 am
.dwnarw. 15 8 am-8 pm 7 am-7 pm 6 am-6 pm 5 am-5 pm 4 am-4 pm 3
am-3 pm 2 am-2 pm 1 am-1 pm 8 am-3 pm 7 am-2 pm 6 am-1 pm 5 am-N 4
am-11 am 3 am-10 am 2 am-9 am 1 am-8 am
[0219]
6TABLE 6 When to Avoid Light Exposures to Avoid Stimulating the
Light PRC (and When to Take Melatonin, a Melatonin Agonist or a
Compound that Stimulates Endogenous Melatonin Production, and When
to Avoid Light Exposure to Enhance their Phase-Shifting Effects);
When to Reduce Light Suppression of Endogenous Melatonin Production
in order to Stimulate the Melatonin PRC. (Row 0 is in Embarkation
Time; all others are in Destination Time.) Day 1 Day 2 Day 3 Day 4
Day 5 Day 6 Day 7 Day 8 Avoid Stim. Light 10 am-10 pm 11 am-11 pm
N-M 1 pm-1 am 2 pm-2 am 3 pm-3 am 4 pm-4 am PRC: Stim. Mel. PRC: 10
am-5 pm 11 am-6 pm N-7 pm 1 pm-8 pm 2 pm-9 pm 3 pm-10 pm 4 pm-11 pm
Avoid Stim. Light 11 am-11 pm N-M 1 pm-1 am 2 pm-2 am 3 pm-3 am 4
pm-4 am 5 pm-5 am PRC: Stim. Mel. PRC: 11 am-6 pm N-7 pm 1 pm-8 pm
2 pm-9 pm 3 pm-10 pm 4 pm-11 pm 5 pm-M Avoid Stim. Light N-M 1 pm-1
am 2 pm-2 am 3 pm-3 am 4 pm-4 am 5 pm-5 am 6 pm-6 am PRC: Stim.
Mel. PRC: N-7 pm 1 pm-8 pm 2 pm-9 pm 3 pm-10 pm 4 pm-11 pm 5 pm-M 6
pm-1 am Avoid Stim. Light 1 pm-1 am 2 pm-2 am 3 pm-3 am 4 pm-4 am 5
pm-5 am 6 pm-6 am 7 pm-7 am PRC: Stim. Mel. PRC: 1 pm-8 pm 2 pm-9
pm 3 pm-10 pm 4 pm-11 pm 5 pm-M 6 pm-1 am 7 pm-2 am Avoid Stim.
Light 2 pm-2 am 3 pm-3 am 4 pm-4 am 5 pm-5 am 6 pm-6 am 7 pm-7 am 8
pm-8 am PRC: Stim. Mel. PRC: 2 pm-9 pm 3 pm-10 pm 4 pm-11 pm 5 pm-M
6 pm-1 am 7 pm-2 am 8 pm-3 am Avoid Stim. Light 3 pm-3 am 4 pm-4 am
5 pm-5 am 6 pm-6 am 7 pm-7 am 8 pm-8 am 9 pm-9 am PRC: Stim. Mel.
PRC: 3 pm-10 pm 4 pm-11 pm 5 pm-M 6 pm-1 am 7 pm-2 am 8 pm-3 am 9
pm-4 am Avoid Stim. Light 4 pm-4 am 5 pm-5 am 6 pm-6 am 7 pm-7 am 8
pm-8 am 9 pm-9 am 10 pm-10 am PRC: Stim. Mel. PRC: 4 pm-11 pm 5
pm-M 6 pm-1 am 7 pm-2 am 8 pm-3 am 9 pm-4 am 10 pm-5 am Avoid Stim.
Light 5 pm-5 am 6 pm-6 am 7 pm-7 am 8 pm-8 am 9 pm-9 am 10 pm-10 am
11 pm-11 am PRC: Stim. Mel. PRC: 5 pm-M 6 pm-1 am 7 pm-2 am 8 pm-3
am 9 pm-4 am 10 pm-5 am 11 pm-6 am Avoid Stim. Light 6 pm-6 am 7
pm-7 am 8 pm-8 am 9 pm-9 am 10 pm-10 am 11 pm-11 am M-N PRC: Stim.
Mel. PRC: 6 pm-1 am 7 pm-2 am 8 pm-3 am 9 pm-4 am 10 pm-5 am 11
pm-6 am M-7 am Avoid Stim. Light 7 pm-7 am 8 pm-8 am 9 pm-9 am 10
pm-10 am 11 pm-11 am M-N 1 am-1 pm PRC: Stim. Mel. PRC: 7 pm-2 am 8
pm-3 am 9 pm-4 am 10 pm-5 am 11 pm-6 am M-7 am 1 am-8 am Avoid
Stim. Light 8 pm-8 am 9 pm-9 am 10 pm-10 am 11 pm-11 am M-N 1 am-1
pm PRC: Stim. Mel. PRC: 8 pm-3 am 9 pm-4 am 10 pm-5 am 11 pm-6 am
M-7 am 1 am-8 am Avoid Stim. Light 9 pm-9 am 10 pm-10 am 11 pm-11
am M-N 1 am-1 pm PRC: Stim. Mel. PRC: 9 pm-4 am 10 pm-5 am 11 pm-6
am M-7 am 1 am-8 am Avoid Stim. Light 10 pm-10 am 11 pm-11 am M-N 1
am-1 pm PRC: Stim. Mel. PRC: 10 pm-5 am 11 pm-6 am M-7 am 1 am-8 am
Avoid Stim. Light 11 pm-11 am M-N 1 am-1 pm PRC: Stim. Mel. PRC: 11
pm-6 am M-7 am 1 am-8 am Avoid Stim. Light M-N 1 am-1 pm PRC: Stim.
Mel. PRC: M-7 am 1 am-8 am Avoid Stim. Light 1 am-1 pm PRC: Stim.
Mel. PRC: 1 am-8 am East 0 Avoid Stim. Light 1 pm-1 am PRC: Stim.
Mel. PRC: 9 pm-1 am .dwnarw. 1 Avoid Stim. Light 2 pm-2 am 1 pm-1
am PRC: Stim. Mel. PRC: 10 pm-2 am 9 pm-1 am .dwnarw. 2 Avoid Stim.
Light 3 pm-3 am 2 pm-2 am 1 pm-1 am PRC: Stim. Mel. PRC: 11 pm-3 am
10 pm-2 am 9 pm-1 am .dwnarw. 3 Avoid Stim. Light 4 pm-4 am 3 pm-3
am 2 pm-2 am 1 pm-1 am PRC: Stim. Mel. PRC: M-4 am 11 pm-3 am 10
pm-2 am 9 pm-1 am .dwnarw. 4 Avoid Stim. Light 5 pm-5 am 4 pm-4 am
3 pm-3 am 2 pm-2 am 1 pm-1 am PRC: Stim. Mel. PRC:- 1 am-5 am M-4
am 11 pm-3 am 10 pm-2 am 9 pm-1 am .dwnarw. 5 Avoid Stim. Light 6
pm-6 am 5 pm-5 am 4 pm-4 am 3 pm-3 am 2 pm-2 am 1 pm-1 am PRC:
Stim. Mel. PRC: 2 am-6 am 1 am-5 am M-4 am 11 pm-3 am 10 pm-2 am 9
pm-1 am .dwnarw. 6 Avoid Stim. Light 7 pm-7 am 6 pm-6 am 5 pm-5 am
4 pm-4 am 3 pm-3 am 2 pm-2 am 1 pm-1 am PRC: Stim. Mel. PRC: 3 am-7
am 2 am-6 am 1 am-5 am M-4 am 11 pm-3 am 10 pm-2 am 9 pm-1 am
.dwnarw. 7 Avoid Stim. Light 8 pm-8 am 7 pm-7 am 6 pm-6 am 5 pm-5
am 4 pm-4 am 3 pm-3 am 2 pm-2 am PRC: Stim. Mel. PRC: 4 am-8 am 3
am-7 am 2 am-6 am 1 am-5 am M-4 am 11 pm-3 am 10 pm-2 am .dwnarw. 8
Avoid Stim. Light 9 pm-9 am 8 pm-8 am 7 pm-7 am 6 pm-6 am 5 pm-5 am
4 pm-4 am 3 pm-3 am PRC: Stim. Mel. PRC: 5 am-9 am 4 am-8 am 3 am-7
am 2 am-6 am 1 am-5 am M-4 am 11 pm-3 am .dwnarw. 9 Avoid Stim.
Light 10 pm-10 am 9 pm-9 am 8 pm-8 am 7 pm-7 am 6 pm-6 am 5 pm-5 am
4 pm-4 am PRC: Stim. Mel. PRC: 6 am-10 am 5 am-9 am 4 am-8 am 3
am-7 am 2 am-6 am 1 am-5 am M-4 am .dwnarw. 10 Avoid Stim. Light 11
pm-11 am 10 pm-10 am 9 pm-9 am 8 pm-8 am 7 pm-7 am 6 pm-6 am 5 pm-5
am PRC: Stim. Mel. PRC: 7 am-11 am 6 am-10 am 5 am-9 am 4 am-8 am 3
am-7 am 2 am-6 am 1 am-5 am .dwnarw. 11 Avoid Stim. Light M-N 11
pm-11 am 10 pm-10 am 9 pm-9 am 8 pm-8 am 7 pm-7 am 6 pm-6 am PRC:
Stim. Mel. PRC: 8 am-N 7 am-11 am 6 am-10 am 5 am-9 am 4 am-8 am 3
am-7 am 2 am-6 am .dwnarw. 12 Avoid Stim. Light 1 am-1 pm M-N 11
pm-11 am 10 pm-10 am 9 pm-9 am 8 pm-8 am 7 pm-7 am PRC: Stim. Mel.
PRC: 9 am-1 pm 8 am-N 7 am-11 am 6 am-10 am 5 am-9 am 4 am-8 am 3
am-7 am .dwnarw. 13 Avoid Stim. Light 2 am-2 pm 1 am-1 pm M-N 11
pm-11 am 10 pm-10 am 9 pm-9 am 8 pm-8 am PRC: Stim. Mel. PRC: 10
am-2 pm 9 am-1 pm 8 am-N 7 am-11 am 6 am-10 am 5 am-9 am 4 am-8 am
.dwnarw. 14 Avoid Stim. Light 3 am-3 pm 2 am-2 pm 1 am-1 pm M-N 11
pm-11 am 10 pm-10 am 9 pm-9 am PRC: Stim. Mel. PRC: 11 am-3 pm 10
am-2 pm 9 am-1 pm 8 am-N 7 am-11 am 6 am-10 am 5 am-9 am .dwnarw.
15 Avoid Stim. Light 4 am-4 pm 3 am-3 pm 2 am-2 pm 1 am-1 pm M-N 11
pm-11 am 10 pm-10 am PRC: Stim. Mel. PRC: N-4 pm 11 am-3 pm 10 am-2
pm 9 am-1 pm 8 am-N 7 am-11 am 6 am-10 am Day 9 Day 10 Day 11 Day
12 Day 13 Day 14 Day 15 Day 16 5 pm-5 am 6 pm-6 am 7 pm-7 am 8 pm-8
am 9 pm-9 am 10 pm- 11 pm- M-N 1 am-1 pm 10 am 11 am 5 pm-M 6 pm-1
am 7 pm-2 am 8 pm-3 am 9 pm-4 am 10 pm-5 am 11 pm-6 am M-7 am 1
am-8 am 6 pm-6 am 7 pm-7 am 8 pm-8 am 9 pm-9 am 10 pm- 11 pm- M-N 1
am-1 pm 10 am 11 am 6 pm-1 am 7 pm-2 am 8 pm-3 am 9 pm-4 am 10 pm-5
am 11 pm-6 am M-7 am 1 am-8 am 7 pm-7 am 8 pm-8 am 9 pm-9 am 10
pm-10 am 11 pm- M-N 1 am-1 pm 11 am 7 pm-2 am 8 pm-3 am 9 pm-4 am
10 pm-5 am 11 pm-6 am M-7 am 1 am-8 am 8 pm-8 am 9 pm-9 am 10 pm-10
am 11 pm-11 am M-N 1 am-1 pm 8 pm-3 am 9 pm-4 am 10 pm-5 am 11 pm-6
am M-7 am 1 am-8 am 9 pm-9 am 10 pm-10 am 11 pm-11 am M-N 1 am-1 pm
9 pm-4 am 10 pm-5 am 11 pm-6 am M-7 am 1 am-8 am 10 pm-10 am 11
pm-11 am M-N 1 am-1 pm 10 pm-5 am 11 pm-6 am M-7 am 1 am-8 am 11
pm-11 am M-N 1 am-1 pm 11 pm-6 am M-7 am 1 am-8 am M-N 1 am-1 pm
M-7 am 1 am-8 am 1 am-1 pm 1 am-8 am East 0 .dwnarw. 1 .dwnarw. 2
.dwnarw. 3 .dwnarw. 4 .dwnarw. 5 .dwnarw. 6 .dwnarw. 7 1 pm-1 am 9
pm-1 am .dwnarw. 8 2 pm-2 am 1 pm-1 am 10 pm-2 am 9 pm-1 am
.dwnarw. 9 3 pm-3 am 2 pm-2 am 1 pm-1 am 11 pm-3 am 10 pm-2 am 9
pm-1 am .dwnarw. 10 4 pm-4 am 3 pm-3 am 2 pm-2 am 1 pm-1 am M-4 am
11 pm-3 am 10 pm-2 am 9 pm-1 am .dwnarw. 11 5 pm-5 am 4 pm-4 am 3
pm-3 am 2 pm-2 am 1 pm-1 am 1 am-5 am M-4 am 11 pm-3 am 10 pm-2 am
9 pm-1 am .dwnarw. 12 6 pm-6 am 5 pm-5 am 4 pm-4 am 3 pm-3 am 2
pm-2 am 1 pm-1 am 2 am-6 am 1 am-5 am M-4 am 11 pm-3 am 10 pm-2 am
9 pm-1 am .dwnarw. 13 7 pm-7 am 6 pm-6 am 5 pm-5 am 4 pm-4 am 3
pm-3 am 2 pm-2 am 1 pm-1 am 3 am-7 am 2 am-6 am 1 am-5 am M-4 am 11
pm-3 am 10 pm-2 am 9 pm-1 am .dwnarw. 14 8 pm-8 am 7 pm-7 am 6 pm-6
am 5 pm-5 am 4 pm-4 am 3 pm-3 am 2 pm-2 am 1 pm-1 am 4 am-8 am 3
am-7 am 2 am-6 am 1 am-5 am M-4 am 11 pm-3 am 10 pm-2 am 9 pm-1 am
.dwnarw. 15 9 pm-9 am 8 pm-8 am 7 pm-7 am 6 pm-6 am 5 pm-5 am 4
pm-4 am 3 pm-3 am 2 pm-2 am 1 pm-1 am 5 am-9 am 4 am-8 am 3 am-7 am
2 am-6 am 1 am-5 am M-4 am 11 pm-3 am 10 pm-2 am 9 pm-1 am
[0220]
7TABLE 7 Times to Take a .beta.-Blocker. With or Without a
Delayed-Release (DR). .beta.-Blocker of 7-hour Duration Going East,
4-hour Duration Going West. Assume Immediate Onset of Action. Time
Zones Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 15 5 am 6 am
7 am 8 am 9 am 10 am 11 am Noon 14 6 am 7 am 8 am 9 am 10 am 11 am
Noon 1 pm 13 7 am 8 am 9 am 10 am 11 am Noon 1 pm 2 pm 12 8 am 9 am
10 am 11 am Noon 1 pm 2 pm 3 pm 11 9 am 10 am 11 am Noon 1 pm 2 pm
3 pm 4 pm 10 10 am 11 am Noon 1 pm 2 pm 3 pm 4 pm 5 pm 9 11 am Noon
1 pm 2 pm 3 pm 4 pm 5 pm 6 pm 8 Noon 1 pm 2 pm 3 pm 4 pm 5 pm 6 pm
7 pm 7 1 pm 2 pm 3 pm 4 pm 5 pm 6 pm 7 pm 8 pm 6 2 pm 3 pm 4 pm 5
pm 6 pm 7 pm 8 pm 5 3 pm 4 pm 5 pm 6 pm 7 pm 8 pm 4 4 pm 5 pm 6 pm
7 pm 8 pm 3 5 pm 6 pm 7 pm 8 pm 2 6 pm 7 pm 8 pm 1 7 pm 8 pm 0 8 pm
0 9 pm, 4 h Dr 1 9 pm, 5 h Dr 9 pm, 4 h Dr 2 9 pm, 6 h Dr 9 pm, 5 h
Dr 9 pm, 4 h Dr 3 9 pm, 7 h Dr 9 pm, 6 h Dr 9 pm, 5 h Dr 9 pm, 4 h
Dr 4 9 pm, 8 h Dr 9 pm, 7 h Dr 9 pm, 6 h Dr 9 pm, 5 h Dr 9 pm, 4 h
Dr 5 9 pm, 9 h Dr 9 pm, 8 h Dr 9 pm, 7 h Dr 9 pm, 6 h Dr 9 pm, 5 h
Dr 9 pm, 4 h Dr 6 7 am 9 pm, 9 h Dr 9 pm, 8 h Dr 9 pm; 7 h Dr 9 pm,
6 h Dr 9 pm, 5 h Dr 9 pm, 4 h Dr 7 8 am 7 am 9 pm, 9 h Dr 9 pm, 8 h
Dr 9 pm, 7 h Dr 9 pm, 6 h Dr 9 pm, 5 h Dr 9 pm, 4 h Dr 8 9 am 8 am
7 am 9 pm, 9 h Dr 9 pm, 8 h Dr 9 pm, 7 h Dr 9 pm, 6 h Dr 9 pm, 5 h
Dr 9 10 am 9 am 8 am 7 am 9 pm, 9 h Dr 9 pm, 8 h Dr 9 pm, 7 h Dr 9
pm, 6 h Dr 10 11 am 10 am 9 am 8 am 7 am 9 pm, 9 h Dr 9 pm, 8 h Dr
9 pm, 7 h Dr 11 Noon 11 am 10 am 9 am 8 am 7 am 9 pm, 9 h Dr 9 pm,
8 h Dr 12 1 pm Noon 11 am 10 am 9 am 8 am 7 am 9 pm, 9 h Dr 13 2 pm
1 pm Noon 11 am 10 am 9 am 8 am 7 am 14 3 pm 2 pm 1 pm Noon 11 am
10 am 9 am 8 am 15 4 pm 3 pm 2 pm 1 pm Noon 11 am 10 am 9 am Time
Zones Day 9 Day 10 Day 11 Day 12 Day 13 Day 14 Day 15 Day 16 15 1
pm 2 pm 3 pm 4 pm 5 pm 6 pm 7 pm 8 pm 14 2 pm 3 pm 4 pm 5 pm 6 pm 7
pm 8 pm 13 3 pm 4 pm 5 pm 6 pm 7 pm 8 pm 12 4 pm 5 pm 6 pm 7 pm 8
pm 11 5 pm 6 pm 7 pm 8 pm 10 6 pm 7 pm 8 pm 9 7 pm 8 pm 8 8 pm 7 6
5 4 3 2 1 0 0 1 2 3 4 5 6 7 8 9 pm, 4 h Dr 9 9 pm, 5 h Dr 9 pm, 4 h
Dr 10 9 pm, 6 h Dr 9 pm, 5 h Dr 9 pm, 4 h Dr 11 9 pm, 7 h Dr 9 pm,
6 h Dr 9 pm, 5 h Dr 9 pm, 4 h Dr 12 9 pm, 7 h Dr 9 pm, 7 h Dr 9 pm.
6 h Dr 9 pm, 5 h Dr 9 pm, 4 h Dr 13 9 pm, 8 h Dr 9 pm, 8 h Dr 9 pm,
7 h Dr 9 pm, 6 h Dr 9 pm, 5 h Dr 9 pm, 4 h Dr 14 7 am 9 pm, 9 h Dr
9 pm, 8 h Dr 9 pm, 7 h Dr 9 pm, 6 h Dr 9 pm, 5 h Dr 9 pm, 4 h Dr 15
8 am 7 am 9 pm, 9 h Dr 9 pm, 8 h Dr 9 pm, 7 h Dr 9 pm, 6 h Dr 9 pm,
5 h Dr 9 pm, 4 h Dr
[0221]
8TABLE 8 When to Take Middle-of-the-night Melatonin Going East,
Combined with a Lower to Moderate Dose IR Formulation at Bedtime
(Assume About 9 pm and About 0.5 mg has About a 5 h duration). Do
Not Take After: Time Zones Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day
7 Day 8 Day 9 Day 10 Day 11 East 0 1 am .dwnarw. 1 1 am .dwnarw. 2
1 am .dwnarw. 3 1 am .dwnarw. 4 1 am .dwnarw. 5 1 am .dwnarw. 6 2
am 1 am .dwnarw. 7 3 am 2 am 1 am .dwnarw. 8 4 am 3 am 2 am 1 am
.dwnarw. 9 5 am 4 am 3 am 2 am 1 am .dwnarw. 10 6 am 5 am 4 am 3 am
2 am 1 am .dwnarw. 11 7 am 6 am 5 am 4 am 3 am 2 am 1 am .dwnarw.
12 8 am 7 am 6 am 5 am 4 am 3 am 2 am 1 am .dwnarw. 13 9 am 8 am 7
am 6 am 5 am 4 am 3 am 2 am 1 am .dwnarw. 14 10 am 9 am 8 am 7 am 6
am 5 am 4 am 3 am 2 am 1 am .dwnarw. 15 11 am 10 am 9 am 8 am 7 am
6 am 5 am 4 am 3 am 2 am 1 am
[0222]
9TABLE 9 Maximal (Ideal) Duration of Melatonin at Bedtime (Assume
About 9 pm), With or Without a Delayed-Release (DR). Time Zones Day
1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 .Arrow-up bold. 15 1 h
2 h 3 h 4 h 5 h 6 h 7 h .Arrow-up bold. 14 2 h 3 h 4 h 5 h 6 h 7 h
8 h .Arrow-up bold. 13 3 h 4 h 5 h 6 h 7 h 8 h 9 h .Arrow-up bold.
12 4 h 5 h 6 h 7 h 8 h 9 h 10 h .Arrow-up bold. 11 5 h 6 h 7 h 8 h
9 h 10 h 11 h .Arrow-up bold. 10 6 h 7 h 8 h 9 h 10 h 11 h 12 h
.Arrow-up bold. 9 7 h 8 h 9 h 10 h 11 h 12 h 12 h, 1 h DR .Arrow-up
bold. 8 8 h 9 h 10 h 11 h 12 h 12 h, 1 h DR 12 h, 2 h DR .Arrow-up
bold. 7 9 h 10 h 11 h 12 h 12 h, 1 h DR 12 h, 2 h DR 12 h, 3 h DR
.Arrow-up bold. 6 10 h 11 h 12 h 12 h, 1 h DR 12 h, 2 h DR 12 h, 3
h DR 12 h, 4 h DR .Arrow-up bold. 5 11 h 12 h 12 h, 1 h DR 12 h, 2
h DR 12 h, 3 h DR 12 h, 4 h DR .Arrow-up bold. 4 12 h 12 h, 1 h DR
12 h, 2 h DR 12 h, 3 h DR 12 h, 4 h DR .Arrow-up bold. 3 12 h, 1 h
DR 12 h, 2 h DR 12 h, 3 h DR 12 h, 4 h DR .Arrow-up bold. 2 12 h, 2
h DR 12 h, 3 h DR 12 h, 4 h DR .Arrow-up bold. 1 12 h, 3 h DR 12 h,
4 h DR West 0 12 h, 4 h DR East 0 4 h .dwnarw. 1 5 h 4 h .dwnarw. 2
6 h 5 h 4 h .dwnarw. 3 7 h 6 h 5 h 4 h .dwnarw. 4 8 h 7 h 6 h 5 h 4
h .dwnarw. 5 9 h 8 h 7 h 6 h 5 h 4 h .dwnarw. 6 10 h 9 h 8 h 7 h 6
h 5 h 4 h .dwnarw. 7 11 h 10 h 9 h 8 h 7 h 6 h 5 h .dwnarw. 8 12 h
11 h 10 h 9 h 8 h 7 h 6 h .dwnarw. 9 12 h, 1 h DR 12 h 11 h 10 h 9
h 8 h 7 h .dwnarw. 10 12 h, 2 h DR 12 h, 1 h DR 12 h 11 h 10 h 9 h
8 h .dwnarw. 11 12 h, 3 h DR 12 h, 2 h DR 12 h, 1 h DR 12 h 11 h 10
h 9 h .dwnarw. 12 12 h, 4 h DR 12 h, 3 h DR 12 h, 2 h DR 12 h, 1 h
DR 12 h 11 h 10 h .dwnarw. 13 12 h, 5 h DR 12 h, 4 h DR 12 h, 3 h
DR 12 h, 2 h DR 12 h, 1 h DR 12 h 11 h .dwnarw. 14 12 h, 6 h DR 12
h, 5 h DR 12 h, 4 h DR 12 h, 3 h DR 12 h, 2 h DR 12 h, 1 h DR 12 h
.dwnarw. 15 12 h, 7 h DR 12 h, 6 h DR 12 h, 5 h DR 12 h, 4 h DR 12
h, 3 h DR 12 h, 2 h DR 12 h, 1 h DR Time Zones Day 9 Day 10 Day 11
Day 12 Day 13 Day 14 Day 15 Day 16 .Arrow-up bold. 8 h 9 h 10 h 11
h 12 h 12 h, 1 h DR 12 h, 2 h DR 12 h, 3 h DR 12 h, 4 h DR
.Arrow-up bold. 9 h 10 h 11 h 12 h 12 h, 1 h DR 12 h, 2 h DR 12 h,
3 h DR 12 h, 4 h DR .Arrow-up bold. 10 h 11 h 12 h 12 h, 1 h DR 12
h, 2 h DR 12 h, 3 h DR 12 h, 4 h DR .Arrow-up bold. 11 h 12 h 12 h,
1 h DR 12 h, 2 h DR 12 h, 3 h DR 12 h, 4 h DR .Arrow-up bold. 12 h
12 h, 1 h DR 12 h, 2 h DR 12 h, 3 h DR 12 h, 4 h DR .Arrow-up bold.
12 h, 1 h DR 12 h, 2 h DR 12 h, 3 h DR 12 h, 4 h DR .Arrow-up bold.
12 h, 2 h DR 12 h, 3 h DR 12 h, 4 h DR .Arrow-up bold. 12 h, 3 h DR
12 h, 4 h DR .Arrow-up bold. 12 h, 4 h DR .Arrow-up bold. .Arrow-up
bold. .Arrow-up bold. .Arrow-up bold. .Arrow-up bold. .Arrow-up
bold. West East .dwnarw. .dwnarw. .dwnarw. .dwnarw. .dwnarw.
.dwnarw. .dwnarw. 4 h .dwnarw. 5 h 4 h .dwnarw. 6 h 5 h 4 h
.dwnarw. 7 h 6 h 5 h 4 h .dwnarw. 8 h 7 h 6 h 5 h 4 h .dwnarw. 9 h
8 h 7 h 6 h 5 h 4 h .dwnarw. 10 h 9 h 8 h 7 h 6 h 5 h 4 h .dwnarw.
11 h 10 h 9 h 8 h 7 h 6 h 5 h 4 h .dwnarw. 12 h 11 h 10 h 9 h 8 h 7
h 6 h 5 h 4 h
[0223]
10TABLE 10 When to Take Low-Dose of Melatonin, About 12-hour
Duration, Going East or West, With or Without a Delayed-Release
(DR). Time Zones Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8
.Arrow-up bold. 15 10 am 11 am Noon 1 pm 2 pm 3 pm 4 pm .Arrow-up
bold. 14 11 am Noon 1 pm 2 pm 3 pm 4 pm 5 pm .Arrow-up bold. 13
Noon 1 pm 2 pm 3 pm 4 pm 5 pm 6 pm .Arrow-up bold. 12 1 pm 2 pm 3
pm 4 pm 5 pm 6 pm 7 pm .Arrow-up bold. 11 2 pm 3 pm 4 pm 5 pm 6 pm
7 pm 8 pm .Arrow-up bold. 10 3 pm 4 pm 5 pm 6 pm 7 pm 8 pm 9 pm
.Arrow-up bold. 9 4 pm 5 pm 6 pm 7 pm 8 pm 9 pm 9 pm, 1 h DR
.Arrow-up bold. 8 5 pm 6 pm 7 pm 8 pm 9 pm 9 pm, 1 h DR 9 pm, 2 h
DR .Arrow-up bold. 7 6 pm 7 pm 8 pm 9 pm 9 pm, 1 h DR 9 pm, 2 h DR
9 pm, 3 h DR .Arrow-up bold. 6 7 pm 8 pm 9 pm 9 pm, 1 h DR 9 pm, 2
h DR 9 pm, 3 h DR 9 pm, 4 h DR .Arrow-up bold. 5 8 pm 9 pm 9 pm, 1
h DR 9 pm, 2 h DR 9 pm, 3 h DR 9 pm, 4 h DR .Arrow-up bold. 4 9 pm
9 pm, 1 h DR 9 pm, 2 h DR 9 pm, 3 h DR 9 pm, 4 h DR .Arrow-up bold.
3 9 pm, 1 h DR 9 pm, 2 h DR 9 pm, 3 h DR 9 pm, 4 h DR .Arrow-up
bold. 2 9 pm, 2 h DR 9 pm, 3 h DR 9 pm, 4 h DR .Arrow-up bold. 1 9
pm, 3 h DR 9 pm, 4 h DR West 0 9 pm, 4 h DR East 0 1 pm .dwnarw. 1
2 pm 1 pm .dwnarw. 2 3 pm 2 pm 1 pm .dwnarw. 3 4 pm 3 pm 2 pm 1 pm
.dwnarw. 4 5 pm 4 pm 3 pm 2 pm 1 pm .dwnarw. 5 6 pm 5 pm 4 pm 3 pm
2 pm 1 pm .dwnarw. 6 7 pm 6 pm 5 pm 4 pm 3 pm 2 pm 1 pm .dwnarw. 7
8 pm 7 pm 6 pm 5 pm 4 pm 3 pm 2 pm .dwnarw. 8 9 pm 8 pm 7 pm 6 pm 5
pm 4 pm 3 pm .dwnarw. 9 9 pm, 1 h DR 9 pm 8 pm 7 pm 6 pm 5 pm 4 pm
.dwnarw. 10 9 pm, 2 h DR 9 pm, 1 h DR 9 pm 8 pm 7 pm 6 pm 5 pm
.dwnarw. 11 9 pm, 3 h DR 9 pm, 2 h DR 9 pm, 1 h DR 9 pm 8 pm 7 pm 6
pm .dwnarw. 12 9 pm, 4 h DR 9 pm, 3 h DR 9 pm, 2 h DR 9 pm, 1 h DR
9 pm 8 pm 7 pm .dwnarw. 13 9 pm, 5 h DR 9 pm, 4 h DR 9 pm, 3 h DR 9
pm, 2 h DR 9 pm, 1 h DR 9 pm 8 pm .dwnarw. 14 9 pm, 6 h DR 9 pm, 5
h DR 9 pm, 4 h DR 9 pm, 3 h DR 9 pm, 2 h DR 9 pm, 1 h DR 9 pm
.dwnarw. 15 9 pm, 7 h DR 9 pm, 6 h DR 9 pm, 5 h DR 9 pm, 4 h DR 9
pm, 3 h DR 9 pm, 2 h DR 9 pm, 1 h DR Time Zones Day 9 Day 10 Day 11
Day 12 Day 13 Day 14 Day 15 Day 16 .Arrow-up bold. 5 pm 6 pm 7 pm 8
pm 9 pm 9 pm, 1 h DR 9 pm, 2 h DR 9 pm, 9 pm, 3 h DR 4 h DR
.Arrow-up bold. 6 pm 7 pm 8 pm 9 pm 9 pm, 1 h DR 9 pm, 2 h DR 9 pm,
3 h DR 9 pm, 4 h DR .Arrow-up bold. 7 pm 8 pm 9 pm 9 pm, 1 h DR 9
pm, 2 h DR 9 pm, 3 h DR 9 pm, 4 h DR .Arrow-up bold. 8 pm 9 pm 9
pm, 1 h DR 9 pm, 2 h DR 9 pm, 3 h DR 9 pm, 4 h DR .Arrow-up bold. 9
pm 9 pm, 1 h DR 9 pm, 2 h DR 9 pm, 3 h DR 9 pm, 4 h DR .Arrow-up
bold. 9 pm, 1 h DR 9 pm, 2 h DR 9 pm, 3 h DR 9 pm, 4 h DR .Arrow-up
bold. 9 pm, 2 h DR 9 pm, 3 h DR 9 pm, 4 h DR .Arrow-up bold. 9 pm,
3 h DR 9 pm, 4 h DR .Arrow-up bold. 9 pm, 4 h DR .Arrow-up bold.
.Arrow-up bold. .Arrow-up bold. .Arrow-up bold. .Arrow-up bold.
.Arrow-up bold. West East .dwnarw. .dwnarw. .dwnarw. .dwnarw.
.dwnarw. .dwnarw. .dwnarw. 1 pm .dwnarw. 2 pm 1 pm .dwnarw. 3 pm 2
pm 1 pm .dwnarw. 4 pm 3 pm 2 pm 1 pm .dwnarw. 5 pm 4 pm 3 pm 2 pm 1
pm .dwnarw. 6 pm 5 pm 4 pm 3 pm 2 pm 1 pm .dwnarw. 7 pm 6 pm 5 pm 4
pm 3 pm 2 pm 1 pm .dwnarw. 8 pm 7 pm 6 pm 5 pm 4 pm 3 pm 2 pm 1 pm
.dwnarw. 9 pm 8 pm 7 pm 6 pm 5 pm 4 pm 3 pm 2 pm 1 pm
[0224]
11TABLE 11 When to Take Melatonin, Going West. Assume About 0.5 mg
has About a 5 h Duration. Take No Earlier Than: Time Zones Day 1
Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 West 1 am .dwnarw. Midnight 1
am .dwnarw. 11 pm Midnight 1 am .dwnarw. 10 pm 11 pm Midnight 1 am
.dwnarw. 9 pm 10 pm 11 pm Midnight 1 am .dwnarw. 8 pm 9 pm 10 pm 11
pm Midnight 1 am .dwnarw. 7 pm 8 pm 9 pm 10 pm 11 pm Midnight 1 am
.dwnarw. 6 pm 7 pm 8 pm 9 pm 10 pm 11 pm Midnight .dwnarw. 5 pm 6
pm 7 pm 8 pm 9 pm 10 pm 11 pm .dwnarw. 4 pm 5 pm 6 pm 7 pm 8 pm 9
pm 10 pm .dwnarw. 3 pm 4 pm 5 pm 6 pm 7 pm 8 pm 9 pm .dwnarw. 2 pm
3 pm 4 pm 5 pm 6 pm 7 pm 8 pm .dwnarw. 1 pm 2 pm 3 pm 4 pm 5 pm 6
pm 7 pm .dwnarw. Noon 1 pm 2 pm 3 pm 4 pm 5 pm 6 pm .dwnarw. Time
Zones Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14 West .dwnarw.
.dwnarw. .dwnarw. .dwnarw. .dwnarw. .dwnarw. .dwnarw. 1 am .dwnarw.
Midnight 1 am .dwnarw. 11 pm Midnight 1 am .dwnarw. 10 pm 11 pm
Midnight 1 am .dwnarw. 9 pm 10 pm 11 pm Midnight 1 am .dwnarw. 8 pm
9 pm 10 pm 11 pm Midnight 1 am .dwnarw. 7 pm 8 pm 9 pm 10 pm 11 pm
Midnight 1 am .dwnarw.
[0225]
12TABLE 12 Shiftworkers Delaying to On-Work Schedule with
Melatonin, About a 12 h duration, Sustained-Release (SR), With or
Without a Delay Release (DR). Day Time 0 1 am 1 1 am 2 2 am 3 3 am
4 4 am 5 5 am 6 6 am 7 7 am 8 8 am 9 9 am 10 9 am, 1 h DR 11 9 am,
2 h DR 12 9 am, 3 h DR 13 9 am, 4 h DR
[0226]
13TABLE 13 Shiftworkers Delaying to On-Work Schedule with
.beta.-Blocker (Assume Immediate Onset of Action), About a 4 h
Duration, Immediate-Release (IR). Day Time 0 9 pm 1 9 pm 2 10 pm 3
11 pm 4 Midnight 5 1 am 6 2 am 7 3 am 8 4 am 9 5 am 10 6 am 11 7 am
12 8 am 13 9 am
[0227]
14TABLE 14 Shiftworkers Advancing to Onwork Schedule with
Melatonin. About a 12 h duration. Sustained-Release (SR), With or
Without Delayed-Release (DR). Day Time 0 9 am, 4 h DR 1 9 am, 4 h
DR 2 9 am, 3 h DR 3 9 am, 2 h DR 4 9 am, 1 h DR 5 9 am 6 8 am 7 7
am 8 6 am 9 5 am 10 4 am 11 3 am 12 2 am 13 1 am
[0228]
15TABLE 15 Shiftworkers Advancing to On Work Schedule with
.beta.-Blocker (Assume Immediate Onset of Action), About a 7 h
Duration, Immediate-Release (IR), With or Without a Delayed-Release
(DR). Day Time 0 1 am 1 1 am 2 Midnight 3 11 pm 4 10 pm 5 9 pm 6 8
pm 7 7 pm 8 6 pm 9 5 pm 10 9 am, 7 h DR 11 9 am, 6 h DR 12 9 am, 5
h DR 13 9 am, 4 h DR
[0229]
16TABLE 16 Shiftworkers Advancing to Off-Work Schedule with
Melatonin, About a 12 h duration, Sustained-Release (SR), With or
Without a Delayed-Release (DR). Day Time 0 9 pm, 4 h DR 1 9 pm, 4 h
DR 2 9 pm, 3 h DR 3 9 pm, 2 h DR 4 9 pm, 1 h DR 5 9 pm 6 8 pm 7 7
pm 8 6 pm 9 5 pm 10 4 pm 11 3 pm 12 2 pm 13 1 pm
[0230]
17TABLE 17 Shiftworkers Advancing to Off-Work Schedule with
.beta.-Blocker (Assume Immediate Onset of Action), About a 7 h
Duration, Immediate-Release (IR), With or Without a Delayed Release
(DR). Day Time 0 1 pm 1 1 pm 2 Noon 3 11 am 4 10 am 5 9 am 6 8 am 7
7 am 8 9 pm, 9 h DR 9 9 pm, 8 h DR 10 9 pm, 7 h DR 11 9 pm, 6 h DR
12 9 pm, 5 h DR 13 9 pm, 4 h DR
[0231]
18TABLE 18 Shiftworkers Advancing to Off-Work Schedule with
Melatonin, Sustained-Release (SR, About a 12 h duration), With or
Without a Delayed-Release (DR). Day Time 0 1 pm 1 1 pm 2 2 pm 3 3
pm 4 4 pm 5 5 pm 6 6 pm 7 7 pm 8 8 pm 9 9 pm 10 9 pm, 1 h DR 11 9
pm, 2 h DR 12 9 pm, 3 h DR 13 9 pm, 4 h DR
[0232]
19TABLE 19 Shiftworkers Advancing to On-Work Schedule with
.beta.-Blocker, About a 4 h Duration, Immediate-Release (IR). Day
Time 0 9 am 1 9 am 2 10 am 3 11 am 4 Noon 5 1 pm 6 2 pm 7 3 pm 8 4
pm 9 5 pm 10 6 pm 11 7 pm 12 8 pm 13 9 pm
* * * * *