U.S. patent application number 10/945843 was filed with the patent office on 2006-07-27 for methods for treating circadian rhythm phase disturbances.
This patent application is currently assigned to Oregon Health and Sciences University, Oregon Health and Sciences University. Invention is credited to Alfred J. Lewy, Robert L. Sack.
Application Number | 20060165786 10/945843 |
Document ID | / |
Family ID | 22335408 |
Filed Date | 2006-07-27 |
United States Patent
Application |
20060165786 |
Kind Code |
A1 |
Lewy; Alfred J. ; et
al. |
July 27, 2006 |
Methods for treating circadian rhythm phase disturbances
Abstract
A method for treating circadian rhythm phase disorders is
described. The invention provides methods to specifically advance
or delay the phase of certain circadian rhythms in humans. The
disclosed methods relate to the administration of melatonin at
times determined with relation to the time of dim light endogenous
melatonin onset. Embodiments capable of alleviating the effects of
jet lag, winter depression and shift-work sleep disturbance
are,provided.
Inventors: |
Lewy; Alfred J.; (Portland,
OR) ; Sack; Robert L.; (Portland, OR) |
Correspondence
Address: |
MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP
300 S. WACKER DRIVE
32ND FLOOR
CHICAGO
IL
60606
US
|
Assignee: |
Oregon Health and Sciences
University
|
Family ID: |
22335408 |
Appl. No.: |
10/945843 |
Filed: |
September 21, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10202645 |
Jul 23, 2002 |
6794407 |
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10945843 |
Sep 21, 2004 |
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09580075 |
May 30, 2000 |
6423738 |
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10202645 |
Jul 23, 2002 |
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08778842 |
Jan 6, 1997 |
6069164 |
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09580075 |
May 30, 2000 |
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08110878 |
Aug 24, 1993 |
5591768 |
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08778842 |
Jan 6, 1997 |
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07842723 |
Feb 25, 1992 |
5242941 |
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08110878 |
Aug 24, 1993 |
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07621866 |
Dec 4, 1990 |
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07842723 |
Feb 25, 1992 |
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Current U.S.
Class: |
424/468 ;
514/419 |
Current CPC
Class: |
A61K 45/06 20130101;
A61K 2300/00 20130101; A61K 31/165 20130101; A61K 31/165 20130101;
A61K 31/165 20130101; A61K 31/4045 20130101; A61K 31/40 20130101;
A61K 31/40 20130101; A61K 31/40 20130101; A61K 31/40 20130101; A61K
31/40 20130101 |
Class at
Publication: |
424/468 ;
514/419 |
International
Class: |
A61K 9/22 20060101
A61K009/22; A61K 31/405 20060101 A61K031/405 |
Claims
1-43. (canceled)
44. A method for achieving a circadian rhythm phase-shifting effect
in a human comprising the step of administering an amount of
melatonin, a melatonin agonist or compound that increases
endogenous production of melatonin in the human, wherein the
administered amount of melatonin agonist or compound that increases
endogenous production of melatonin in the human is sufficient to
achieve a circadian rhythm phase-shifting effect in the human, so
that where the circadian rhythm phase-shifting effect is a phase
advance, melatonin agonist levels, or endogenous melatonin levels
increased by a compound that increases endogenous production of
melatonin in the human rise after about CT 6 and before about CT
18, and where the circadian rhythm phase-shifting effect is a phase
delay, melatonin agonist levels, or endogenous melatonin levels
increased by a compound that increases endogenous production of
melatonin in the human rise after about CT 18 and before about CT
6.
45. A method for achieving a circadian rhythm phase-shifting effect
in a human, the method comprising administering to the human an
amount of melatonin, a 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 for a time or in a concentration that is different
during a time interval from about CT 6 to about CT 18 than that
produced during the time interval from about CT 18 to about CT 6,
wherein when the circadian rhythm phase-shifting effect is a phase
advance, wherein the time interval of greater concentration is
between about CT 6 and about CT 18, or when the circadian rhythm
phase-shifting effect is a phase delay, wherein the time interval
of greater concentration is between about CT 18 and about CT 6.
46. The method of claims 44 or 45 wherein melatonin, the melatonin
agonist or compound that increases endogenous production of
melatonin in the human is administered in an immediate release,
sustained release or delayed release formulation or combination
thereof.
47. The method of claim 46 wherein melatonin, the melatonin agonist
or compound that increases endogenous production of melatonin in
the human is administered at wake-up time, breakfast time,
lunchtime, dinnertime or bedtime.
48. The method of claims 44, 45, or 47 wherein the phase-shifting
effect is the adjustment of circadian rhythms into synchrony with
local time following transmeridional travel.
49. The method of claims 44, 45, or 47 wherein the phase-shifting
effect is alleviating winter seasonal affective disorder.
50. The method of claims 44, 45, or 47 wherein the phase-shifting
effect is alleviating schedule-related circadian rhythm
disorders.
51. The method of claims 44, 45, or 47 wherein the phase-shifting
effect is the adjustment of circadian rhythms into synchrony with
the day/night, light/dark cycle in a human having advanced sleep
phase disorder.
52. The method of claims 44, 45, or 47 wherein the phase-shifting
effect is the adjustment of circadian rhythms into synchrony with
the day/night, light/dark cycle in a human having delayed sleep
phase disorder.
53. The method of claims 44, 45, or 47 wherein the administration
time can change from day to day.
54. The method of claims 44, 45, or 47 optionally including the
step of providing bright light at an intensity of about 500 lux to
about 100,000 lux.
55. The method of claims 44, 45, or 47 wherein a pharmaceutical
agent is administered to the human that is capable of stimulating
melatonin receptors in the suprachiasmatic nuclei of the
hypothalamus or elsewhere in the animal to achieve a phase-shifting
effect.
56. The method of claims 44, 45, or 47 optionally including the
step of administering to the human an amount of a pharmaceutical
agent, said agent being capable of stimulating melatonin receptors
in the suprachiasmatic nuclei of the hypothalamus or elsewhere in
the animal to achieve a phase-shifting effect.
57. The method of claims 44, 45, or 47, the method further
comprising the step of regulating exposure of the human to light
wherein the human is subjected to reduced light intensity or
darkness at a time from about CT 14 to about CT 18, or at a time
from about CT 18 to about CT 1.
58. A method according to claim 57 wherein the phase-shifting
effect is a phase advance, and the human is subjected to reduced
light intensity or darkness at a time from about CT 14 to about CT
18
59. A method according to claim 57, wherein the phase-shifting
effect is a phase delay, and the human is subjected to reduced
light intensity or darkness at a time from about from about CT 18
to about CT 1.
Description
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 07/842,723, filed Feb. 25, 1992, now U.S. Pat.
No. 5,242,941, issued Sep. 7, 1993, which is a continuation of U.S.
patent application Ser. No. 07/621,866, filed Dec. 4, 1990.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The field of the invention disclosed in 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 transmeridional travel (i.e., jet lag); methods for
alleviating circadian phase disturbance-based psychological
disorders (such as winter depression or seasonal affective
disorder); and 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. Such re-synchrony
enabled by the methods of this invention is achieved by the
administration of effective amounts of melatonin at specific and
predictable times based upon an individual human's circadian rhythm
phase response curve (PRC).
[0004] 2. Background of the Related Art
[0005] The phenomenon of circadian rhythms in biology is well
known, and circadian rhythms are exhibited by all eucaryotic 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.
[0006] In nature, circadian rhythms are closely tied to
environmental cues that impose a 24-hour pattern on many of these
fluctuations. Experimental inquiry has established that when these
cues are absent, most circadian rhythms have a periodicity of
approximately 25 hours. Circadian rhythms that are not 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 the circadian rhythm. The environmental
signals that affect entrainment have been termed zeitgebers, an
example of which is the light-dark cycle.
[0007] 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 nucleus (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 produces melatonin
(N-acetyl-5-methoxytryptamine), which is regulated by the SCN.
[0008] Disruption of circadian rhythms can result in a number of
pathophysiological states in humans; 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.
[0009] 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 1-10 mg of melatonin, taken at destination bedtime, and
again upon premature awakening in the middle of the night. In view
of the fact that such large dosages of melatonin are known to exert
a soporific (sleep-inducing) effect, and further that external
zeitgebers such as the light/dark cycle also act to re entrain the
circadian rhythm of a human's sleep/wake cycle following
transmeridional flight, it is not clear whether melatonin is
capable of directly causing any change in the circadian rhythm of
endogenous melatonin production when it is administered according
to the teachings of these patents.
[0010] Gwinner and Benzinger, 1978, J. Comp. Physiol. 126: 123-129
teach that daily injections of melatonin can entrain the
activity/rest cycle in birds.
[0011] 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.
[0012] Underwood, 1986, J. Pineal Res. 3: 187-196 discloses a PRC
for melatonin in the lizard Sceloporus occidentalis.
[0013] Arendt et al., 1987, Ergonomics 3: 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 and upon awakening in the middle of the
night.
[0014] 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 three days after cessation of the melatonin treatment.
[0015] Armstrong et al., 1989, Experientia 45: 932-938 disclose
that in rats the effects of exogenous melatonin administration on
the circadian rhythm of the sleep/wake cycle depends on the time of
administration relative to the sleep/wake cycle, and that the
effect was greatest when exogenous melatonin was administered a few
hours before the effective start of the nocturnal activity cycle.
However, these authors were unable to demonstrate phase-delay
shifts or graded changes in magnitude of phase-advance shifts, nor
did and they relate the timing of exogenous melatonin
administration to the time of the endogenous melatonin onset.
[0016] Petrie et al., 1989, Br. 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.
[0017] Skene et al., 1989, Sleep '88 (J. Horne, ed.), pp. 39-41
teach the use of melatonin to treat jet lag.
[0018] 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 hr
local time for 3 days before the time shift, and at 1400 hr local
time for 4 days afterwards.
[0019] Nickelsen 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.
[0020] Claustrat et al., 1992, Biol. Psychiatry 32: 705-711 teach
the use of melatonin to affect circadian rhythms.
[0021] Entrainment and regulation of the melatonin circadian
rhythms have been demonstrated in a number of animal species. The
ability to effect an actual change in phase of the circadian rhythm
would be useful for the alleviation of a number of circadian-rhythm
related disorders.
[0022] Lewy and Sack, U.S. Pat. No. 5,242,941, issued Sep. 7, 1993
to the present inventors, was the first disclosure of a
phase-response curve for melatonin in humans. This reference shows
that the appropriate time to administer melatonin to induce a
change in phase of a variety of human circadian rhythms is related
to the time of dim light melatonin onset (DLMO). Contrary to the
rather simplistic view held by the prior art (i.e., that melatonin
was simply associated with darkness, which came to be thought of as
being equivalent to sleep in diurnal animals), this patent
disclosure 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 produce both phase advances and phase delays in human
circadian rhythms. A particularly novel teaching of this patent
disclosure was that the magnitude and direction (i.e., phase
advance or phase delay) of the desired circadian rhythm phase shift
was dependent on the time of melatonin administration that resulted
in the desired circadian rhythm phase-shifting effect. Again
contrary to the established teachings of the prior art, this patent
prescribed administration of non-soporific 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 this patent are hereby expressly incorporated by
reference.
[0023] The human melatonin PRC clearly shows that melatonin acts
like darkness on the circadian rhythm of the wake/sleep cycle in
humans. Sleep alone has been found to have little if any
chronobiologic effect in humans; however it is possible that sleep
may potentiate the phase-shifting effects of melatonin and
darkness. Melatonin is produced in humans 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 thus might be a more effective
darkness zeitgeber than darkness alone in the absence of
melatonin.
[0024] The human melatonin PRC described in U.S. Pat. No. 5,242,941
suggested that exogenous melatonin would be most effective when
administered during the light period, to compete with light as a
"substitute for darkness". The present invention is based on our
further findings that the critical variable in determining the
proper time for melatonin administration is the relationship
between the time of melatonin administration and the DLMO time of
an individual human. This finding has provided the basis for the
methods of the instant invention, which methods enable treatment of
a variety of circadian rhythm phase disturbances in humans by
administration of exogenous melatonin at the times described
hereinbelow.
SUMMARY OF THE INVENTION
[0025] This invention relates to methods for achieving a
chronobiologic (phase -shifting) effect in a human. This effect is
achieved by affecting a human's circadian rhythm by administering
exogenous melatonin to the human at an appropriate time relative to
the human's dim light endogenous melatonin onset time.
[0026] The circadian rhythm of melatonin production in a human is
entrained principally by the (bright) light-dark cycle and reflects
a variety of other biological properties which vary with a
circadian rhythm. The methods of the invention entail the
phase-shifting of the circadian rhythm by administration of
exogenous melatonin. More specifically, the method of the invention
involves the administration of a particular dosage of melatonin to
the human. 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 melatonin
PRC by an appropriate degree. A linear dose effect has been found
as described hereinbelow at melatonin dosages from about 0.125 mg
to about 0.5 mg melatonin. Thus, in a preferred embodiment,
melatonin is administered in dosages preferably from about 0.05 to
5 mg, more preferably from about 0.1 to 2 mg, and most preferably
from about 0.1 to 1 mg. In a preferred embodiment, the total dose
of melatonin is given in one dose.
[0027] The present invention also contemplates the use of melatonin
precursors, agonists, antagonists, and compounds which mimic
melatonin activity, in place of melatonin
(N-acetyl-5-hydroxytryptamine) itself.
[0028] Further, the method of the invention relates to the timing
of the administration of the dosage of melatonin to the human. The
timing of this dosage in the human as described results in a
specific phase shift in the human's circadian rhythm of endogenous
melatonin production. The method described in the invention can be
used to advance or delay the phase of the circadian rhythm of
melatonin production in, the human. In this way, the present
invention is able to alleviate circadian rhythm disorders of both
the phase-delay and the phase-advance types.
[0029] The present inventors have discovered that the time of
administration of exogenous melatonin relative to the time of
endogenous melatonin onset is critical to the production of the
appropriate phase-shifting effect. The time of exogenous melatonin
administration is kept constant relative to the human's DLMO time,
which changes during a course of exogenous melatonin treatment as
provided by the methods of the invention. Thus, the actual
clock-time of melatonin administration also changes during the
course of melatonin treatment using the methods of this invention.
The time of endogenous melatonin onset, termed the dim light
melatonin onset (DLMO) time, will vary in each individual human;
however, the DLMO occurs at about 9 o'clock PM [circadian time (CT)
14] for most diurnal humans. Since the actual times of exogenous
melatonin administration as provided by the methods of the instant
invention are dependent on the time of an individual human's dim
light melatonin onset (DLMO) time (which will vary for each
individual), circadian time will be used to most effectively
represent all times discussed in this specification.
[0030] The present invention is based on the melatonin
phase-response curve (PRC; see U.S. Pat. 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-advance responses. Within this interval, the time
of administration of melatonin is related to the magnitude of the
resulting phase advance shift of the PRC. The human melatonin PRC
also indicates the presence of a time interval for each individual
during which administration of exogenous melatonin results in clear
and unequivocal phase-delay responses. Within this interval, the
time of administration of melatonin is related to the magnitude of
the resulting phase delay shift of the PRC. The present invention
directs the administration of melatonin to achieve phase advances
between about CT 3 to about CT 18, and to achieve a phase delay
between about CT 12 to about CT 6. The predicted phase advance or
phase delay is more likely if the melatonin administration time
occurs within these two intervals, respectively. The methods of the
invention also take into account the additional fact that the zones
for phase advance and phase delay overlap (i.e., between about CT 3
and CT 6 and also between about CT 12 and CT 19), as shown in FIG.
1.
[0031] The invention also relies on the identification of more
precise intervals of melatonin administration times wherein the
intervals of phase advance and phase delay responses do not
overlap. For a phase advance, this unequivocal melatonin
administration interval ranges from about CT 7 to about CT 11. For
a phase delay, the melatonin administration interval is from about
CT 20 to about CT 2.
[0032] The methods of the present invention thus provide for the
administration of exogenous melatonin to effect a phase advance or
a phase delay in the endogenous melatonin PRC. Preferred times of
melatonin administration to effect a phase advance are about CT 3
to about CT 18, more preferably about CT 7 to about CT 11, most
preferably about CT 7 to about CT 8. Preferred times of melatonin
administration to effect a phase delay are about CT 12 to about CT
6, more preferably about CT 20 to about CT 2, and most preferably
at about CT 0.
[0033] It will be understood by those with skill in this art that
the methods of this invention thus prescribe exogenous melatonin
administration times which will change relative to clock time
during the course of exogenous melatonin treatment to effect a
circadian rhythm phase shift. One novel and important aspect of the
instant invention is that exogenous melatonin administration times
are predicted relative to an internal circadian rhythm marker, the
DLMO time, rather than external markers such as clock time (e.g.,
"destination bedtime"). This aspect enables the instant invention
to provide methods for achieving circadian rhythm phase-shifting
effects that result in the effective treatment of a variety of
circadian rhythm phase disturbances. In preferred embodiments, such
circadian rhythm phase disturbances include jet lag, winter
depression and shift-work and other human activity schedule-related
disorders and de-synchronies with external zeitgebers.
[0034] Also contemplated as components of the methods of the
instant invention are embodiments wherein melatonin administration
is accompanied, either at administration times coincident with
melatonin administration times or at appropriate times other than
melatonin administration times, by exposure of a human to bright
light, either artificial or naturally-occurring, or by limiting
such exposure, that is, by prescribing the use of dark or
red-colored goggles or other means to prevent a human from exposure
to a light stimulus. Appropriate combinations of exogenous
melatonin administration, dim light or bright light treatments are
provided by this invention, as described more filly below.
[0035] 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
[0036] FIG. 1 illustrates a double-plotted human phase response
curve, wherein the right-hand plot also represents the flat
cross-over point between CT 12 and CT 19 and the steep cross-over
point betweenm CT 2 and CT6;
[0037] FIG. 2 illustrates the results of the experiment described
in Example 2;
[0038] FIGS. 3 and 4 disclose the experimental results of Example
3;
[0039] FIGS. 5 and 6 disclose the experimental results of Example
4;
[0040] FIG. 7 illustrates a double plot of melatonin administration
times for the protocol used to alleviate the effects of jet lag
caused by airline travel between Portland, Oreg. and Maui, Hawaii
as described in Example 5;
[0041] FIG. 8 illustrates the pharmacokinetic appearance of
exogenous melatonin in blood after oral administration;
[0042] FIG. 9 illustrates the phase shifts achieved using the
melatonin administration protocols of Example 5 to alleviate jet
lag;
[0043] FIG. 10 shows the relationship between the degree of
improvement in SIGH-SAD ratings in patients with winter depression
and melatonin treatment as described in Example 6;
[0044] FIG. 11 depicts baseline and post-treatment DLMO times for
two winter depressive patients treated with melatonin and
atenolol;
[0045] FIG. 12 illustrates the linear relationship between dose of
melatonin and the amount of phase shift achieved in experiments
using 0.125 mg melatonin+100 mg atenolol treatment and melatonin at
dosages of 0.25 and 0.5 mg without atenolol;
[0046] FIG. 13 shows the average phase shift in DLMO after 2 weeks
of melatonin administration as described in Example 6;
[0047] FIG. 14 relates the degree of phase shift caused by
melatonin administration to changes in winter depression as
measured by the SIGH-SAD criteria;
[0048] FIG. 15 illustrates the inverse relationship between the
magnitude of the induced melatonin phase shift and improvement in
the SIGH-SAD ratings in winter depressive patients;
[0049] FIG. 16 shows melatonin profiles and sleep time of six night
shift-workers obtained using the methods described in Example
7;
[0050] FIG. 17 provides a graphic summary of the data depicted in
FIG. 15;
[0051] FIG. 18 shows phase shifts for six shift-workers treated as
described in Example 7;
[0052] FIG. 19 illustrates plasma melatonin and sleep times for
shift-worker CS;
[0053] FIG. 20 shows plasma melatonin and sleep times for
shift-worker SH;
[0054] FIG. 21 shows plasma (grey curve) and salivary (black curve)
melatonin levels in a night shift-worker treated with 0.5 mg of
melatonin taken at bedtime;
[0055] FIGS. 22-25 show the degree and direction of phase shifting
achieved by treating night shift-workers using the protocol
described in Example 7;
[0056] FIG. 26 illustrates the average (.+-. standard error) amount
of melatonin production (in pg) in a subject exposed to three
different levels of light, with or without wearing sunglasses;
and
[0057] FIG. 27 shows the magnitude of phase delays (in minutes)
achieved in a subject using a protocol of 0.5 mg melatonin taken
for 4 days on two separate occassions, once while wearing
sunglasses and once without wearing sunglasses.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0058] The amount of melatonin administered to a human subject
should be sufficient to achieve the desired circadian rhythm
phase-shifting effect. In a preferred embodiment of this invention,
a dosage of about 0.1 mg to about 1 mg, most preferably about 0.5
mg, of exogenous melatonin is used to effect the desired change in
phase of the circadian rhythm of endogenous melatonin production.
In a preferred embodiment, the total dose of melatonin is given in
one administered dose.
[0059] 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, 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.
[0060] It may also be adantageous to administer melatonin in
formulations wherein the melatonin is continuously released
physiologically for a set time (e.g., sustained-release
formulations), or in formulations wherein the physiological release
of melatonin is delayed (e.g., delayed release formulations), or in
combinations thereof.: The present invention encompasses the use of
such melatonin formulations in the methods of the instant
invention.
[0061] In a preferred embodiment of this invention, a phase advance
or phase delay in the circadian rhythm of endogenous melatonin
production is effected by the administration of an amount of
exogenous melatonin sufficient to achieve the phase advance or
delay based upon the actual phase response curve of the individual,
or the predicted phase response curve of the individual, or on
their actual or estimated DLMO time. A phase advance in the
circadian rhythm of endogenous melatonin production is effected by
the administration of an effective dose of melatonin between about
CT 3 to about CT 18, more preferably between about CT 7 to about CT
11, most preferably from about CT 7 to about CT 8. A phase delay in
the circadian rhythm of endogenous melatonin production is effected
by the administration of an amount of exogenous melatonin
sufficient to achieve the phase delay at administration times from
about CT 12 to about CT 6, more preferably from about CT 20 to
about CT 2, most preferably at about CT 0.
[0062] In newly-appreciated aspect of the human melatonin PRC,
there are found overlapping and non-overlapping areas between the
advance and delay zones (as seen in FIG. 1); this characteristic
results in "narrow" and "broad" intervals in which the effect of
the timing of melatonin administration on the production of either
a phase advance or phase delay is less critical in the latter
versus in the former. There are also regions of reduced
responsiveness towards exogenous melatonin, termed "dead zones",
between the phase advance and phase delay portions of the PRC (see
FIG. 1). The cross-over point in the "narrow" dead zone between
advance and delay phase shifting regions of the melatonin PRC
separates phase shifts of them greatest magnitude, whereas the
cross-over point in the "broad" dead zone between advance and delay
phase shifting regions of the melatonin PRC separates phase shifts
of the lesser magnitude. Consequently, it is possible to prescribe
melatonin administration times based on either the broad
overlapping zones or narrow exclusive zones. It is also possible
view the decision on which set of administration times to prescribe
as being a conservative approach, in which one wants above all else
to avoid shifting a person in the wrong direction. These
conservative times of melatonin administration are about CT 7 to
about CT 8. for phase advances and about CT 0 for phase delays. Use
of this conservative approach requires a user to be willing to
settle for a smaller phase shift. Using a more aggressive approach,
on the other hand, exogenous melatonin administration times closer
to the steep cross-over point in the melatonin PRC can be chosen,
resulting in the possibility of achieving larger phase shifts.
However, this aggressive approach also carries the risk that a
phase shift will be effected in the direction opposite to the
desired direction, and is thus an inappropriate strategy for many
applications of the methods disclosed herein (see Examples
below).
[0063] At least for phase advances, the beginning of the exogenous
melatonin stimulus pulse should be used as the reference phase for
administration time. As compared with the human PRC disclosed in
U.S. Pat. No. 5,242,941, the current embodiment of the human
melatonin phase response curve is shifted about one hour earlier,
because most of the administration times therein disclosed were
taken to be the average of the times of administration of a split
dose of melatonin.
[0064] The easiest way to estimate circadian times are relative to
"sleep offset", which is equal to the time of awakening for humans
awakening to sunshine or other bright light. For humans who awaken
before dawn, sleep offset is the time of their dawn exposure to
sunlight, or nore accurately a short time thereafter, since even
sunlight is fairly dim light right around dawn. This time is taken
to be equal to CT 0. For most humans, the average time of dim light
melatonin onset (DLMO) is 14 hours later, or at CT 14. For
conversion back to clock time, CT 14 is on average 9 p.m., for the
average person who awakens at 7 a.m.
[0065] A modification of the method of Lewy and Markey (1978,
Science 201: 741-3) may be used to determine the time of onset of
the patient's endogenous melatonin production. The preferred use of
this method is taught in Example 1.
[0066] Determination of circadian time is done optimally using the
DLMO time. However, in some individuals (who have very low
melatonin production, encompassing less than 10% of the population)
determination of the entire melatonin curve may be preferable, or,
alternatively, an algorithm can be applied to correct the circadian
time of the DLMO. Determination of the entire melatonin profile may
be preferred in some individuals for other reasons known to those
with skill in the art as well.
[0067] Other markers for circadian time are also useful, for
example sleep onset (bedtime) or sleep offset (wake time), and in
some cases these markers are more convenient than the DLMO time.
There are also other physiological markers that be used, such as
the core body temperature minimum or the rising limb of the
cortisol circadian rhythm. These markers are more or less tightly
coupled with each other, whereas other 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).
[0068] 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;
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; 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; 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; the aged; the sick, or those who require dosages of
medication at appropriate times in the circadian cycle; and animal
breeders, for use in controlling circadian time. Five types of
insomnia can also be helped by melatonin administration. One,
termed pure insomnia, is not particularly related to a circadian
phase disturbance. Two 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.
[0069] The present invention provides methods useful in the
treatment of jet lag, winter depression, maladaptation to
work/off-work schedules or any of the other above-listed
conditions, under direct medical supervision, wherein melatonin
administration times are chosen pursuant to a determination of the
actual DLMO time for an individual. Other such instances include
patients whose PRC must be specifically determined, or where the
use of melatonin precursors, agonists or antagonists require a more
precise determination of dose and timing of exogenous melatonin
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.
[0070] 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 prescribed, 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 times of exogenous melatonin
administration based on the number of time zones crossed in travel
and the direction of travel, either based on characteristically
"normal" human DLMO times or with reference to any other indicia of
an individual's actual DLMO time. In other such specific
embodiments of the invention, melatonin may be administered in
time-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.
[0071] Preferred embodiment of the methods of this invention
encompass melatonin administration times based upon an individual's
PRC and DLMO time. Administration times are prescribed relative to
the DLMO time, which will change with re-adjustment of an
individual's melatonin PRC (accompanied by re-synchronization of
the individual's circadian rhythms with the external environment).
According to the methods of this invention, the magnitude and
direction of the desired circadian rhythm phase shift are dependent
on melatonin administration times and the pattern and direction of
the change in the clock time of such administration times with
adaptation of the melatonin circadian rhythm.
[0072] One example of the teachings of the instant invention
embodying the aspects of the timing of exogenous melatonin
administration and the change in the clock time of melatonin
administration times that accompanies the shift in the melatonin
PRC is shown in Table I. The Table illustrates the predicted times
of exogenous melatonin administration for alleviating jet lag. As
can be seen from the Table, the time of melatonin administration
depends on both the magnitude and the direction of the desired
phase shift. Also shown in the Table is the change in melatonin
administration times during the course of melatonin treatment,
wherein the melatonin administration time remains constant relative
to the DLMO time (which changes in response to the melatonin PRC
shift). This Table is based on our finding that the appropriate
shift (conservatively estimated) in exogenous melatonin
administration times in jet lag alleviation protocols is about one
hour per dose of melatonin (for a 0.5 mg dose).
[0073] Generally speaking, the timing of exogenous melatonin
administration can be safely estimated as described above, or
specifically determined by diagnostic testing. In practice, these
approaches can be employed seriatim, i.e., one can start by using
sleep onset or offset (i.e., awakening) time as a marker for
circadian time. In cases where this estimate proves to be
unsatisfactory, a more reliable physiological marker, such as the
DLMO time, can be determined. Alternatively, the nighttime
melatonin profile can be obtained by testing blood, urine, saliva
or other body fluid for the presence of melatonin or physiological
or metabolized products thereof. The easiest way to estimate an
individual's circadian time is relative to the time of sleep offset
(awakening) corresponding to "bright lights on", as described
above.
[0074] It is contemplated that in some cases, it may be necessary
to empirically determine a rather highly defined PRC for an
individual in order to know exactly when to administer medication
optimally. For most people, however, general rubrics can be used
based on average characteristics or on the average correlation
between observable circadian rhythm markers (such as wakefulness
and sleep) and melatonin and other more occult human circadian
rhythms. An example of the utility of such generalized methods is
the jet lag-related table of proper administration times described
above (Table I).
[0075] Melatonin administration times are optimally adjusted on a
daily basis for methods used to accomplish large (i.e., greater
than a total of 1 hour) shifts in the melatonin PRC. This can be
advantageously and conveniently achieved using a melatonin delivery
system that is, formulated to release melatonin on schedule, i.e.,
so that the melatonin can be released to act at a time that changes
daily, although the time of administration of the melatonin
formulation does not change. For convenience, a delayed-release
melatonin preparation would be optimal, particularly if the
formulation resulted in increased physiological melatonin levels of
short duration. Such advantageous controlled-release melatonin
preparations would not only be capable of sustaining physiological
melatonin levels at a desired level for desired period of time, but
would also enable such physiological availability to commence and
cease at fairly precise times. For example, as described more fully
hereinbelow, an optimal delayed-release melatonin formulation could
be used in the treatment of either shift workers or air travellers,
whereby physiological melatonin levels would be increased at a
slightly different time each day, so that an individual would only
need remember to take the formulation at the same time of day.
[0076] It is also possible to formulate melatonin delivery systems
that can produce a sustained physiological level (i.e.,
sustained-release formulations) over a period of time corresponding
to a selected interval of the individual's PRC. This form of
therapy could be used to shift the PRC without necessitating the
continued administration of melatonin by the individual. In some
individuals, a broader pulse width of melatonin covering the widest
possible zone, for either the conservative or aggressive approach
of treatment, to produce the appropriate phase'shift would be
desirable.
[0077] 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.
[0078] Similarly, bright light exposure can be used along with the
exogenous melatonin administration methods provided herein. One
aspect of the usefulness of this embodiment is for the bright
light-mediated suppression of endogenous melatonin production when
such endogenous melatonin production occurs at the "wrong" time,
i.e., at a time relative to the PRC which would be antagonistic to
the desired phase shift.
[0079] Inappropriate endogenous melatonin production can also be
suppressed pharmacologically using a number of pharmaceutical
agents, including but not limited to noradrenergic and serotonergic
re-uptake blockers, alpha-1-noradrenergic agonists, monoamine
oxidase inhibitors, beta-adrenergic blockers and benzodiazepines.
It may also be desirable to suppress part of the endogenous
melatonin profile, for example, by causing receptor
super-sensitivity; by removing endogenous melatonin from
stimulating the undesirable part of the melatonin PRC; or to
eliminate potentiating effects of a competing melatonin or darkness
(sleep) signal. One example of this embodiment (described in more
detail below in Example 6) is the use of atenolol plus a very low
dose of melatonin (0.125 mg) in the treatment of winter depression.
Atenolol is given at about CT 14 and low-dose melatonin at CT 8.
Atenolol blocks endogenous melatonin production during the delay
zone (which promotes a phase advance), and it also induces
super-sensitivity to the melatonin administered at 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.
[0080] Certain other drugs (tricyclic antidepressants and
alpha-2-adrenergic antagonists, for example) can raise endogenous
melatonin levels, particularly at night. This side effect will also
affect an individual patient's "biological clock" in ways predicted
by the melatonin PRC.
[0081] Melatonin precursors such as tryptophan,
5-hydroxytryptophan, serotonin and N-acetylserotonin may also
affect endogenous melatonin levels and the melatonin PRC, either
via their conversion to melatonin, or by the direct action of these
compounds on melatonin receptors in the SCN. Such influences are
predictable using the melatonin PRC, adjusted to account for
absorption time, metabolic conversion rates, etc.
[0082] Phase-shifting effects of melatonin agonists can also in
like manner be predicted by the melatonin PRC. The phase-shifting
effects of melatonin antagonists, on the other hand, are somewhat
more complex, because these effects depend on whether a particular
antagonist acts directly on melatonin receptors in the SCN or
whether such antagonists act to block endogenous melatonin
activity. However, in either case their effects can be predicted by
the melatonin PRC, once the effects of absorption time, etc., are
taken into account.
[0083] 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. Pat. No. 5,242,941, issued Sep. 7, 1993 and
incorporated herein by reference), any administration of exogenous
melatonin will potentially cause a melatonin PRC phase shift
(unless said administration time falls within one of the "dead
zones" of relative insensitivity of the PRC to the effects of
exogenous melatonin). Melatonin administration performed in
ignorance of such effects on an individual's PRC run the risk of
causing inpppropriate melatonin PRC phase shifts, which may act
contra to the physiological effect 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.
[0084] These considerations become especially important in the
treatment of certain circadian rhythm-related patholigical
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 a certain zone of the melatonin PRC
and to avoid stimulation of other zones, as well as to take
advantage of any soporific side effects associated with
administration of pharmacological dosages of melatonin. For
example, in the treatment of delayed sleep phase syndrome, a
physiological dose should begin at about CT 7-8, then increase to a
pharmacological dose just before bedtime (about CT 14-16) and end
before any delay responses begin, at about CT 17-19. For pure
insomnia (no phase disturbance) any dose of melatonin that would
promote sleep would also be potentially able to cause a phase shift
(although the low phase-shifting doses do not necessarily cause
sedation) and therefore these phase shifts must be avoided. There
are two ways to do this: one way is to give melatonin exclusively
at the dead zone, that is between about CT 14-16. The other way is
to give melatonin sufficiently early to cause a phase advance that
will balance out any phase delay caused by its administration
during sleep.
[0085] For some individuals, optimal phase advancing would be
accomplished by having the exogenous melatonin pulse continuous
with the offset of endogenous melatonin, and optimal phase delaying
would be accomplished by having the exogenous melatonin pulse
continuous with the onset of endogenous melatonin. The possible
combinations of melatonin dosages and administration times are
flexible enough to allow individually-tailored treatments as
needed, but all treatments have in common the feature of being tied
to intervention based upon the melatonin PRC.
Melatonin Administration Under Medical Supervision
[0086] A certain portion of the human population falls outside of
what is considered the "normal" human characteristics of drug
absorption, or ability of circadian rhythms to adapt or respond to
melatonin treatment. These individuals may require a more accurate
determination of the individual 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 DLMO before intervention. In a
controlled setting, under medical supervision, a more precise and
specific intervention of the melatonin PRC can be accomplished
using the methods of the present invention to effect predictable
phase advances or delays.
[0087] Under medical supervision, a subject can have their 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
spetroscopy (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 the DLMO time in a
predictable manner.
Melatonin Administration by the Individual
A. Kit for determining DLMO.
[0088] Alternatively, 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 DLMO time by sampling biological
fluids at short intervals during the course of part of a normal
day.
[0089] 1. Dip Stick for Saliva
[0090] 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 his 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.
[0091] 2. Blood Drop Test
[0092] 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 means
would result in a qualitatively similar but 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.
B. Fixed Dose Melatonin Formulations
[0093] 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 normals
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.
[0094] 1. Based on an Individual's Actual DLMO Time
[0095] 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 shift result 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.
[0096] 2. Based on an Individual's Estimated DLMO Time
[0097] In many instances, the magnitude of the desired phase shift,
or the magnitude of an individual's desire for the phase shift
[i.e., whether phase shifting is medically-necessary e.g., in
winter depression patients) or simply a matter of convenience
(e.g., jet lag)], may permit the administration of melatonin based
upon an estimated DLMO time. This can be done by using the position
of an individual's typical wake time and sleep times as being about
CT 0 and CT 14, respectively. Using exogenous melatonin
administration schedules based on such rough estimates of the DLMO
time allow very general intervention and adjustment of the DLMO.
Such interventions are best accomplished using lower doses of
melatonin administered over a wider period of time, to encompass
most of the estimated advance or delay portion of the PRC without
overlapping with the region of the PRC specifying 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 man-made circadian rhythm desynchronizations of human
circadian rhythms.
C. Timed Release Melatonin Formulations
[0098] 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.
[0099] 1. That Shift Release Time Over the Period of
Administration.
[0100] A novel feature of the present invention is the use
of-melatonin administration times that remain constant relative to
the DLMO time, and change relative to clock time as the melatonin
PRC undergoes a phase shift. However, this feature necessitates
that melatonin be taken at different times during the
administration protocol, and this feature may make the methods
undesirably inconvenient in practice. In order to facilitate ease
of use, 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
administration time without requiring the individual to vary daily
administration times.
[0101] 2. That are of Fixed the of Release but can Vary in
Dosage
[0102] The linear relationship between phase shift and melatonin
dose has been demonstrated (see Example 6). 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 the melatonin
PRC in individuals having unique requirements, for example, due to
work schedule, disease, personal reaction to melatonin, life style,
or other factors.
[0103] 3. That Shift Release Time and Released Dosage
[0104] 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 doses of melatonin during desired
hours of alertness. Similarly, sustained low-level release of
melatonin during desired hours of alertness can be followed by
release of higher levels of melatonin during desired sleep times to
enhance the phase-shifting effect.
D. Simplified Administration Schedule
[0105] Depending on the desired result, the schedule of
administration of melatonin, the dose, type of formulation, and
period of administration are all variables that can be altered to
suit individual requirements. These variables can also be
simplified for the type of administration desired, so that the
average person can use kits providing appropriate melatonin
formulations and instructions on their use to effect the desired
melatonin phase shifts.
[0106] The simplest form of instruction would be a look-up,
cross-indexed tables referenced to the DLMO time, that would allow
an individual to pick the amount of phase shift desired and the
correct melatonin dose and administration times to effect the
desired phase shift.
[0107] 1. Jet Lag
[0108] For example, jet lag can be efficiently and effectively
treated using the teachings of the invention. An individual can use
either his estimated DLMO time or a kit-derived estimate of his
DLMO time (or even a medically-supervised DLMO time determination)
to identify his DLMO time at a time prior to travel. This
information can then be used as the baseline DLMO time for
intervention. The direction of travel will determine whether a
phase advance or a phase delay is desired, and the number of time
zones travelled will determine the magnitude of phase shift
required to ameliorate the effects of jet lag on the individual.
Melatonin can then be administered using human melatonin
PRC-derived schedules, exemplified by Table I, to achieve the
desired phase shift. The choice of formulation taken can be varied,
so that the exact methods of melatonin administration will conform
to individual needs. Integrated kits providing melatonin
formulations and administration protocols can be provided to
alleviate jet lag caused by transmeridional flight travelling to
and returning from any destination.
[0109] 2. Whiter Depression
[0110] A small shift in an individual's DLMO time (about 0.5 hour)
has been found to be capable of vastly improving psychological
ratings of winter depression in patients suffering from this
disorder (see Example 6 below). These results indicate that simple
formulations of melatonin capable of effecting such small phase
shifts in DLMO time would be useful to individual suffering from
winter depression. Since only a small melatonin phase shift is
required, individuals could use estimated DLMO times to determine
the appropriate time of exogenous melatonin administration.
However, preferred embodiments of this method would also encompass
accurate, medically-supervised determinations of the DLMO time, as
the inappropriate administration of melatonin to winter depressives
has been found to exacerbate the symptoms of winter depression in
some such patients. Melatonin formulations, doses, times and
duration of administration can be tailored to the needs of
individual patients.
[0111] 3. Maladjustment to Work Schedule
[0112] In individuals who must adjust their work schedule to fit
reversals from normal environmental zeitgebers (such as night-shift
workers), melatonin administration can effect a phase shift
resulting in adjustment to the new-sleep cycle. Melatonin
administration protocols can be used based on estimated DLMO times
in such individuals, but more accurate determinations of DLMO times
are preferred. Melatonin formulations for treatment of these
individuals can be tailored for convenience to result in the
desired phase shift without causing unwanted soporific side
effects.
[0113] 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 Spectroscopy
[0114] Prior to collection of human blood, subjects are kept in dim
light for about 5 hours (usually between 6 PM and 11 PM). An
intravenous line or heparin lock is inserted in a forearm vein and
5 ml of blood drawn every 30 minutes between 7 PM and 11 PM. The
blood samples are centrifuged for 5 minutes at 1000 g and 4.degree.
C., and the plasma aspirated into a silanized glass or plastic
tube. Samples are assayed immediately or frozen for later analysis.
To a 1 ml aliquot of such plasma was added 15-40 picograms of
N-acetyl-5-methoxy(.alpha.,.alpha.,.beta.,.beta.-D.sub.4)tryptamine
as a chromatographic control. An equal volume of normal saline is
added and the mixture gently shaken with 10 volumes of petroleum
ether. The organic phase is 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 10 volumes of
chloroform. The aqueous phase is then discarded, and the chloroform
evaporated to dryness.
[0115] The dried extract containing melatonin and the added
N-acetyl-5-methoxy(.alpha.,.alpha.,.beta.,.beta.-D.sub.4)tryptamine
control is dissolved in 0.4 ml of anhydrous acetonitrile. The
melatonin contained in the plasma samples and the added
N-acetyl-5-methoxy(.alpha.,.alpha.,.beta.,.beta.-D.sub.4)tryptamine
control are then derivatized by the addition of 25 .mu.l of
pentafluoroproprionic acid anhydride and 0.5 ml of a solution of 5%
trimethylamine in anhydrous benzene and reacted at 100.degree. C.
for 10 minutes. The reaction products are washed sequentially with
1 ml water and 1 ml 5% ammonium hydroxide. The mixture is
centrifuged briefly at 13,000 g and the organic phase withdrawn and
evaporated to dryness under nitrogen. The dried extract is
partitioned between 0.5 ml acetonitrile and 1 ml hexane by vigorous
mixing followed by centrifugation. The hexane layer is removed and
the acetonitrile evaporated to dryness under nitrogen. This
partitioning step is performed two times for each sample. The dried
extract is re-partitioned for storage. The derivatives are stable
and can be stored at -20.degree. C. for several weeks.
[0116] The amount of melatonin present in each sample is determined
by analysis using a gas chromatograph-mass spectrometer (GC-MS).
Before injection onto the GC column, the dried derivatives are
dissolved in 15 .mu.l of ethyl acetate. Approximately half this
volume was applied to a 30 m.times.25 .mu.m fused silica capillary
column [0.15 micron film thickness with a 1 m retention gap
(DB-225, J&W Scientific, Folsom Calif.)]. "The oven is
programmed from 60.degree. C. to 240.degree. C. (at 2.5.degree.
C./min) with helium as carrier gas (10 psi head pressure) and
methane used as make-up gas (ionizer, 0.6 torr). Derivatized
melatonin and the added
N-acetyl-5-methoxy(.alpha.,.alpha.,.beta.,.beta.-D.sub.4)tryptamine
derivatized control are found to elute from the column after 10-14
minutes. Mass spectrographic analysis of the column eluant is then
performed. Mass spectra are recorded using a Finnigan 4000-GC-CI
analyzer and INCOS data system. A Finnigan PPIMCI electron
multiplier with 3 kV conversion was used, signal referenced to
ground. The relative signals of melatonin and the added
N-acetyl-5-methoxy(.alpha.,.alpha.,.beta.,.beta.-D.sub.4)tryptamine
control are 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.sub.4)tryptamine
control.
EXAMPLE 2
Phase Advance in the Human Melatonin Phase Response Curve
[0117] The effect of exogenous melatonin administration on
circadian rhythms of sighted people was tested. Eight normal
subjects were treated in a two-week protocol. During the first
week, the subjects were given a placebo at 1700 and 1900 hours and
the time, extent and amount of dim light melatonin onset (DLMO) was
measured as described in Example 1. During the second week,
subjects were given placebo at 1700 and 1900 hours for two days,
and then melatonin was administered in two doses of 0.25 mg at 1700
and 1900 hours for 4 days and the subjects' DLMO determined.
[0118] Seventeen trials were conducted on the eight subjects. The
results of this study are shown in FIG. 2. The Figure defines the
human melatonin phase response curve, showing the relationship
between the degree of phase shift obtained and the interval between
the time of administration of exogenous melatonin and the
endogenous DLMO (this interval is also known as the phase angle).
The earlier the exogenous melatonin is administered the greater is
the magnitude of the phase advance; that is, there is a positive
correlation between the extent of phase advance achieved by
exogenous melatonin administration and the time interval between
the time of exogenous melatonin administration and the time of
endogenous melatonin onset. These results confirm that exogenous
melatonin administration can effect a phase advance in humans, and
that the timing of exogenous melatonin administration relative to
the onset of endogenous melatonin is critically important for phase
shifting circadian rhythms.
EXAMPLE 3
Relationship Between Exogenous Melatonin Administration Time and
DLMO Time
[0119] The effect of exogenous melatonin treatment administered at
earlier times relative to the endogenous melatonin rhythm was
tested in sighted people. Twenty-four trials were conducted in, the
eight normal subjects who were treated in a two-week protocol
similar to the one used in Example 2. During the first week,
placebo was administered and the time, extent and amount of dim
light melatonin onset (DLMO) was determined. Subsequently in the
second week, melatonin was administered at various times prior to
the time of endogenous melatonin onset, and the subjects'
endogenous melatonin onset was determined. The results of this
study are shown in FIGS. 3 and 4. FIG. 3 expresses the results in
terms of circadian time [assuming the DLMO occurs at circadian time
(CT) 14], and FIG. 4 expresses the same results in terms of
military time [assuming that DLMO is at 2000 hours (8 PM)]. These
results show that the maximum degree of phase advance in the onset
of endogenous melatonin occurred after administration of exogenous
melatonin at CT 8, or 6 hours prior to the normal time of melatonin
onset in the subjects (CT 14). This corresponds to a time of about
8-10 hours before normal bedtime in these subjects. The observed
phase advance declines rapidly when exogenous melatonin is
administered prior to CT 8. Between CT 8 and CT 14, the decline in
the degree of phase advance is linear and proportional to the phase
angle between time of administration and time of endogenous onset.
Minimal effect, if any, on the circadian rhythm of endogenous
melatonin onset is seen when the time of administration of
exogenous melatonin coincides with the normal time of onset of
endogenous melatonin (CT 14).
EXAMPLE 4
Phase Delay in the Human Melatonin Phase Response Curve
[0120] Experiments to investigate the use of exogenous melatonin to
effect a phase delay were also performed. These experiments
followed the protocol explained in Example 2; however, the time of
administration of melatonin was different. A total of 6 trials were
performed. The results of this experiment are shown in FIGS. 5 and
6. In this regime, exogenous melatonin was administered about 11-19
hours before normal bedtime. It was found that administration of
exogenous melatonin from about 9 hours to about 17 hours before the
endogenous melatonin onset resulted in the greatest degree of phase
delay in the onset of endogenous melatonin production.
EXAMPLE 5
Melatonin Administration for Alleviating Jet Lag
[0121] A series of experiments were performed to illustrate the
usefulness of the instant invention for alleviating jet lag in six
subjects caused by transmeridional flight across three time zones
in both the easterly and westerly dictions. The six subjects were
flown from Portland, Oreg., to Maui, Hawaii, remained there for 6
days and then were flown back to Portland. For each subject, the
experiment was performed on two occasions, randomly ordered: once
to illustrate the instant method, and a second time for comparison
with methods of melatonin administration to alleviate jet lag known
in the prior art.
[0122] During the experiment, the circadian rhythm of endogenous
dim light melatonin onset (DLMO), a very accurate marker for body
clock time, was determined physiologically by taking blood samples
of the subjects every 30 minutes in dim light (<50 lux) in the
evening on selected days. In addition, subjective impressions of
chronobiological well-being were solicited from the subjects after
concluding the experiment.
[0123] FIG. 7 shows the experimental protocol for travel. The dark
shaded bars denote scheduled sleep time. The lightly shaded area
represents the time spent in Hawaii. The black boxes indicate
administration times of 5 mg melatonin according to the teachings
of the prior art, while white boxes indicate administration times
of 0.5 mg melatonin according to the teachings of the instant
invention. The time of 5 mg melatonin administration using the
prior art teachings was the same at each administration (i.e.,
destination bedtime), while the time of 0.5 mg melatonin
administration using the instant invention differed from the prior
art administration times in two distinct ways. First, the time of
administration was not linked to destination bedtime for travel
across three time zones (although it should be recognized that the
time established by the instant invention as the appropriate time
for melatonin administration may coincide with destination bedtime
at some destinations). Second, the time of melatonin administration
changed over the course of the experiment, as the circadian
rhythms, including the melatonin PRC, were expected to adjust to
local time.
[0124] The subjects were given melatonin in the appropriate dosages
for each experiment before and after travel, as well as on the day
of travel from Portland to Hawaii and back for a total of six (6)
days for each direction of travel. Under each experimental
protocol, subjects were not aware of what dose of melatonin was
being administered to them. In addition, when subjects were given
melatonin according to a given protocol (i.e., the prior art
administration times or the instant invention administration
times), they were also given placebo capsules at the times when the
alterative protocol called for melatonin administration, and
subjects were not aware of when they were receiving melatonin and
when they were receiving placebo.
[0125] The time of administration of 0.5 mg melatonin required to
have the desired chronobiological effect was predicted from the
endogenous PRC of the individual, and depended on the number of
time zones crossed in the experiment. Table I illustrates the
predicted time of initial melatonin administration depending on the
direction of travel and the number of time zones crossed between
place of origin and destination. In addition, the clock time of
melatonin administration changed over the course of the experiment,
as the circadian rhythms, including the melatonin PRC, was
predicted to become adjusted to the local conditions. The subjects
were given melatonin in the appropriate dosages before and after
travel, as well as on the day of travel, for a total of six days
for each direction of travel.
[0126] Melatonin was administered at two different dosages: 5 mg
doses were used as prescribed by the prior art, and 0.5 mg doses
were given using the administration protocol of instant invention.
FIG. 8 shows the pharmacokinetic profile of melatonin in a
subject's bloodstream obtained consequent to melatonin
administration for both dosages. Melatonin levels in blood samples
were analyzed using conventional techniques of radioimmunoassay
(RIA). As shown in FIG. 8, administration of 0.5 mg of melatonin
raised melatonin blood levels to approximately the maximum normal
physiological blood level. In contrast, administration of 5 mg of
melatonin raised melatonin levels to more than twelve (12) times
the maximum normal physiological blood level.
[0127] FIG. 9 shows the results of DLMO phase-shifting achieved
using the two melatonin administration protocols with 2
representative individuals during melatonin-induced phase delay in
Hawaii. In travelling to Hawaii, the subject travels 3 time zones
west, so that the endogenous circadian rhythm is ahead of the
environmental light-dark cycle at the Hawaiian destination. This
means that the subject became tired and sleepy approximately 3
hours before it was locally appropriate for going to sleep. In
order to effectively alleviate the circadian rhythm disruption of
jet lag, the subject's DLMO time had to be delayed by 3 hours in
order for the subject to stay alert in the evening and to become
sleepy at the locally appropriate time. The desired effect of
melatonin administration was thus to effectuate a phase delay in
DLMO.
[0128] While in Hawaii, subjects were kept in dim light after 4 PM
for DLMO determinations, to avoid the confounding effects of late
afternoon sunlight or other bright light that would suppress the
DLMO and artifactually delay it. As a consequence, re-alignment of
the circadian rhythm of DLMO with the local light/dark cycle was
not completely achieved during the trip to Hawaii. It appeared that
complete readjustment was not possible in the absence of the late
afternoon sun zeitgeber. Thus, the critical day in Hawaii for
comparing the effects of the 2 protocols on the melatonin circadian
rhythm was determined to be the third (last) post-travel day of
melatonin administration.
[0129] Melatonin is administered in the morning according to the
schedule predicted by the melatonin PRC (Table I) to effect a phase
delay. As can be seen in FIG. 9, melatonin administration using
this protocol resulted in a DLMO time that was correctly
phase-shifted 1 hour later. These results are in contrast to the
DLMO time produced using the method that teaches taking melatonin
at destination bedtime. These results indicated that the instant
invention is more efficacious in effecting the appropriate phase
delay than is melatonin administration at destination bedtime.
[0130] FIG. 9 also shows the results of the phase-shifting
experiment with these subjects in Portland after the return trip.
In travelling to Portland, the subjects travelled 3 time zones
east, so that the endogenous circadian rhythm was behind the
environmental light-dark cycle at the Portland destination. This
meant that the subjects did not become sleepy until 3 hours after
the locally-appropriate time and had difficulty arriving at the
locally appropriate time. Thus, to be efficacious the melatonin
administration protocol had to accomplish a phase advance of the
DLMO time.
[0131] In contrast to the subject's experiences in Hawaii, for the
return trip to Portland, access to morning sunlight was found to
help all of the subjects to re-adjust by the last day of melatonin
administration. The appropriate day in Portland, therefore, for
comparing the effects of the present invention was the day after
the second post-travel day of melatonin administration. Melatonin
was administered in the afternoon according to the teachings of the
instant invention as directed by the melatonin PRC, to cause a
phase advance. FIG. 9 shows that the DLMO time was approximately 1
hour earlier using the instant invention than the DLMO time
produced by melatonin administration protocol at destination
bedtime. These results indicated that the instant invention is more
efficacious in effectuating the appropriate phase advance is
melatonin administration at a different and fixed time of day
(i.e., destination bedtime).
[0132] The cumulative results of the experimental data acquired in
these experiments are shown in Table II. The Table presents a
comparison between the experimental results obtained using
melatonin administration times according to instant invention and
those prescribed by the prior art. When mean DLMO times were
compared, there was about a 1 hour difference in the degree of
melatonin circadian rhythm phase shift produced, with the instant
invention proving to be more efficacious in producing both phase
delays and phase advances, depending on the time of melatonin
administration. These results were consistent with the predictions
of the melatonin PRC (disclosed in U.S. Pat. No. 5,232,941,
incorporated by reference). Specifically, for the trip to Hawaii
the instant invention produced a later DLMO time more rapidly than
the methods known in the prior art in 5 of the subjects; the
results with the sixth subject were also better, albeit marginally.
For the trip back to Portland, the instant invention worked
significantly better in 5 of the subjects (defined as achieving an
earlier DLMO time than the prior art method), while the prior art
method worked marginally better for 1 subject.
[0133] Statistical analyses were performed and these results are
shown in Table III. In 10 of 12 comparisons for the entire data
set, the methods of the instant invention produced better results
(defined as a greater degree of phase advance or phase delay) as
assessed by .sub.x.sup.2 analysis (statistical
significance=p<0.025). Specifically, on the trip to Hawaii, the
instant invention shifted the DLMO time to a time later than the
prior art methods by almost 1 hour on average. This was
statistically significant at the p<0.02 level (using a 2 tailed
paired t test). On the trip back to Portland, the instant invention
advanced the DLMO time to a time earlier than melatonin
administration at destination bedtime by almost 1 hour on average;
these results were statistically significant at the p<0.05 level
in a 1-tailed paired t test.
[0134] During the study, one of the subjects (#6) had a hematocrit
(a measure of the number of red blood cells) that precluded taking
blood samples for determining plasma melatonin levels for her
second trip to and from Hawaii; saliva samples were taken instead
and analyzed as an alterative using gas chromatography-mass
spectrometry (GC-MS). To avoid inappropriate comparisons between
these data and the remaining samples in the data set, statistical
analyses were also performed after deleting the data corresponding
to this subject from the data set.
[0135] When the DLMO data for the trip to Hawaii obtained from
subject #6 were removed from the data set, the differences between
degree of melatonin-induced circadian rhythm phase shift achieved
using the administration methods of the instant invention versus
administration at detination bedtime remained significant at the
p<0.01 level on a 2-tailed paired t test. When the DLMO data for
the return trip to Portland obtained from subject #6 were removed
from the data set, the differences between the instant method and
the prior art methods were found to be no longer statistically
significant. However, even when the data from subject #6 were
deleted from the data set as a whole, nine of the ten comparisons
of the 2 melatonin administration protocols favored the method of
the instant invention by .sub.x.sup.2 analysis, achieving a
statistical significance of p<0.02.
[0136] Subjective impressions of the study participants were also
elicited, and these subjective assessments were, by and large,
consistent with the more objective (and more reliable)
physiological data. These experiments demonstrate the efficacy of
the methods of the instant invention in relieving the circadian
rhythm phase-shifting effects of transmeridional flight (i.e., jet
lag). The instant method is capable of achieving an appropriate
adjustment of the DLMO circadian rhythm and in alleviating the
physiological symptoms of jet lag.
[0137] The results demonstrate that physiological doses of
melatonin given at times according to the melatonin PRC of
endogenous melatonin production, and adjusting the administration
times on a daily basis in accordance to the predicted shifts of the
melatonin PRC, is more efficacious than melatonin administration
schemes based on fixed administration times (destination sedation)
of high dosages of exogenous melatonin.
EXAMPLE 6
Melatonin Administration to Treat Winter Depression
[0138] A series of experiments were performed to illustrate the
usefulness of the instant invention for alleviating winter
depression (seasonal affective disorder) in 10 subjects.
[0139] Exogenous melatonin was administered to subjects orally in
capsule form at a specific time in relation to the individual's dim
light melatonin onset (DLMO) time. This treatment was continued for
one week. The following week, the time of administration of the
melatonin dose was advanced one hour, in order to take into account
the shift in the DLMO time predicted by the human phase response
curve (PRC) due to the prior week's treatment. The time of
administration for this study was centered at CT 8. The subjects
were given two capsules a day, a placebo capsule in the morning and
a melatonin-containing capsule in the afternoon, at the appropriate
test time [i.e., CT 8 (3 PM) on week 1 and CT 8 (2 PM) on week
2].
[0140] This study was performed in double-blind fashion.
Physiological melatonin levels were determined in each subject at
the beginning of the study and at the end of the two-week period.
Blood samples were taken every thirty minutes in the evening while
the subjects were in dim light in order to determine each
individual's DLMO. Physiological melatonin blood levels were
determined use GC-MS, as described above in Example 1.
[0141] Subjects were medically and psychologically screened for
participation in the study, and the subjects studies were uniformly
in generally good physical condition, met the DSM-III-R criteria
for moderate to severe major depressive disorder (without psychotic
episodes) or bipolar disorder [depressed or not otherwise specified
(NOS)] with winter type seasonal pattern, scored .gtoreq.20 on the
Structured Interview Guide for the Hamilton-Seasonal Affective
Disorder (SIGH-SAD) with Hamilton Depression Rating Scale (HDRS)
.gtoreq.10 and an atypical score .gtoreq.5, and reported that
depression had developed during the fall or winter and had remitted
the following spring for at least the two preceding winters.
Further, the subjects were not suicidal and had not used or been
treated with psychoactive drugs during the month preceding the
study. SIGH-SAD is a 29-item interview-based instrument that was
used to assess depressive symptom severity. Twenty-one of the items
are identical with items in the HDRS (which is a widely-used
psychiatric instrument). In addition, SIGH-SAD contains eight items
which specifically assay symptoms characteristic of winter
depression, such as carbohydrate craving, weight gain and
hypersomnia. Scores greater than or equal to 20 out of the 29 items
indicate moderate to severe depression.
[0142] The first group of 4 subjects received 0.5 mg of melatonin
in the afternoon capsule. All patients on melatonin improved when
it was administered at a time to cause a phase-advance as predicted
by the PRC. Three out of four individuals given 0.5 mg of melatonin
recorded a significant phase shift. Three out of four of these
individuals also showed a significant improvement in the SIGH-SAD
rating after two weeks. These results are shown in FIG. 10.
Statistically-significant decreases in the average depression
rating (SIGH-SAD) were seen for patients undergoing melatonin
treatment as herein described. However, there were also complaints
of early morning awakening and/or afternoon sleepiness following
this treatment, which are disfavored because they could be mistaken
by these already-depressed patient as signs of lingering winter
depression. These data indicated that an individual's positive
response to the phase-shifting effect of exogenous melatonin
administration, i.e., improvement in SIGH-SAD rating, may be
dependent on a specific shift, and that the magnitude of the phase
shift may be important in influencing the therapeutic effectiveness
of exogenous melatonin treatment.
[0143] Since the 0.5 mg dose was found to induce soporific side
effects that a patient could confuse with lingering depression
(thereby potentially exacerbating the depression), the study was
repeated using a 0.25 mg dose of melatonin administered to four
subjects essentially as described above. This dosage was less
likely to result in an excessive degree of "phase-advance" which
could also have created the soporific side effects observed using
higher doses of melatonin. In these four subjects treated with 0.25
mg of melatonin in the afternoon, the anti-depressive response was
remarkably better than the results obtained using 0.5 mg
administrations, and there were fewer complaints of early morning
awakening or afternoon sleepiness in these subjects. All of these
individuals showed a shift in the PRC. On average, the magnitude of
the phase advance was less than the phase advance found in
individuals treated with 0.5 mg; these results were predicted by
the PRC as shown in Example 3. The smaller degree of phase advance,
and reduced soporific side-effects, found using 0.25 mg melatonin
administration doses also resulted in significant improvements in
the depression rating measured by SIGH-SAD in these four
individuals. One noteworthy result from this series of experiments
was that the individual with the smallest amount of improvement in
depression rating was also the individual with the greatest phase
shift.
[0144] Two other subjects were given 0.125 mg of melatonin in
combination with 100 mg atenolol, a beta-adrenergic blocker that
inhibits endogenous melatonin production without changing the
effect of exogenous melatonin binding. These subjects' winter
depression ratings responded similarly to those subjects treated
with the 0.25 mg dose protocol. These subjects also showed a slight
phase advance similar in magnitude to the phase advance produced in
those subjects treated with 0.25 mg melatonin alone. The results of
this study are shown in FIG. 11, which shows the phase advance of
one of the subjects' DLMO time after treatment as described herein.
These results were most readily explained as resulting from the
combined reduction of endogenous melatonin production at the wrong
time (i.e., the delay zone of the melatonin PRC), and the exogenous
administration of melatonin at the correct time, thereby creating a
phase shift almost equal in magnitude to the phase shift produced
by administration of the higher dose. These data also indicated
that smaller phase, shifts resulted in greater improvement in
SIGH-SAD depression ratings. These results are tabulated in Table
IV, which presents both the SIGH-SAD and DLMO data for the
individual subjects.
[0145] These results are summarized in FIGS. 12-15. FIG. 12
illustrates the linear |relationship between the administered dose
of melatonin and the magnitude of the phase shift achieved in
experiments using 0.125 mg melatonin+100 mg atenolol treatment and
treatment with 0.25 and 0.5 mg dosages of melatonin alone. FIG. 13
shows that the average phase shift in DLMO after 2 weeks of
melatonin administration is statistically-significant. FIG. 14
relates the degree of phase shift achieved to changes in winter
depression as measured by the SIGH-SAD criteria. Finally, the
inverse relationship between the magnitude of the induced melatonin
phase shift and improvement in the SIGH-SAD ratings is shown in
FIG. 15. These results demonstrate that the optimal decrease in
symptoms of winter depression in these patients (as measured by the
SIGH-SAD ratings) occurred when the melatonin PRC was phase-shifted
by a phase advance of about 0.5 h. Individuals who were shifted by
nearly 1.0 or more recorded much lower improvement in SIGH-SAD
ratings.
[0146] The results indicate that the administration of melatonin at
specific times relative to DLMO as predicted by the melatonin PRC
caused the DLMO time to advance, and that the phase advance was
related to alleviation of the symptoms of winter depression. The
result of exogenous melatonin administration as described herein
represents a controlled shift in the endogenous circadian
pacemaker, resulting in amelioration of the symptoms of winter
depression. Small shifts in the endogenous circadian pacemaker, as
indicated by the shift of the DLMO time, were found to be effective
in causing this amelioration of winter depressive symptoms. The
optimal magnitude of phase advance was found to be a shift of about
0.5 hour in the DLMO time, which resulted in the greatest degree of
improvement in patients' SIGH-SAD ratings. The instant results also
showed that the time of melatonin administration resulting in
greatest amount of improvement in winter depression symptoms was
dependent on the baseline DLMO time of the individual, as well as
idiosyncratic responses to the dosage of exogenously administered
melatonin.
EXAMPLE 7
Melatonin Administration to Schedule-Related Circadian Phase
Disturbances
[0147] Another application of the circadian rhythm phase-shifting
methods provided by the present invention enables alleviation of
circadian phase disturbances caused by changes in an individual's
schedule or pattern of activity. One example of schedule-related
circadian phase disturbances occurs in night shift-workers. Workers
who are assigned to the night shift face the problem of
synchronizing their bodily rhythms (usually triggered by light
cycle cues) with their altered behavioral sleep pattern. Even
though such workers can force a phase shift of 8-12 hours in their
sleep pattern, their other circadian rhythms (which are coupled
more tightly to the endogenous circadian pacemaker) may not shift.
This state of internal desynchronization between sleep and other
circadian rhythms may account for much of the difficulties
encountered by night workers. The present example illustrates the
use of melatonin treatment in conjunction with specific timing of
melatonin administration in relation to the melatonin PRC for the
resynchronization of internal circadian rhythms with the sleep
cycle.
[0148] The subjects of this test were hospital shift workers
(nurses and other paramedical personnel) who worked on a "7-70"
rotating shift, consisting of seven consecutive 10-hour night
shifts (9 PM-7 AM), alternating with seven days off-duty. Thus,
these subjects made a 10-12 hour shift in their sleep cycle every
week. During the study, blood samples were drawn Weekly using a
protocol of hourly blood draw under dim light (<50 lux)
conditions for 24 hours. These blood samples were immediately
centrifuged and frozen for later analysis of melatonin
concentration.
[0149] Melatonin was measured using an RIA developed by Schumacher
et al. (as described in Zimmerman et al., 1990, Fertil. Steril. 54:
612-618). The sensitivity of this assay is approximately 2.5 pg/ml;
the coefficient of variability is 10.2% for concentrations of 15
pg/ml. A gas chromatographic mass spectrometric (GC-MS) assay was
used to calibrate the RIA, and to validate critical samples. [The
GC-MS assay has a lower limit of detection of approximately 0.5
pg/ml and a coefficient of variability of 2.7% for concentrations
of 20 pg/ml.]
[0150] For plasma samples, circadian phase position was calculated
by interpolation from the time that the melatonin concentrations
rose above a 10 pg/ml threshold (the DLMO time). To test the
potential benefits of melatonin administration on phase resetting,
for convenience subjects were given melatonin (0.5 mg) at bedtime
for one two-week block, and placebo for the other two-week block,
formulated in identical-looking cornstarch-filled gelatin capsules.
Subjects did not know the identity of the treatment received (i.e.,
whether they were taking melatonin or placebo), and the order of
treatment was randomized. To assess the ability of melatonin and
placebo treatments to promote adaptation to a nocturnal schedule,
the phase of the DLMO time was compared after each treatment with
each subject's normal diurnal phase (see FIGS. 16 and 17). The
results for subjects using placebo or no treatment showed that four
of the six subjects had no substantial change in their DLMO times
after a week of night work and daytime sleep (average shift for
these four subjects was 0:34.+-.1:09 hours). However, one subject
shifted 12:30 hours and another subject shifted 3:54 hours,
indicating considerable inter-individual variability in adaptation
responses to melatonin administration. These data support the
conclusion that even after seven night shifts, underlying circadian
rhythms do not readily re-entrain to synchronize with the
sleep-activity schedule.
[0151] In contrast to the placebo results, melatonin treatment
given during the week of nighttime, work caused large phase shifts
of the melatonin profile and improved adaptation to the nocturnal
schedule (see FIGS. 16 and 17). All six subjects phase shifted with
melatonin, the magnitude of the phase shifts ranging from 1:27 to
9:37 hours. The average phase difference between off work weeks and
work weeks was 7:35.+-.4:52 hours after melatonin treatment and
2:21.+-.5:21 hours after placebo treatment (p.ltoreq.0.02, paired
t-test). Because one subject responded to neither treatment, and
another subject completely adapted on both treatments, the subgroup
of four remaining subjects was analyzed separately. The average
phase difference between off work and work weeks was
7:58.ltoreq.2:37 hours after melatonin treatment, compared to
0:47.+-.2:16 hour after placebo treatment (p.ltoreq.0.01, paired t
test).
[0152] Because the results appeared to be influenced by an order
effect, we also analyzed the data for phase shifts by subtracting
the phase of the DLMO at the end of each week from the phase of the
DLMO at the beginning of each week. In the four subjects who were
treated with placebo the first two weeks, there were no baseline
(pretreatment) data obtained at the beginning of the first week;
for these data points, the DLMO times and melatonin PRC phase was
assumed to be the same as the DLMO times and PRC phase after
placebo treatment on a comparable schedule. In the two subjects who
were treated with melatonin the first week, we obtained a baseline
DLMO. For this analysis it was assumed that each subject delayed
when adapting to a nocturnal schedule, and advanced when adapted to
a diurnal schedule [although this may not have been the case in all
subjects (as shown in FIG. 18)].
[0153] Subjects BD and SH each exemplify a different order of
treatment. Subject BD received placebo treatments first, followed
by melatonin (FIG. 19). When first measured after a week of work
taking placebo, the melatonin profile was delayed 3:54 hours
compared with the subsequent off-work week but was still in a
nighttime phase and out of synchrony with daytime sleep. On the
second week, after seven days off work and receiving placebo, the
melatonin rhythm was in normal phase (DLMO 20:07). After a two week
hiatus, the subject returned to work and took melatonin. At the end
of the week of treatment, the subject's DLMO time had shifted 10:22
hours and was synchronized to her daytime sleep pattern. After the
fourth week, when the subject was off work and taking melatonin,
the melatonin profile was back at the nighttime phase
(DLMO=19:01).
[0154] Subject SH received the reverse order of treatment (FIG.
20). A baseline profile after seven nights of work (but prior to
any treatment) showed the melatonin rhythm in normal phase,
indicating no adaptation to a nocturnal schedule (DLMO=21:03).
Melatonin treatment given the next week (the off-work week) was
administered during the dead zone of melatonin PRC and predictably
caused a relatively small phase shift in the endogenous melatonin
profile (DLMO=20:34). During the second week (while working at
night), the subject took melatonin in the delay zone of the
melatonin PRC, and the endogenous melatonin profile delayed about
10 hours (DLMO=06:34) so that it was aligned with her daytime
sleep. On the next week (off-work week) she was crossed over to
placebo: her melatonin profile remained relatively unchanged
(DLMO=05:13) and was significantly out of phase with her nighttime
sleep. On the fourth week (placebo treatment) the subject returned
to work on the night shift: the melatonin profile delayed a few
hours (DLMO=10:00), remaining once again relatively in phase with
daytime sleep.
[0155] In these two subjects first treated with melatonin, the
potency of the administration of melatonin is underscored by the
carry-over effect observed in the subsequent placebo week. From the
initial melatonin profile, it appeared that these two subjects did
not shift their circadian rhythms after working at night (see FIG.
18). However, after melatonin administration, both subjects made
shifts so large that they were unable to return to the baseline
phase during the subsequent placebo week (FIG. 18). Salivary
samples taken mid-week in one subject indicated larger phase shifts
at the beginning and middle of the week than at the end of the
week. As shown in FIG. 21, the amount of phase shift was greater at
the beginning and middle of the week than at the end of the week.
This suggests that the melatonin PRC is gradually delaying, moving
the fixed administration time relatively earlier towards the zone
of reduced responses.
[0156] In all subjects but one, melatonin treatment achieved
significant shifts in the DLMO as predicted by the present
invention. The failure of one subject to phase shift may be a
function of the fact that for this person melatonin was
administered during one of the cross-over points of the melatonin
PRC, where reduced responses can occur. Indeed, the heterogeneous
responses to melatonin in this study can be explained by each
individual's circadian time of administration.
[0157] Retrospective analysis of these shift-work experiments leads
to the conclusion that shift-workers would be effectively
phase-shifted by exogenous melatonin treatments conducted using a
more rigorous determination of each shift-worker's DLMO time and
administration times coordinated so as to keep the time of
administration constant relative to the DLMO time. Phase-shifting
results cast in terms of the worker's initial and average circadian
time of administration (FIGS. 22-25) show that phase advances
occurred at melatonin administration times corresponding to between
about CT 6 and about CT 12, whereas phase delays occurred at
melatonin administration times corresponding to between about CT 19
and about CT 2.
EXAMPLE 8
Utility of Dark Goggles Enhancing Circadian-Phase Shifting in
Humans
[0158] In order to accurately measure melatonin production,
avoidance of bright light is important since melatonin production
is suppressed or masked by exposure to bright light. In the past,
welder's goggles or sunglasses capable of selectively filtering
blue and green wavelengths of light (the segment of the spectrum
most active in suppressing melatonin production) have been used (an
example is Serengreti.RTM. Vermillion sunglasses). A study was
performed on one subject using sunglasses to inhibit bright light
suppression of melatonin production.
[0159] Serial blood samples were collected from this subject on a
half-hourly schedule from 2300 hours to 0400 hours on three
separate occasions. Samples were centrifuged and plasma separated
and frozen immediately for analysis of melatonin content by
radioimmunoassay (RIA) as described previously (Example 7). From
2300 to 0200 hours, the subject remained in dim light (less than 50
lux) or the subject was exposed to 250 lux or 2,500 lux while
wearing Serengreti.RTM. sunglasses; following this, from 0200 to
0400 hours, the subject was exposed to light treatment without
wearing sunglasses.
[0160] The results depicted in FIG. 26 show the average (.+-.
standard error) melatonin levels found during two intervals for the
three lighting conditions. During the first interval (when glasses
were worn), melatonin levels were higher under dim light
conditions; about 20% lower with exposure to 250 lux; and 30% lower
upon exposure to 2,500 lux. When the sunglasses were removed,
melatonin production fell to less than 30% of the levels measured
under dim light. These results illustrate the effectiveness of eye
wear that can filter out blue and green wavelengths of light for
inhibiting bright lights suppression of endogenous melatonin
production.
[0161] Using this information, the use of filtered eye wear (i.e.,
sunglasses or goggles) to enhance the treatment of individuals with
melatonin was performed. A subject was monitored using serial blood
assays as described above, and then treated using an exogenous
melatonin administration protocol for six days. The first two
capsules given to the subject were placebo capsules, and the last
four contained 0.5 mg melatonin taken at 0900 hours. Analysis of
the subject's DLMO at the end of this period showed that the DLMO
time had been delayed by about 25 minutes compared to its reference
baseline DLMO determined prior to the start of the experiment one
week before.
[0162] In a second trial, the subject was given the same doses of
melatonin administered at 0830 hours. During this trial, the
subject was instructed to wear dark tinted (Serengreti.RTM.)
goggles on days when the subject was taking melatonin. The subject
wore the goggles for six hours (i.e., from the time the, subject
took the capsules until 1430 hours). At the end of the week,
analysis of the subject's DLMO showed a phase delay of over 1 hour
(abour 61 min) compared to the reference baseline DLMO one week
earlier. [Note that these times of administration, i.e., 0900 or
0830 hours were nearly identical administration times for the
subject relative to his circadian rhythm time (i.e., CT 1.26 versus
CT 1.86, respectively).]
[0163] The results of these experiments are shown in FIG. 27. FIG.
27 illustrates the phase shift found in the two experiments. From
the results described above (see FIG. 26), these sunglasses had
been established as being capable of suppressing bright
light-induced production of endogenous melatonin in the subject.
Taken together, these results demonstrated that the phase-shifting
effect of exogenous melatonin treatment could be enhanced by the
use of sunglasses, goggles or other means to create a concurrent
"dark plus melatonin" signal indicating "nighttime darkness" to the
subject's endogenous circadian pacemaker. This means that "darkness
plus melatonin" administration during the day (even if the subject
is not sleeping or avoiding morning bright light exposure) may
convince the endogenous circadian pacemaker that it is, in fact,
nighttime. This signal could possibly be made even more effective
by suppressing endogenous melatonin production at night (either
pharmacologically or with bright light exposure). Using bright
light exposure and goggles to adjust the light-dark cycle could
also be used in combination with the protocol for exogenous
melatonin administration disclosed herein.
[0164] 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. TABLE-US-00001 TABLE I Melatonin Administration Times Upon
Arriving at Destination according to the melatonin PRC Time
Difference Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 1 hour east
3:00 PM 2 hours east 4:00 PM 3:00 PM 3 hours east 5:00 PM 4:00 PM
3:00 PM 4 hours east 6:00 PM 5:00 PM 4:00 PM 3:00 PM 5 hours east
7:00 PM 6:00 PM 5:00 PM 4:00 PM 3:00 PM 6 hours east 8:00 PM 7:00
PM 6:00 PM 5:00 PM 4:00 PM 3:00 PM 7 hours east 9:00 PM 8:00 PM
7:00 PM 6:00 PM 5:00 PM 4:00 PM 3:00 PM 8 hours east 10:00 PM 9:00
PM 8:00 PM 7:00 PM 6:00 PM 5:00 PM 4:00 PM 9 hours east 11:00 PM
10:00 PM 9:00 PM 8:00 PM 7:00 PM 6:00 PM 5:00 PM 10 hours east
12:00 AM 11:00 PM 10:00 PM 9:00 PM 8:00 PM 7:00 PM 6:00 PM 11 hours
east 1:00 AM 12:00 AM 11:00 PM 10:00 PM 9:00 PM 8:00 PM 7:00 PM 12
hours west 7:00 PM 8:00 PM 9:00 PM 10:00 PM 11:00 PM 12:00 AM 1:00
AM 11 hours west 8:00 PM 9:00 PM 10:00 PM 11:00 PM 12:00 AM 1:00 AM
2:00 AM 10 hours west 9:00 PM 10:00 PM 11:00 PM 12:00 AM 1:00 AM
2:00 AM 3:00 AM 9 hours west 10:00 PM 11:00 PM 12:00 AM 1:00 AM
2:00 AM 3:00 AM 4:00 AM 8 hours west 11:00 PM 12:00 AM 1:00 AM 2:00
AM 3:00 AM 4:00 AM 5:00 AM 7 hours west 12:00 AM 1:00 AM 2:00 AM
3:00 AM 4:00 AM 5:00 AM 6:00 AM 6 hours west 1:00 AM 2:00 AM 3:00
AM 4:00 AM 5:00 AM 6:00 AM 5 hours west 2:00 AM 3:00 AM 4:00 AM
5:00 AM 6:00 AM 4 hours west 3:00 AM 4:00 AM 5:00 AM 6:00 AM 3
hours west 4:00 AM 5:00 AM 6:00 AM 2 hours west 5:00 AM 6:00 AM 1
hour west 6:00 AM
[0165] TABLE-US-00002 TABLE II Dim Light Melatonin Onset (DLMO)
Times.sup.a Pro- Trip to Hawaii Trip to Portland Phase Shifts.sup.b
Subject tocol 0.5 mg 5.0 mg 0.5 mg 5.0 mg Hawaii Portland 1 A 19:18
18:07 21:39 22:01 1:11 0:22 2 B 18:52 18:31 21:31 22:12 0:21 0:41 3
A 20:07 18:22 21:05 00:10 1:45 3:05 4 B 21:01 19:54 23:04 23:16
1:07 0:12 5 A 17:40 16:38 20:52 20:44 1:02 -0:08.sup.1 6 B 17:37
17:35 20:08 21:42 .sup. 0:02.sup.2 1:34 Average 19:05 18:11 21:23
22:20 0:54 0:57 SD.sup.c 1:20 1:04 0:59 0:56 0:37 0:11 Two
experimental protocols were used: Protocol A = Short invention
protocol used on the 1st trip (9/22-10/5), the Lewy invention
protocol used on the 2 d trip (10/6-10/19) Protocol B = Lewy
invention protocol used on the 1st trip (9/22-10/5), the Short
invention protocol used on the 2 d trip (10/6-10/19) .sup.a= in
military time (24 hour clock)/hours:minutes .sup.b= phase shifts
are defined as the difference between the DLMO time found using the
Lewy invention and the DLMO time found using the Short invention; a
positive number indicates a greater phase shift in the appropriate
direction using the Lewy invention .sup.c= standard deviation
.sup.1= The negative number indicates that the phase shift induced
by the Short invention was 8 minutes greater in the appropriate
direction than the phase shift induced by the Lewy invention in
this subject. .sup.2= This number was calculated using saliva
melatonin levels on a subject whose hematocrit was too low to
permit blood collection on the 2 d trip.
[0166] TABLE-US-00003 TABLE III Statistical Analysis of DLMO Phase
Shift Data Size.sup.a N = 6 N = 5 H/0.5 H/5.0 P/0.5 P/5.0 H/0.5
H/5.0 P/0.5 P/5.0 Mean 19:05 18:11 21:23 22:20 19:24 18:19 21:39
22:29 SD.sup.b 1:20 1:04 0:59 0:56 1:16 1:10 0:52 1:18 t.sup.c 3.57
-1.97 4.86 -1.45 df.sup.d 6 5 4 4 p.sup.e 0.016 0.106 0.008 0.220 H
= Hawaii; P = Portland .sup.a= sample size; the dataset with N = 5
does not include subject 6 (see Exhibit D) .sup.b= standard
deviation .sup.c= t statistic (paired t test) .sup.d= degrees of
freedom .sup.e= significance level
[0167] TABLE-US-00004 TABLE IV Winter Depression 1993 Sigh-Sad and
DLMO Data DLMO DATA GCMS Values SIGH-SAD DATA Change in Change in
(in decimal) Subject Dosage Schedule Baseline Week 1 Week 2
Sigh-Sad Wk1 Sigh-Sad Wk2 Baseline Week 2 Phase Shift LD 0.5 mg
1600 30.5 15 18.5 15.5 12 23.26 21.87 1.39 RH 0.5 mg 1600 28 32 34
-4 -6 23.54 21.62 1.92 LZ 0.5 mg 1600 40 19 32.5 21 7.5 25.00 22.87
2.13 AF 0.5 mg 1530 24 28 12.5 -4 11.5 19.75 19.81 -0.07 MB 0.25 mg
1500 36 7 7 29 29 19.86 19.03 0.83 LB 0.25 mg 1500 35.5 25 28 10.5
7.5 20.21 18.54 1.67 LH 0.25 mg 1500 32 14 15 18 17 18.66 18.54
0.12 PL 0.25 mg 1500 23 5 2 18 21 20.12 20.05 0.07 MD 0.125 mg
1600* 24 18 6 6 18 25.00 24.36 0.64 CL 0.125 mg 1600** 39 23 15 16
24 22.50 22.47 0.03 Average 31.20 18.60 17.05 12.60 14.15 21.79
20.92 0.87 SE 2.01 2.75 3.54 3.36 3.15 0.74 0.64 0.27 *schedule
changed to 1900 after 10 days **schedule changed to 1500 after
first week
* * * * *