U.S. patent application number 12/647247 was filed with the patent office on 2010-05-13 for treatment of conditions through modulation of the autonomic nervous system during at least one predetermined menstrual cycle phase.
Invention is credited to Partic Yuarn-Bor Lee, Anthony Joonkyoo Yun.
Application Number | 20100119482 12/647247 |
Document ID | / |
Family ID | 35310162 |
Filed Date | 2010-05-13 |
United States Patent
Application |
20100119482 |
Kind Code |
A1 |
Yun; Anthony Joonkyoo ; et
al. |
May 13, 2010 |
Treatment of Conditions Through Modulation of the Autonomic Nervous
System During at Least One Predetermined Menstrual Cycle Phase
Abstract
Methods are provided for treating a subject for a condition. In
accordance with the subject methods, at least a portion of a
subject's autonomic nervous system is modulated during at least one
predetermined phase of the subject's menstrual cycle to alter the
parasympathetic activity/sympathetic activity ratio in a manner
that is effective to treat the subject for the condition. The
subject methods find use in the treatment of a variety of different
conditions, including various disease conditions, that increase in
severity and/or occurrence during one or more phases of the
menstrual cycle. Also provided are systems and kits for use in
practicing the subject methods.
Inventors: |
Yun; Anthony Joonkyoo; (Palo
Alth, CA) ; Lee; Partic Yuarn-Bor; (Menlo Park,
CA) |
Correspondence
Address: |
BOZICEVIC, FIELD & FRANCIS LLP
1900 UNIVERSITY AVENUE, SUITE 200
EAST PALO ALTO
CA
94303
US
|
Family ID: |
35310162 |
Appl. No.: |
12/647247 |
Filed: |
December 24, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10846486 |
May 13, 2004 |
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12647247 |
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Current U.S.
Class: |
424/85.6 ;
206/539; 206/540; 424/133.1; 424/85.7; 514/1.1; 514/171; 514/173;
514/183; 514/235.8; 514/236.2; 514/277; 514/280; 514/307; 514/312;
514/315; 514/342; 514/343; 514/356; 514/381; 514/393; 514/394;
514/397; 514/412; 514/415; 514/419; 514/423; 514/43; 514/460;
514/510; 514/538; 514/543; 514/571; 514/6.9; 514/61; 514/620;
514/630; 514/635; 514/648; 514/652; 514/653; 514/91 |
Current CPC
Class: |
A61K 38/095 20190101;
A61P 15/00 20180101; A61P 15/18 20180101; A61K 38/26 20130101; A61K
31/137 20130101; A61K 38/4813 20130101; A61P 25/00 20180101; A61K
31/4745 20130101; A61K 31/57 20130101; A61P 5/24 20180101; A61P
9/00 20180101; A61P 31/04 20180101; A61K 38/085 20130101; A61K
38/2221 20130101 |
Class at
Publication: |
424/85.6 ;
514/630; 514/620; 514/415; 514/312; 514/235.8; 514/171; 514/173;
514/381; 514/394; 514/397; 514/423; 514/91; 514/412; 514/307;
514/419; 514/277; 514/460; 514/510; 514/543; 514/571; 514/356;
514/61; 514/635; 514/315; 514/342; 514/343; 514/393; 514/280;
514/183; 514/648; 424/85.7; 514/43; 514/652; 514/653; 514/538;
514/236.2; 514/12; 424/133.1; 206/540; 206/539 |
International
Class: |
A61K 38/21 20060101
A61K038/21; A61K 31/167 20060101 A61K031/167; A61K 31/165 20060101
A61K031/165; A61K 31/404 20060101 A61K031/404; A61K 31/4704
20060101 A61K031/4704; A61K 31/5377 20060101 A61K031/5377; A61K
31/58 20060101 A61K031/58; A61K 31/41 20060101 A61K031/41; A61K
31/4184 20060101 A61K031/4184; A61K 31/4178 20060101 A61K031/4178;
A61K 31/401 20060101 A61K031/401; A61K 31/675 20060101 A61K031/675;
A61K 31/403 20060101 A61K031/403; A61K 31/472 20060101 A61K031/472;
A61K 31/40 20060101 A61K031/40; A61K 31/435 20060101 A61K031/435;
A61K 31/366 20060101 A61K031/366; A61K 31/215 20060101 A61K031/215;
A61K 31/216 20060101 A61K031/216; A61K 31/192 20060101 A61K031/192;
A61K 31/455 20060101 A61K031/455; A61K 31/702 20060101 A61K031/702;
A61K 31/155 20060101 A61K031/155; A61K 31/45 20060101 A61K031/45;
A61K 31/4439 20060101 A61K031/4439; A61K 31/465 20060101
A61K031/465; A61K 31/4188 20060101 A61K031/4188; A61K 31/4375
20060101 A61K031/4375; A61K 31/395 20060101 A61K031/395; A61K
31/135 20060101 A61K031/135; A61K 31/7056 20060101 A61K031/7056;
A61K 31/138 20060101 A61K031/138; A61K 31/24 20060101 A61K031/24;
A61K 38/22 20060101 A61K038/22; A61P 15/00 20060101 A61P015/00;
A61K 39/395 20060101 A61K039/395; B65D 83/04 20060101 B65D083/04;
B65D 85/00 20060101 B65D085/00 |
Claims
1.-68. (canceled)
69. A multi-dose pharmacological agent package comprising: a
plurality of unit dosage forms of a pharmacological agent in a
single pack, wherein the plurality of unit dosage forms is selected
to modulate at least a portion of the autonomic nervous system to
increase the parasympathetic activity/sympathetic activity ratio in
a manner effective to treat a female subject for a condition which
is increased in severity or occurrence during a phase of the
subject's menstrual cycle.
70. The multi-dose package according to claim 69, wherein the
plurality of unit dosage forms comprises unit dosage forms for
daily administration.
71. The multi-dose package according to claim 69, wherein the
plurality of unit dosage forms is in the form of a monthly
pack.
72. The multi-dose package according to claim 69, wherein the
plurality of unit dosage forms is sufficient to treat the subject
for 30 to 90 days.
73. The multi-dose package according to claim 69, wherein the
plurality of unit dosage forms comprises two different dosages of
the pharmacological agent.
74. The multi-dose package according to claim 73, wherein the
number of unit dosage forms of a first dosage in the pack is equal
to the number of days of a particular phase of the subject's
menstrual cycle over the treatment period.
75. The multi-dose package according to claim 69, wherein the pack
further comprises a second pharmacological agent.
76. The multi-dose package according to claim 75, wherein the
second pharmacological agent is effective for treating the subject
for a second condition which is increased in severity or occurrence
during a phase of the subject's menstrual cycle.
77. The multi-dose package according to claim 69, wherein each of
the unit dosage forms is individually packaged.
78. A method of treating a female subject for a condition which is
increased in severity or occurrence during a phase of the subject's
menstrual cycle, the method comprising: administering to the
subject one of a plurality of unit dosage forms of a
pharmacological agent contained in a single pack, wherein the
plurality of unit dosage forms is selected to modulate at least a
portion of the autonomic nervous system to increase the
parasympathetic activity/sympathetic activity ratio in a manner
effective to treat the subject for a condition which is increased
in severity or occurrence during a phase of the subject's menstrual
cycle.
79. The method according to claim 78, wherein the plurality of unit
dosage forms comprises unit dosage forms for daily
administration.
80. The method according to claim 78, wherein the plurality of unit
dosage forms is in the form of a monthly pack.
81. The method according to claim 78, wherein the plurality of unit
dosage forms is sufficient to treat the subject for 30 to 90
days.
82. The method according to claim 78, wherein the plurality of
daily unit dosage forms comprises two different dosages of the
pharmacological agent.
83. The method according to claim 82, wherein the number of daily
unit dosage forms of a first dosage in the pack is equal to the
number of days of a particular phase of the subject's menstrual
cycle.
84. The method according to claim 78, wherein the pack further
comprises a second pharmacological agent.
85. The method according to claim 84, wherein the second
pharmacological agent is effective for treating the subject for a
second condition which is increased in severity or occurrence
during a phase of the subject's menstrual cycle.
86. The multi-dose package according to claim 78, wherein each of
the unit dosage forms is individually packaged.
Description
FIELD OF THE INVENTION
[0001] The field of this invention is the treatment of conditions
associated with the autonomic nervous system and more specifically
the treatment of conditions through modulation of at least a
portion of the autonomic nervous system during at least one
predetermined phase of the menstrual cycle.
BACKGROUND OF THE INVENTION
[0002] There are a variety of conditions that can affect a female's
health and well-being. Certain conditions increase in severity
and/or occurrence during one or more phases of a female's menstrual
cycle. While the exacerbation of certain medical conditions during
specific phases of the menstrual cycle has been recognized
(commonly referred to as conditions that have catamenial
variations), the mechanism underlying the association between
exacerbation of medical conditions and certain menstrual phases is
poorly understood.
[0003] Treatment options directed to treating these types of
conditions have thus far failed to be wholly satisfactory. For
example, since the causes are poorly understood, such options are
typically merely palliative, i.e., are designed for the relief of
symptoms of the condition rather than being directed at the
cause.
[0004] As such, there continues to be an interest in the
development of new protocol options for treating conditions that
increase in severity and/or occurrence during one or more phases of
a female's menstrual cycle.
SUMMARY OF THE INVENTION
[0005] Methods are provided for treating a subject for a condition.
In accordance with the subject methods, at least a portion of a
subject's autonomic nervous system is modulated during at least one
predetermined phase of the subject's menstrual cycle to alter the
parasympathetic activity/sympathetic activity ratio in a manner
that is effective to treat the subject for the condition. The
subject methods find use in the treatment of a variety of different
conditions, including various disease conditions, that increase in
severity and/or occurrence during one or more phases of the
menstrual cycle. Also provided are systems and kits for use in
practicing the subject methods.
DETAILED DESCRIPTION OF THE INVENTION
[0006] Methods are provided for treating a subject for a condition.
In accordance with the subject methods, at least a portion of a
subject's autonomic nervous system is modulated during at least one
predetermined phase of the subject's menstrual cycle to alter the
parasympathetic activity/sympathetic activity ratio in a manner
that is effective to treat the subject for the condition. The
subject methods find use in the treatment of a variety of different
conditions, including various disease conditions, that increase in
severity and/or occurrence during one or more phases of the
menstrual cycle. Also provided are systems and kits for use in
practicing the subject methods.
[0007] Before the present invention is described, it is to be
understood that this invention is not limited to particular
embodiments described, as such may, of course, vary. It is also to
be understood that the terminology used herein is for the purpose
of describing particular embodiments only, and is not intended to
be limiting, since the scope of the present invention will be
limited only by the appended claims.
[0008] Where a range of values is provided, it is understood that
each intervening value, to the tenth of the unit of the lower limit
unless the context clearly dictates otherwise, between the upper
and lower limit of that range and any other stated or intervening
value in that stated range is encompassed within the invention. The
upper and lower limits of these smaller ranges may independently be
included in the smaller ranges is also encompassed within the
invention, subject to any specifically excluded limit in the stated
range. Where the stated range includes one or both of the limits,
ranges excluding either or both of those included limits are also
included in the invention.
[0009] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
any methods and materials similar or equivalent to those described
herein can also be used in the practice or testing of the present
invention, the preferred methods and materials are now described.
All publications mentioned herein are incorporated herein by
reference to disclose and describe the methods and/or materials in
connection with which the publications are cited.
[0010] It must be noted that as used herein and in the appended
claims, the singular forms "a", "an", and "the" include plural
referents unless the context clearly dictates otherwise.
[0011] The publications discussed herein are provided solely for
their disclosure prior to the filing date of the present
application. Nothing herein is to be construed as an admission that
the present invention is not entitled to antedate such publication
by virtue of prior invention. Further, the dates of publication
provided may be different from the actual publication dates which
may need to be independently confirmed.
[0012] As will be apparent to those of skill in the art upon
reading this disclosure, each of the individual embodiments
described and illustrated herein has discrete components and
features which may be readily separated from or combined with the
features of any of the other several embodiments without departing
from the scope or spirit of the present invention.
[0013] As summarized above, the subject invention provides methods
for treating a subject for a condition that has catamenial
variations by modulating at least a portion of the autonomic
nervous system during at least one predetermined phase of the
menstrual cycle. The modulation may increase the parasympathetic
activity/sympathetic activity ratio or decrease the parsympathetic
activity/sympathetic activity ratio. In certain embodiments, the
differential between the parasympathetic activity level and the
sympathetic activity level will just be altered (increased or
decreased), but the parsympathetic activity/sympathetic activity
ratio may stay the same. In further describing the subject
invention, representative embodiments of the subject methods are
described first in greater detail, followed by a review of various
representative applications in which the subject methods may find
use. Next, a review of systems and kits for use in the subject
methods is provided.
Methods
[0014] As noted above, the subject methods are methods for treating
a female subject for a condition by modulating at least a portion
of the autonomic nervous system during at least one predetermined
phase of the subject's menstrual cycle. Conditions include those
that are at least suspected of increasing in severity and/or
occurrence during at least one phase of a subject's menstrual cycle
and include known and to be discovered conditions that have
catamenial variations. Accordingly, the subject methods may be
employed to at least decrease the severity and/or occurrence of
such a condition at least during the one or more phases of the
menstrual cycle in which the condition is at least suspected of
increasing in severity and/or occurrence.
[0015] The modulation of at least a portion of the autonomic
nervous system during at least one predetermined menstrual cycle
phase may be accomplished using any suitable method. For example,
certain embodiments may include pharmacologically modulating and/or
electrically modulating (i.e., applying electrical energy) at least
a portion of the autonomic nervous system to modulate the
parasympathetic activity/sympathetic activity ratio in a manner
effective to treat a female for a condition, for example to
increase the parasympathetic activity/sympathetic activity ratio or
decrease the parsympathetic activity/sympathetic activity ratio. In
certain embodiments the autonomic nervous system is modulated
during at least one predetermined menstrual cycle phase to increase
the sympathetic/parasympathetic ratio.
[0016] Exacerbation of certain medical conditions during specific
phases of the menstrual cycle has long been recognized. Mechanisms
of the cyclic variation are poorly understood, but are often
attributed to fluctuation in reproductive hormones. However, the
inventors of the subject invention have discovered that, in fact,
variations in autonomic balance during the menstrual cycle, which
may have evolved as adaptations for reproduction, may at least
contribute partially if not completely, to catamenial variations in
conditions and are independent of hormonal variations.
[0017] Accordingly, to address these autonomic system
dependant-catamenial variations of conditions, embodiments of the
subject invention include modulating at least a portion of a
subject's autonomic nervous system during at least one
predetermined phase of a subject's menstrual cycle to increase or
decrease the parasympathetic activity/sympathetic activity ratio in
a manner effective to treat the subject for the condition. In
accordance with the subject invention, modulating at least a
portion of autonomic nervous system may be achieved by any suitable
method, e.g., administering an effective amount of at least one
pharmacological agent and/or by applying stimulatory or inhibitory
electrical energy, in a manner to effectively treat the subject for
a condition.
[0018] Modulation of a subject's autonomic nervous system may
include increasing one or more aspects of autonomic nervous system
activity in at least a portion of the autonomic nervous system
and/or decreasing one or more aspects of autonomic nervous system
activity in at least a portion of the autonomic nervous system. By
"modulating at least a portion of a subject's autonomic nervous
system" and analogous terms is meant altering or changing at least
a portion of a subject's autonomic nervous system by suitable means
to provide a change, alteration or shift in at least one component
or aspect of the autonomic nervous system to increase or decrease
the parasympathetic activity/sympathetic activity ratio. The
modulation of the autonomic nervous system may affect central motor
output and/or nerve conduction and/or transmitter release and/or
synaptic transmission and/or receptor activation, but in any event
is a change that provides an increase or decrease in the
parasympathetic activity/sympathetic activity ratio (as used herein
"activity" and "function" are used interchangeably).
[0019] Embodiments of the subject methods may be employed to alter
the dominance of the parasympathetic and sympathetic systems and/or
may be employed to modulate the differential between the two
systems. Modulation of the autonomic nervous system may be
accomplished by increasing and/or decreasing activity in a portion
of the autonomic nervous system. By "increasing activity" and
analogous terms is meant the activity in at least a portion of the
autonomic nervous system may be increased, relative to the activity
level prior to employing the subject methods, to modulate at least
a portion of the autonomic nervous system. For example, activity in
any portion of the one or more nerve fibers of the parasympathetic
nervous system and/or sympathetic nervous system may be increased
or "up-regulated" to provide the desired ratio of parasympathetic
activity/sympathetic activity. By "decreasing activity" and
analogous terms is meant that activity in at least a portion of
autonomic nervous system is decreased or inhibited, relative to its
activity level prior to employing the subject methods, to modulate
at least a portion of the autonomic nervous system. By "decreased"
or "inhibited" activity (used herein interchangeably) is meant to
include, but is not limited to, disruption, down-regulating,
dampening and partial and complete blockage of function or nerve
impulses in at least a portion of the autonomic nervous system. For
example, activity in any portion of the one or more nerve fibers of
the parasympathetic nervous system and/or sympathetic nervous
system may be decreased or "down-regulated" to provide the desired
ratio of parasympathetic activity/sympathetic activity.
[0020] Embodiments of the subject invention may include
pharmacologically modulating at least a portion of a subject's
autonomic nervous system to increase or decrease the
parasympathetic activity/sympathetic activity ratio in at least a
portion of the autonomic nervous system in a manner effective to
treat a condition. Accordingly, embodiments of the subject
invention may include pharmacologically increasing or decreasing
parasympathetic activity in at least a portion of the autonomic
nervous system and/or pharmacologically increasing or decreasing
sympathetic activity in at least a portion of the autonomic nervous
system. In other words, modulating at least a portion of autonomic
nervous system to treat a condition may be achieved by
administering an effective amount of at least one pharmacological
agent, e.g., an amount sufficient to treat the condition of
interest, during at least one predetermined phase of the menstrual
cycle.
[0021] Embodiments of the subject invention may include
electrically modulating at least a portion of a subject's autonomic
nervous system to increase or decrease the parasympathetic
activity/sympathetic activity ratio in at least a portion of the
autonomic nervous system, in a manner effective to treat a
condition, using electrical energy. Accordingly, embodiments of the
subject invention may include electrically increasing or decreasing
parasympathetic activity in at least a portion of the autonomic
nervous system and/or electrically increasing or decreasing
sympathetic activity in at least a portion of the autonomic nervous
system. Embodiments may include electrically ablating one or more
nerve fibers. In other words, modulating at least a portion of
autonomic nervous system to treat a condition may be achieved by
administering electrical energy to at least a portion of the
autonomic nervous system in an amount sufficient to treat the
condition of issue, during at least one phase of the menstrual
cycle.
[0022] Accordingly, embodiments of the subject invention may
include modulating at least a portion of a subject's autonomic
nervous system to achieve a desired parasympathetic
activity/sympathetic activity ratio, e.g., a ratio analogous to an
average parasympathetic activity/sympathetic activity ratio
observed in healthy females in the same or analogous menstrual
cycle phase (e.g., of like age as the treated subject) not
experiencing the condition being treated or not experiencing an
exacerbation of the condition being treated. In other words, a
parasympathetic activity/sympathetic activity ratio observed in a
healthy, "like" or, i.e., analogous subject (e.g., a subject in the
same or analogous phase of the menstrual cycle with respect to the
exacerbation of the subject's condition and/or not experiencing an
abnormality in the autonomic nervous system). As such, an average
parasympathetic activity/sympathetic activity ratio as observed in
healthy females may be referred to as an average "normal" ratio,
whereas deviation from this average normal ratio to a degree that
causes or at least exacerbates a condition may be referred to as an
"abnormal" ratio (analogous descriptors may be used to refer to
activity levels specific to the sympathetic nervous system and to
the parasympathetic nervous system).
[0023] Embodiments of the subject invention may include modulating
at least a portion of a subject's autonomic nervous system to
achieve a desired parasympathetic activity/sympathetic activity
ratio, wherein the desired ratio is one that is analogous to the
average ratio observed in the same subject during a menstrual cycle
phase that is different from the menstrual cycle phase during which
the subject's autonomic nervous system is modulated (i.e., a phase
other than the menstrual cycle phase in which the condition being
treated is exacerbated). Accordingly, as the parasympathetic
activity/sympathetic activity ratio varies during different phases
of a female's menstrual cycle, a desired parasympathetic
activity/sympathetic activity ratio may be one that is commensurate
with that observed during a particular menstrual cycle phase or
phases of the subject during which exacerbation of the condition of
interest is not observed. For example, if exacerbation of a given
condition is observed in the luteal phase and not in the follicular
phase, a desired parasympathetic activity/sympathetic activity
ratio may be one that is analogous to an average ratio observed
during the follicular phase. In other embodiments, if exacerbation
of the conditions is observed during the luteal phase of a subject,
a desired parasympathetic activity/sympathetic activity ratio may
be one that is analogous to an average ratio observed in females in
the luteal phase, but who do not have the condition of interest or
who have the condition of interest but the condition is not
exacerbated in the luteal phase. In such instances, an average
parasympathetic activity/sympathetic activity ratio observed in the
same subject during a menstrual cycle phase other than the
menstrual cycle phase during which modulation is performed (i.e.,
during which an exacerbation of a condition is observed) may be
referred to as an average "normal" ratio, whereas deviation from
this average normal ratio to a degree that causes or at least
exacerbates a condition may be referred to as an "abnormal" ratio
(analogous descriptors may be used to refer to activity levels
specific to the sympathetic nervous system and to the
parasympathetic nervous system).
[0024] Accordingly, a parasympathetic activity/sympathetic activity
ratio observed in a subject during a predetermined menstrual cycle
phase in which a condition is exacerbated may be characterized as
abnormal with respect to (1) an average parasympathetic
activity/sympathetic activity ratio observed in the same subject
during a menstrual cycle phase other than the menstrual cycle phase
during which the exacerbation of a condition is observed, and/or
(2) an average parasympathetic activity/sympathetic activity ratio
observed in a healthy, "like", i.e., analogous subject, in the same
phase of the menstrual cycle as the phase in which the exacerbation
of a condition is observed in the subject and/or (3) an average
parasympathetic activity/sympathetic activity ratio observed in a
healthy, "like", i.e., analogous subject, in a different phase of
the menstrual cycle from the phase in which the exacerbation of a
condition is observed in the subject.
[0025] For example, a subject may experience exacerbation of, e.g.,
an inflammatory condition or the like during the subject's luteal
phase. Accordingly, referring to the embodiment described in (1)
above, an average ratio of parasympathetic activity/sympathetic
activity observed in the subject during, e.g., the follicular
phase, may be characterized as normal wherein the deviation from
this ratio as observed in the subject during the luteal phase may
be characterized as abnormal. Referring to the embodiment described
in (2) above, an average parasympathetic activity/sympathetic
activity ratio observed in healthy analogous subjects during their
luteal phases may be characterized as normal and the deviation from
this ratio as observed in the subject experiencing the exacerbation
of the condition during luteal phase may be characterized as
abnormal. Referring to the embodiment described in (3) above, an
average parasympathetic activity/sympathetic activity ratio
observed in healthy analogous subjects during their follicular
phases (for example) may be characterized as normal and the
deviation from this ratio as observed in the subject experiencing
the exacerbation of the condition during luteal phase may be
characterized as abnormal. Such examples are for exemplary purposes
only and in no way are intended to limit the scope of the
invention.
[0026] The inventors of the subject invention have discovered that
many conditions may be caused or at least exacerbated by a
reproductive-facilitating shift of the autonomic nervous system
during one or more phases of a female's menstrual cycle. For
example, the inventors have discovered that a shift to a
sympathetic bias (i.e., an shift to sympathetic dominance) during
the luteal phase and/or early gestation may at least contribute to
the exacerbation of certain conditions in many instances. While not
being limited to any particular theory or hypothesis, in certain
instances exacerbation of a condition may result from a shift to
sympathetic bias during the luteal phase which promotes a
transition to a more fertility-favorable immune and physiologic
state of a female for accepting and nurturing a successful
implantation. This shift to a sympathetic bias also promotes a
shift to relative T helper (Th)-2 biased immunity which may favor
maternal tolerance of an embryo by attenuating Th-1 mediated
interference of implantation. Sympathetic bias may further support
gestation through physiological effects such as increased cardiac
output and systemic vascular resistance. In such instances where a
shift to sympathetic bias has occurred, e.g., during the luteal
phase and/or menses phase, and a condition is exacerbated, the
autonomic nervous system may be modulated in accordance with the
subject invention in a manner to achieve an increase in the
parasympathetic activity/sympathetic activity ratio, e.g., to a
parasympathetic activity/sympathetic activity ratio observed in one
or more other phases of the subject's menstrual cycle or to a ratio
analogous to one that has not shifted to sympathetic bias during
the luteal phase. As a fertility-favorable sympathetic bias
promotes a shift to T helper (Th)-2 bias, the level of Th2 in a
subject may be determined and the result of that determination may
be employed in the subject methods, e.g., to determine whether a
fertility-favorable level of sympathetic activity is present in a
subject (e.g. to determine whether to begin and/or continue and/or
terminate modulation of the autonomic system). In sum, a
parasympathetic activity/sympathetic activity ratio of a subject,
e.g., analogous to a parasympathetic activity/sympathetic activity
ratio observed during one or more particular phases of the
menstrual cycle wherein exacerbation of a condition of interest is
not observed, may be provided by the subject invention, e.g., by
modulating at least a portion of the autonomic nervous system
during (including just prior to the commencement of) one or more
predetermined phases of the menstrual cycle wherein exacerbation of
a condition of interest is observed.
[0027] A feature of embodiments of the subject methods is that the
ratio of parasympathetic activity to sympathetic activity is
increased. By "increased ratio of parasympathetic activity to
sympathetic activity" and analogous terms is meant that this ratio
(characterized by parasympathetic activity/sympathetic activity) is
increased in at least a portion of the autonomic nervous system,
where the increase is at least great enough to provide the desired
results, e.g., great enough to treat a given condition.
[0028] While the ratio of parasympathetic function/sympathetic
function may be increased according to embodiments of the subject
invention, the net result may be a sympathetic bias (i.e.,
sympathetic dominance), parasympathetic bias (i.e., parasympathetic
dominance) or the activities of the sympathetic system and
parasympathetic system may be substantially equal (i.e., neither is
dominant). By "bias" is meant that the particular "biased"
component of the autonomic nervous system has a higher activity
level than the other component. For example, a sympathetic bias
refers to a higher level of sympathetic activity than
parasympathetic activity, and vice versa, where such bias may be
systemic or localized. The net result of the subject methods to
treat a condition may be higher or greater parasympathetic activity
relative to sympathetic activity in at least the area of the
autonomic system targeted or rather in need of modulation, higher
or greater sympathetic activity relative to parasympathetic
activity in at least the area of the autonomic system targeted or
rather in need of modulation, or substantially equal activity
levels of parasympathetic activity and sympathetic activity.
[0029] A feature of embodiments of the subject methods is that the
ratio of parasympathetic activity to sympathetic activity is
decreased. By "decreased ratio of parasympathetic activity to
sympathetic activity" and analogous terms is meant that this ratio
(characterized by parasympathetic activity/sympathetic activity) is
decreased in at least a portion of the autonomic nervous system,
where the decrease is at least great enough to provide the desired
results, e.g., great enough to treat a given condition.
[0030] While the ratio of parasympathetic function/sympathetic
function may be decreased according to embodiments of the subject
invention, the net result may be a sympathetic bias (i.e.,
sympathetic dominance), parasympathetic bias (i.e., parasympathetic
dominance) or the activities of the sympathetic system and
parasympathetic system may be substantially equal (i.e., neither is
dominant).
[0031] As the subject methods include modulating at least a portion
of a subject's autonomic nervous system, the modulation may be
systemic or regional (i.e., localized). In other words, the entire
autonomic nervous system may be modulated (e.g., the entire
parasympathetic nervous system and/or sympathetic nervous system
may be modulated) or only a portion of the autonomic nervous system
may be modulated (e.g., only a portion of the parasympathetic
nervous system and/or sympathetic nervous system may be modulated).
Localization may be with respect to a particular area or even to a
particular nerve fiber. Localization may be with respect to
innervations of one or more particular organs.
[0032] Embodiments of the subject methods also include determining
and/or monitoring one or more indicators, effects or results of the
autonomic nervous system. For example, the level of T helper cells
(Th1 and/or Th2) may be monitored, e.g., as an indicator of a
parasympathetic activity/sympathetic activity ratio. Other
indicators are described in greater detail below, and include, but
are not limited to, heart rate variability ("HRV"), respiratory
sinus arrhythmia, measures such a low frequency peak ("LF"), high
frequency peak ("HF"), and LF/HF ratio, where such may be used as
surrogates for autonomic balance. Any suitable indicator(s) may be
monitored at any suitable time including before, during and after
modulating the autonomic nervous system in accordance with the
subject invention.
Methods of Treating a Subject for a Condition by Increasing or
Decreasing the Parasympathetic Activity/Sympathetic Activity Ratio
During at Least One Predetermined Phase of the Menstrual Cycle
[0033] As indicated above, embodiments of the subject methods
include treating a subject for a condition by modulating at least a
portion of the autonomic nervous system during at least one
predetermined phase of the subject's menstrual cycle to increase or
decrease the parasympathetic activity/sympathetic activity ratio in
a manner effective to treat the condition of interest. The subject
methods may be employed to treat any condition at least suspected
of being exacerbated during at least one phase of the subject's
menstrual cycle. By "exacerbated" is meant broadly to include an
increase in severity and/or occurrence of the condition.
[0034] Any area of the autonomic nervous system (any nerve of the
autonomic nerve system) may be targeted according to the subject
invention. Specific area(s) of the autonomic nervous system that
may be modulated will vary, and include, but are not limited to,
pre- and post ganglionic nerve fibers, ganglionic structures,
efferent and afferent nerve fibers, the hypothalamus, receptors on
the hypothalamus, afferent autonomic nerves (parasympathetic and
sympathetic) and hormonal receptors on the hypothalamus. In certain
embodiments, a given nerve fiber or the like may be modulated with
respect to parasympathetic and/or sympathetic activity in more than
one area of the nerve fiber.
[0035] The autonomic nervous system may be modulated using any
suitable technique, including, but not limited to, surgical methods
(e.g., surgical isolation of an effector structure from
parasympathetic and/or sympathetic innervation, i.e., surgically
isolating an effector structure from one or more parasympathetic
and/or sympathetic nerve fibers associated with it); ablation
(permanently or reversibly ablating a nerve by employing energy
delivery devices or cryotherapy); cryoablation; thermoablation;
microwave energy; focus ultrasound; magnetic fields including
internal and external magnetic fields; laser energy; optical
energy; radiofrequency energy; pacing mechanisms (e.g., implantable
electrode-based pacing systems, external magnetic-based pacing
system, and the like); transcutaneous electrical nerve stimulation
("TENS") or transmagentic stimulation ("TMS") (see for example
George, M. Stimulating the Brain. Sci Amer 2003 September);
pharmacological modulation; any suitable electrical modulation, and
the like. Exemplary methods using pharmacological methods and
electrical energy applying methods are now described in greater
detail, where such descriptions are in no way intended to limit the
scope of the invention as it is to be understood that modulation of
the autonomic nervous system may be achieved using any suitable
method.
Pharmacological Modulation of at Least a Portion of the Autonomic
Nervous System
[0036] As described above, embodiments include treating a subject
for a condition by pharmacologically modulating at least a portion
of the subject's autonomic nervous system during at least one
predetermined menstrual phase to increase or decrease the
parasympathetic activity/sympathetic activity ratio or increase
parasympathetic activity relative to sympathetic activity. By
"pharmacologically modulating at least a portion of a subject's
autonomic nervous system" is meant altering or changing at least a
portion of an autonomic nervous system by pharmacological means
(i.e., administering a pharmaceutical agent to a subject) to
provide a change, alteration or shift in at least one component or
aspect of the autonomic nervous system. The pharmacological
modulation of the autonomic nervous system may affect central motor
output and/or nerve conduction and/or transmitter release and/or
synaptic transmission and/or receptor activation, and the like, but
in any event provides an increase (or decrease in certain
embodiments) in the parasympathetic activity/sympathetic activity
ratio during at least one predetermined menstrual phase.
[0037] For example, embodiments may include pharmacologically
modulating at least a portion of a subject's autonomic nervous
system to alter, shift or change the activity in at least one of
the sympathetic system and parasympathetic system from a first
state to a second state, where the second state is characterized at
least by an increase in the parasympathetic activity/sympathetic
activity ratio relative to the first state. One or more
pharmacological agents may be employed to increase and/or decrease
activity in at least a portion of the autonomic nervous system. For
example, embodiments may include administering one or more
pharmacological agents to achieve one or more of the following (but
in any event to achieve a net result of an increase or decrease in
parasympathetic activity/sympathetic activity ratio, relative to
the parasympathetic activity/sympathetic activity ratio prior to
pharmacological modulation): (1) increasing activity in at least
one sympathetic nerve fiber to achieve an increase in activity at
least a portion of the sympathetic system, (2) increasing activity
in at least one parasympathetic nerve fiber to achieve an increase
in activity in at least a portion of the parasympathetic system,
(3) inhibiting activity in at least one sympathetic nerve fiber to
achieve a decease in activity at least a portion of the sympathetic
system, and (4) inhibiting activity in at least one parasympathetic
nerve fiber to achieve a decease in activity in at least a portion
of the parasympathetic system. Certain embodiments of the subject
invention may include administering an effective amount of one or
more pharmacological agents to both increase activity in at least a
portion of the autonomic nervous system, e.g., increase activity in
at least one parasympathetic nerve fiber, and inhibit activity in
at least a portion of the autonomic nervous system, e.g., inhibit
activity in at least one sympathetic nerve fiber, to treat
condition.
[0038] Pharmacological modulation in accordance with the subject
invention may be performed prior to and/or at the same time and/or
subsequent to any other medical or clinical treatment regime such
as any one or more of those described above, for example,
electrical modulation of at least a portion of the subject's
autonomic nervous system, e.g., as described in copending U.S.
application Ser. No. 10/661,368, entitled "Treatment of Conditions
Through Electrical Modulation of the Autonomic Nervous System", the
disclosure of which is herein incorporated by reference, and the
like. In other words, the subject methods may include other
concomitant therapies or treatments to treat the same or different
condition.
[0039] According to embodiments of the subject invention,
pharmacological modulation is accomplished by at least
administering an effective amount of at least one pharmacological
agent to a subject to treat the subject for a condition caused,
precipitated or otherwise exacerbated, influenced or affected
during at least one predetermined menstrual phase, to increase the
parasympathetic activity/sympathetic activity ratio during a given
predetermined menstrual phase or phases. In other words, prior to
practicing the subject invention, activity in at least a portion of
the autonomic nervous system is at a level that is at least
contributing to or otherwise affecting or exacerbating a condition
such a disease condition, and as such modulation of the autonomic
nervous system may be employed to treat the condition.
[0040] That is, embodiments of the subject methods include
administering an effective amount, i.e., a therapeutically
effective amount (also referred to as a pharmacologically effective
amount), of one or more pharmacological agents to a subject to
modulate at least a portion of the subject's autonomic nervous
system. By "effective amount" and analogous terms is meant a dosage
sufficient to modulate at least a portion of a subject's autonomic
nervous system for a given period of time. The effective amount
will vary with the age and physical condition of the subject, type
and severity of the condition being treated, the duration of the
treatment, the nature of any concurrent treatment, the
pharmaceutically acceptable carrier used if any, and analogous
factors within the knowledge and expertise of those skilled in the
art. Introduction of an effective amount of a pharmacological agent
to a subject resulting in a modulation of at least a portion of the
autonomic nervous system that may be temporary or permanent.
[0041] In certain embodiments, more than one pharmacological agent
may be administered at the same or different time as another
pharmacological agent to treat a female for the same or different
condition, where the pharmacological agents administered by differ
in one or more respected, e.g., may be different types of agents or
may be the same type pharmacological agent but that differ in mode
of administration, dosage, etc.
[0042] The effective amount of a given pharmacological agent may
vary somewhat from subject to subject, and may depend upon factors
such as, but not limited to, the age of the subject, the health of
the subject, the particular condition being treated, the form of
the pharmacological agent, the route and method of delivery, etc.,
as noted above. Such dosages may be determined in accordance with
routine pharmacological procedures known to those skilled in the
art. Pharmacological agent and/or adjuvants may be administered to
a subject in a single oral dose, one time a day or more for days,
weeks, months, years, even as long as a subject's lifetime or as
long as the subject experiences the condition of interest. For
example, embodiment may include administering a given
pharmacological agent one time a day over a prolonged period of
time, e.g., over a particular time period coinciding with at least
a portion of one or more menstrual cycle phases (e.g., over about
the second half of the menstrual cycle, e.g., the luteal phase or
at least the start of the luteal phase, the menses phase or at
least the start of the menses phase, and the like), e.g., over
about 1 week, e.g., over about 1-3 months, e.g., about 3 months to
about 3 years or more, e.g., orally or with a medical infusion pump
or similar device designed for delivery of a substance over a
prolonged period.
[0043] The frequency of administration of a pharmacological agent
may vary depending, e.g., on one or more of the factors described
above. For example, the frequency of administration of a
pharmacological agent may range from about 1 time per day to
multiple times per day, e.g., about 2 times or more per day or as
necessary to treat or otherwise control or manage a condition. The
duration of therapy depends on the particular condition being
treated and may range from as short as about 24 hours to as long as
the life of the subject. For example, at least one autonomic
nervous system modulating-pharmacological agent may be delivered to
a subject during one or more predetermined phases of a subject's
menstrual cycle such as during about the predetermined second half
of the menstrual cycle, e.g., during a predetermined luteal phase
or the like every month for months, years or even the entire
lifetime of the subject. By "adjuvants" is meant a compound that,
when used in combination with the one or more pharmacological agent
compounds and/or compositions, augments or otherwise alters or
modifies the resultant pharmacological and/or physiological
responses.
[0044] Embodiments may include daily discrete or continuous unit
doses wherein the total number of daily units may be equal to the
total number of days of a given predetermined phase of the
menstrual cycle, the total number of days of a month or menstrual
cycle, and the like, in the form of a pack. For example,
embodiments may include daily discrete or continuous unit doses
wherein the total number of daily units may be equal to the total
number of days of a month or menstrual cycle, e.g., in the form of
a monthly pack. Such a monthly pack may include a plurality of unit
dosage forms having the same or different dosages of a
pharmacological agent. For example, embodiments may include a
monthly pharmacological agent pack wherein the dosage of active
agent of certain unit dosage forms of the pack to be administered
to a subject during one or more predetermined phases of the
menstrual cycle (e.g., one or more predetermined phases of the
menstrual cycle wherein exacerbation of a condition is observed,
e.g., the second half of the menstrual cycle, e.g., the luteal
phase and/or menses phase) may differ in dosage from one or more
other unit dosage forms to be administered to the subject during
one or more other predetermined phases of the menstrual cycle
(e.g., one or more other predetermined phases of the menstrual
cycle wherein exacerbation of a condition is not observed).
[0045] Depending on the particular pharmacological agent
administered to a subject, the pharmacological agent may be
administered to a subject using any convenient means capable of
resulting in the desired modulation of the autonomic nervous
system. Thus, the at least one pharmacological agent may be
incorporated into a variety of formulations for therapeutic
administration. More particularly, the pharmacological agent may be
formulated into pharmaceutical compositions by combination with
appropriate, pharmaceutically acceptable carriers. By
"pharmaceutically acceptable carrier" is meant a component such as
a carrier, diluent, excipient, and the like of a composition that
is compatible with the particular pharmacological agent and other
optional ingredients of the subject pharmacological agent
compositions in that a pharmaceutically acceptable carrier may be
combined with the pharmacological agent without eliminating the
biological or therapeutically effective activity of the
pharmacological agent, and is suitable for use in subjects as
provided herein without undue adverse side effects (such as
toxicity, irritation, allergic response, and death). Side effects
are "undue" when their risk outweighs the benefit provided by the
pharmacological agent. Non-limiting examples of pharmaceutically
acceptable components include, but are not limited to, any of the
standard pharmaceutical carriers such as phosphate buffered saline
solutions, water, emulsions such as oil/water emulsions or
water/oil emulsions, microemulsions, and various types of wetting
agents. Accordingly, the pharmacological agent employed in the
subject methods may be formulated into preparations in solid,
semi-solid (e.g., gel), liquid or gaseous forms, such as tablets,
capsules, powders, granules, ointments, solutions, suppositories,
injections, inhalants and aerosols. As such, administration of a
pharmacological agent may be achieved in various ways, including,
but not limited to, oral, buccal (e.g. sub-lingual), rectal,
topical (including both skin and mucosal surfaces, including airway
surfaces), parenteral (e.g., subcutaneous, intramuscular,
intradermal, intravenous and intrathecal), intraperiactivityal,
transdermal, intracheal, intravaginal, endocervical, intrathecal,
intranasal, intravesicular, in or on the eye, in the ear canal,
etc., administration. In certain embodiments, a given
pharmacological agent may be administered via a transdermal patch
or film system such as or analogous to that described, e.g., in
U.S. Pat. Nos. 6,503,532; 5,302,395; 5,262,165; 5,248,501;
5,232,702; 5,230,896; 5,227,169; 5,212,199; 5,202,125; 5,173,302;
5,154,922; 5,139,786; 5,122,383; 5,023,252; 4,978,532; 5,324,521;
5,306,503; 5,302,395; 5,296,230; 5,286,491; 5,252,334; 5,248,501;
5,230,896; 5,227,169; 5,212,199; 5,202,125; 5,173,302; 5,171,576;
5,139,786; 5,133,972; 5,122,383; 5,120,546; 5,118,509; 5,077,054;
5,066,494; 5,049,387; 5,028,435; 5,023,252; 5,000,956; 4,911,916;
4,898,734; 4,883,669; 4,882,377; 4,840,796; 4,818,540; 4,814,173;
4,806,341; 4,789,547; 4,786,277; 4,702,732; 4,690,683; 4,627,429;
and 4,585,452, the disclosures of which are herein incorporated by
reference.
[0046] As noted above, embodiments may include pharmaceutical
formulations for oral administration that may be formulated using
pharmaceutically acceptable carriers well known in the art in
dosages suitable for oral administration. Such carriers enable the
pharmaceutical formulations to be formulated in unit dosage forms
as tablets, pills, powder, dragees, capsules, liquids, lozenges,
gels, syrups, slurries, suspensions, etc., suitable for ingestion
by the patient. Pharmaceutical preparations for oral use may be
obtained through combination of at least one pharmacological agent
with a solid excipient, optionally grinding a resulting mixture,
and processing the mixture of granules, after adding suitable
additional compounds, if desired, to obtain tablets or dragee
cores. Suitable solid excipients include, but are not limited to,
carbohydrate or protein fillers and include, but are not limited to
sugars, including lactose, sucrose, mannitol, or sorbitol; starch
from corn, wheat, rice, potato, or other plants; cellulose such as
methyl cellulose, hydroxypropylmethyl-cellulose or sodium
carboxymethylcellulose; and gums including arabic and tragacanth;
as well as proteins such as gelatin and collagen. If desired,
disintegrating or solubilizing agents may be added, such as the
cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt
thereof, such as sodium alginate; with optional lubricants, such as
talc or magnesium stearate; and if desired, with diluents,
buffering agents, moistening agents, preservatives and flavoring
agents.
[0047] Accordingly, pharmacological formulations suitable for oral
administration in accordance with the subject invention may be
present in discrete units, such as capsules, cachets, lozenges,
tablets, and the like, each containing a predetermined amount of
the active pharmacological agent; as a powder or granules; as a
solution or a suspension in an pharmacological formulations may be
prepared by any suitable method of pharmacy which includes, but is
not limited to, bringing into association the active
pharmacological agent and a suitable carrier (which may contain one
or more optional ingredients as noted above). For example,
pharmacological formulations for use with the subject invention may
be prepared by uniformly and intimately admixing the active
pharmacological agent with a liquid or finely divided solid
carrier, or both, and then, if necessary, shaping the resulting
mixture. For example, a tablet may be prepared by compressing or
molding a powder or granules containing the active pharmacological
agent, optionally with one or more accessory ingredients.
Compressed tablets may be prepared by compressing, in a suitable
machine, the pharmacological agent in a free-flowing form, such as
a powder or granules optionally mixed with a binder, lubricant,
inert diluent, and/or surface active/dispersing agent(s). Molded
tablets may be made by molding, in a suitable machine, the powdered
pharmacological agent moistened with an inert liquid binder.
[0048] A pharmacological agent of this invention may also be
administered in the form of suppositories for rectal administration
of the drug. These formulations may be prepared by mixing a
pharmacological agent with a suitable non-irritating vehicle or
excipient which is solid at ordinary temperatures but liquid at the
rectal temperatures and will therefore melt in the rectum to
release the drug. Such materials include, but are not limited to,
cocoa butter, carbowaxes and polyethylene glycols. Embodiments
include a pharmacological agent made into suppositories by mixing
with a variety of bases such as emulsifying bases or water-soluble
bases.
[0049] A pharmacological agent of this invention may also be
administered by intranasal, intraocular, intravaginal, and
intrarectal routes including suppositories, insufflation, powders
and aerosol formulations (for examples of steroid inhalants, see
Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann.
Allergy Asthma Immunol. 75:107-111, 1995).
[0050] For example, embodiments may also include a pharmacological
agent in an aerosolized, atomized or nebulized vapor form, e.g.,
administrable via a metered dose device or nebulizer, and the like
such that embodiments also include aerosolizing, vaporing or
nebulizing one or more pharmacological agents for administration to
a subject. Accordingly, a pharmacological agent may be utilized in
aerosol formulation or an analogous formulation to be administered
via inhalation or analogous means. The pharmacological agent
employed in the practice of the present invention may be formulated
into pressurized acceptable propellants such as
dichlorodifluoromethane, propane, nitrogen and the like.
[0051] A pharmacological agent employed in the subject invention
may be delivered transdermally, by a topical route, formulated as
applicator sticks, solutions, suspensions, emulsions, gels, creams,
ointments, pastes, jellies, paints, powders, and aerosols. For
example, embodiments may include a pharmacological agent in the
form of a discrete patch or film or plaster or the like adapted to
remain in intimate contact with the epidermis of the recipient for
a period of time. For example, such transdermal patches may include
a base or matrix layer, e.g., polymeric layer, in which one or more
pharmacological agents are retained. The base or matrix layer may
be operatively associated with a support or backing.
Pharmacological formulations suitable for transdermal
administration may also be delivered by iontophoresis and may take
the form of an optionally buffered aqueous solution of the
pharmacological compound. Suitable formulations may include citrate
or bis/tris buffer (pH 6) or ethanol/water and contain a suitable
amount of active ingredient.
[0052] A pharmacological agent of the invention may also be
delivered as microspheres for slow release in the body. For
example, microspheres may be administered via intradermal injection
of drug-containing microspheres, which slowly release
subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645,
1995); as biodegradable and injectable gel formulations (see, e.g.,
Gao Pharm. Res. 12:857-863, 1995); or, as microspheres for oral
administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674,
1997). Both transdermal and intradermal routes afford constant
delivery for weeks or months.
[0053] A pharmaceutical formulation of the invention may be
provided as a salt and may be formed with many acids, including but
not limited to hydrochloric, sulfuric, acetic, lactic, tartaric,
malic, succinic, etc. Salts tend to be more soluble in aqueous or
other protonic solvents that are the corresponding free base forms.
In other cases, a preparation may be a lyophilized powder that is
combined with buffer prior to use.
[0054] Pharmacological formulations of the subject invention may be
useful for parenteral administration, such as intravenous ("IV")
administration, intramuscular ("IM"), subcutaneous ("SC" or "SQ"),
mucosal. The formulations for administration may include a solution
of the pharmacological agent dissolved in a pharmaceutically
acceptable carrier. Among the acceptable vehicles and solvents that
may be employed, include, but are not limited to, water and
Ringer's solution, an isotonic sodium chloride, etc. In addition,
sterile fixed oils may conventionally be employed as a solvent or
suspending medium. For this purpose any bland fixed oil may be
employed including synthetic mono- or diglycerides. In addition,
fatty acids such as oleic acid can likewise be used in the
preparation of injectables. Accordingly, a pharmacological agent
may be formulated into preparations for injection by dissolving,
suspending or emulsifying them in an aqueous or nonaqueous solvent,
such as vegetable or other similar oils, synthetic aliphatic acid
glycerides, esters of higher aliphatic acids or propylene glycol;
and if desired, with conventional additives such as solubilizers,
isotonic agents, suspending agents, emulsifying agents, stabilizers
and preservatives. These solutions are sterile and generally free
of undesirable matter. These formulations may be sterilized by
conventional, well known sterilization techniques. The formulations
may contain pharmaceutically acceptable auxiliary substances as
required to approximate physiological conditions such as pH
adjusting and buffering agents, toxicity adjusting agents, e.g.,
sodium acetate, sodium chloride, potassium chloride, calcium
chloride, sodium lactate and the like. The concentration of
pharmacological agent in these formulations may vary widely, and
will be selected based on fluid volumes, viscosities, body weight,
and the like, in accordance with the particular mode of
administration selected and the patient's needs. For IV
administration, the formulation may be a sterile injectable
preparation, such as a sterile injectable aqueous or oleaginous
suspension. This suspension may be formulated according to the
known art using those suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a nontoxic
parenterally-acceptable diluent or solvent, such as a solution of
1,3-butanediol, and the like. Accordingly, pharmacological
formulations suitable for parenteral administration may include
sterile aqueous and non-aqueous injection solutions of one or more
active pharmacological agents, which preparations may be isotonic
with the blood of the intended recipient. These preparations may
contain, buffers and solutes which render the formulation isotonic
with the blood of the intended recipient. Aqueous and non-aqueous
sterile suspensions may include suspending agents and thickening
agents. The formulations may be presented in single- or multi-dose
containers, for example sealed ampoules and vials, and may be
stored in a freeze-dried (lyophilized) condition requiring only the
addition of the sterile liquid carrier, for example, saline or
water-for-injection immediately prior to use. Extemporaneous
injection solutions and suspensions may be prepared from sterile
powders, granules and tablets of the kind described above.
[0055] In other embodiments, the pharmacological formulations of
the invention may be delivered by the use of liposomes which fuse
with the cellular membrane or are endocytosed, i.e., by employing
ligands attached to the liposome, or attached directly to the
oligonucleotide, that bind to surface membrane protein receptors of
the cell resulting in endocytosis. By using liposomes, particularly
where the liposome surface carries ligands specific for target
cells, or are otherwise preferentially directed to a specific
organ, one can focus the delivery of the pharmacological agent into
the target cells in vivo. (See, e.g., Al-Muhammed, J.
Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol.
6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989).
Accordingly, embodiments may include a pharmacological agent
administered as liposomal formulations of the pharmacological
agent. Methods for preparing liposomal suspensions are known in the
art and thus will not be described herein in great detail. Briefly,
in those embodiments where the pharmacological agent is an
aqueous-soluble pharmacological agent, the pharmacological agent
may be incorporated into lipid vesicles using conventional liposome
technology. In such instances, due to the water solubility of the
pharmacological agent, the pharmacological agent may be
substantially entrained within the hydrophilic center or core of
the liposomes. The lipid layer employed may be of any conventional
composition and may either contain cholesterol or may be
cholesterol-free. When the pharmacological agent of interest is
water-insoluble, the pharmacological agent may be substantially
entrained within the hydrophobic lipid bilayer which forms the
structure of the liposome employing conventional liposome formation
technology. In either instance, the liposomes which may be produced
may be reduced in size, as through the use of standard sonication
and homogenization techniques. Embodiments of liposomal
formulations containing the pharmacological agent of interest may
be lyophilized to produce a lyophilizate which may be reconstituted
with a pharmaceutically acceptable carrier, such as water, to
regenerate a liposomal suspension.
[0056] Embodiments of the pharmacological agent employed in the
practice of the subject invention may include pharmaceutical
compositions that may be prepared from water-insoluble compounds,
or salts thereof, such as aqueous base emulsions. In such
embodiments, the pharmacological composition will typically contain
a sufficient amount of pharmaceutically acceptable emulsifying
agent to emulsify the desired amount of the pharmacological agent.
Useful emulsifying agents include, but are not limited to,
phosphatidyl cholines, lecithin, and the like.
[0057] As noted above, in addition to active pharmacological agent,
the pharmaceutical compositions of the subject invention may
contain other additives, such as pH-adjusting additives. In
particular, useful pH-adjusting agents include acids, such as
hydrochloric acid, bases or buffers, such as sodium lactate, sodium
acetate, sodium phosphate, sodium citrate, sodium borate, or sodium
gluconate. Furthermore, pharmacological compositions may, though
not always, contain microbial preservatives. Microbial
preservatives that may be employed include, but are not limited to,
methylparaben, propylparaben, and benzyl alcohol. The microbial
preservative may be employed when the pharmacological formulation
is placed in a vial designed for multidose use. Pharmaceutical
compositions for use in practicing the subject methods may be
lyophilized using techniques well known in the art.
[0058] Pharmaceutically acceptable excipients, such as vehicles,
adjuvants, carriers or diluents, that may be employed in the
subject invention are readily available to the public. Moreover,
pharmaceutically acceptable auxiliary substances, such as pH
adjusting and buffering agents, tonicity adjusting agents,
stabilizers, wetting agents and the like, are readily available to
the public.
[0059] Embodiments may also include administration of a
pharmacological agent using a pharmacological delivery device such
as, but not limited to, pumps (implantable or external devices and
combinations of both (e.g., certain components may be implantable
and others may be external to the body such as controls for the
implantable components), epidural injectors, syringes or other
injection apparatus, catheter and/or reservoir operatively
associated with a catheter, etc. For example, in certain
embodiments a delivery device employed to deliver a given
pharmacological agent to a subject may be a pump, syringe, catheter
or reservoir operably associated with a connecting device such as a
catheter, tubing, or the like. Containers suitable for delivery of
a pharmacological agent to a pharmacological agent administration
device include instruments of containment that may be used to
deliver, place, attach, and/or insert the pharmacological agent
into the delivery device for administration of the pharmacological
agent to a subject and include, but are not limited to, vials,
ampules, tubes, capsules, bottles, syringes and bags. Embodiments
may also include administration of a pharmacological agent via a
biodegradable implant drug delivery device. Such may be
accomplished by employing syringes to deposit such a biodegradable
delivery device under the skin of a subject. The implants degrade
completely, so that removal is not necessary.
[0060] Embodiments may include employing an electrode to deliver a
pharmacological agent to a subject. For example, an electrode may
be used that has a small port at its tip which is connected to a
reservoir or pump containing a pharmacological agent. The
pharmacological agent delivery electrode may be implanted using any
suitable technique such as surgical cut down, laproscopy,
endoscopy, percutaneous procedure, and the like. In certain
embodiments a reservoir or pump may also be implanted in the
subject's body. The pharmacological agent delivery electrode, or
other analogous device, may be controllable such that the amount of
pharmacological agent delivered, the rate at which the
pharmacological agent may be delivered, and the time period over
which the pharmacological agent may be delivered, etc., may be
controllable and may be adjusted.
[0061] In certain embodiments, the pharmaceutically acceptable
carrier may be preservative free. By "preservative free" is meant
the substantial absence of chemical, antibacterial, antimicrobial,
or antioxidative additives, or the like, from the pharmaceutically
acceptable carriers of the present invention. "Substantial absence"
may mean that no preservative is present in the compositions or
that trace amounts may be present that impart no detectable effect
otherwise attributable to a preservative. For example, the
pharmaceutically acceptable carrier may be characterized by the
substantial absence of chemical, antibacterial, antimicrobial, or
antioxidative additives or the like (e.g., contain less than about
5.0, 4.0, 3.0, 2.0, 1.0, 0.5, 0.1, 0.05, 0.01, or even about 0.00
percent by weight of a preservative). Further, such formulations
may be substantially or essentially free of alcohols such as
ethanol (e.g., contain less than about 5.0, 4.0, 3.0, 2.0, 1.0,
0.5, 0.1, 0.05, 0.01, or even about 0.00 percent by weight of
alcohols such as ethanol). Examples of suitable pharmacological
formulations include, but are not limited to, formulations that
include one or more active pharmacological agents and physiological
saline solution (optionally including other typical ingredients
such as other active agents and buffers).
[0062] As noted above, in pharmaceutical dosage forms, a given
pharmacological agent may be administered alone or in appropriate
association with, as well as in combination with, other
pharmaceutically active compounds. As used herein, "administered
with" means that a given pharmacological agent and at least one
other adjuvant (including one or more other different
pharmacological agents) are administered at times sufficiently
close that the results observed are indistinguishable from those
achieved when the pharmacological agent and at least one other
adjuvant are administered at the same point in time. The
pharmacological agent and at least one other adjuvant may be
administered simultaneously (i.e., concurrently) or sequentially.
Simultaneous administration may be carried out by mixing a given
pharmacological agent and at least one other adjuvant prior to
administration, or by administering a given pharmacological agent
and at least one other adjuvant at the same point in time. Such
administration may be at different anatomic sites or using
different routes of administration. The phrases "concurrent
administration," "administration in combination," "simultaneous
administration" or "administered simultaneously" may also be used
interchangeably and mean that a given pharmacological agent and at
least one other adjuvant are administered at the same point in time
or immediately following one another. In the latter case, the
pharmacological agent and at least one other adjuvant are
administered at times sufficiently close that the results produced
are synergistic and/or are indistinguishable from those achieved
when the at least one pharmacological agent and at least one other
adjuvant are administered at the same point in time. Alternatively,
a pharmacological agent may be administered separately from the
administration of an adjuvant, which may result in a synergistic
effect or a separate effect. The methods and excipients described
herein are merely exemplary and are in no way limiting.
[0063] Unit dosage forms for oral or rectal administration such as
syrups, elixirs, and suspensions may be provided wherein each
dosage unit, for example, teaspoonful, tablespoonful, tablet or
suppository, contains a predetermined amount of a pharmacological
agent. Similarly, unit dosage forms for injection or intravenous or
other suitable administration route may include the pharmacological
agent(s) in a composition as a solution in sterile water, normal
saline or another pharmaceutically acceptable carrier.
[0064] The term "unit dosage form," and analogous terms as used
herein refers to physically discrete units suitable as unitary
dosages for human and animal subjects, each unit containing a
predetermined quantity of pharmacological agent(s) calculated in an
amount sufficient to produce the desired effect in association with
a pharmaceutically acceptable diluent, carrier or vehicle. The
specifications for the unit dosage forms of a given pharmacological
agent employed in the practice of the present invention depend on,
for example, the particular pharmacological agent employed and the
effect to be achieved, the pharmacodynamics associated with the
particular pharmacological agent in the subject, etc.
[0065] As noted above, those of skill in the art will readily
appreciate that dose levels may vary as a function of the specific
pharmacological agent, the nature of the delivery vehicle, and the
like. Dosages for a given pharmacological agent are readily
determinable by those of skill in the art by a variety of means.
Exemplary dosage levels are provided herein and are not to be
construed to limit the scope of the invention in any manner.
[0066] A wide variety of different pharmacological agents may be
employed in the practice of the subject methods, where the
particular pharmacological agent or combination of pharmacological
agents employed will depend on, e.g., the subject being treated,
the condition being treated, duration of treatment, whether it is
desired to increase activity in the parasympathetic system and/or
increase activity in the sympathetic system and/or decrease
activity in the sympathetic system and/or decrease activity in the
parasympathetic system, etc.
[0067] As noted above, certain embodiments include
pharmacologically modulating at least a portion of the autonomic
nervous system during at least one predetermined menstrual cycle
phase of the subject to increase the parasympathetic
activity/sympathetic activity ratio. Such may be the case, for
example, wherein the subject methods are employed to treat
conditions such as, but not limited to: cardiovascular conditions,
neurodegenerative conditions, orthopedic inflammatory conditions,
inflammatory conditions, lymphoproliferative conditions, autoimmune
conditions, inflammatory conditions, infectious diseases, pulmonary
conditions, gastrointestinal conditions, endocrine conditions,
genitourinary conditions, skin conditions, aging associated
conditions, Th-2 dominant conditions, conditions that cause
hypoxia; conditions that cause hypercarbia; conditions that cause
hypercapnia; conditions that cause acidosis; conditions that cause
acidemia; neurologic conditions, OB-GYN conditions; sudden death
syndromes; menstrual related disorders; peripartum and pregnancy
related disorders; fibrosis; post-operative recovery conditions;
post-procedural recovery conditions; chronic pain; trauma;
bacterial infections; and fibromyalgia. Representative
pharmacological agents (and analogs, derivatives and salts thereof)
that may be used in this regard include, but are not limited to,
one of more of the following:
[0068] beta-blockers (e.g., atenolol (e.g., as sold under the brand
names TENORMIN), betaxolol (e.g., as sold under the brand name
KERLONE), bisoprolol (e.g., as sold under the brand name ZEBETA),
carvedilol (e.g., as sold under the brand name COREG), esmolol
(e.g., as sold under the brand name BREVIBLOC), labetalol (e.g., as
sold under the brand name NORMODYNE), metoprolol (e.g., as sold
under the brand name LOPRESSOR), nadolol (e.g., as sold under the
brand name CORGARD), pindolol (e.g., as sold under the brand name
VISKEN), propranolol (e.g., as sold under the brand name INDERAL),
sotalol (e.g., as sold under the brand name BETAPACE), timolol
(e.g., as sold under the brand name BLOCADREN), carvedilol, and the
like);
[0069] aldosterone antagonists (e.g., spironolactone, eplerenone,
and the like);
[0070] angiotensin II receptor blockades (e.g., candeartan (e.g.,
available under the brand name ALTACAND), eprosarten mesylate
(e.g., available under the brand name TEVETAN), irbesartan (e.g.,
available under the brand name AVAPRO), losartan (e.g., available
under the brand name COZAAR), etelmisartin (e.g., available under
the brand name MICARDIS), valsartan (e.g., available under the
brand name DIOVAN), and the like);
[0071] angiotensin converting enzyme ("ACE") inhibitors (e.g.,
benazapril (e.g., available under the brand name LOTENSIN),
captopril (e.g., available under the brand name CAPOTEN) enalapril
(e.g., available under the brand name VASOTEC) fosinopril (e.g.,
available under the brand name MONOPRIL) lisinopril (e.g.,
available under the brand name PRINIVIL) moexipril (e.g., available
under the brand name UNIVASC) quinapril (e.g., available under the
brand name ACCUPRIL) ramipril (e.g., available under the brand name
ALTACE) trandolapril (e.g., available under the brand name MAVIK),
and the like);
[0072] statins (e.g., atorvastatin (e.g., available under the brand
name LLPITOR), cerivastatin (e.g., available under the brand name
BAYCOL), fluvastatin (e.g., available under the brand name
LLESCOL), lovastatin (e.g., available under the brand name
MEVACOR), prevastatin (e.g., available under the brand name
PRAVACHOL), simvastatin (e.g., available under the brand name
ZOCOR), and the like);
[0073] triglycerides lowering agents (e.g., fenofibrate (e.g.,
available under the brand name TRICOR), genfibrozil (e.g.,
available under the brand name LOPID), and the like);
[0074] niacin;
[0075] diabetes agents (e.g., acarbose (e.g., available under the
brand name PRECOSE), glimepiride (e.g., available under the brand
name AMARYL), glyburide (e.g., available under the brand names
MICRONASE, DIABETA), metformin (e.g., available under the brand
name GLUCOPHASGE), miglitol (e.g., available under the brand name
GLYCET), pioglitazone (e.g., available under the brand name ACTOS),
repaglinide (e.g., available under the brand name PRANDIN),
rosiglitazone (e.g., available under the brand name AVANDIA), and
the like);
[0076] immunomodulators (e.g., interferon beta-1B (e.g., available
under the brand name BETASERON), interferon alfa-2A (e.g.,
available under the brand name ROFERON-A) interferon alfa-2B (e.g.,
available under the brand name INTRON-A), interferon alfa-2B and
Ribavirin combo pack (e.g., available under the brand name
REBETRON), interferon alfa-N3 (e.g., available under the brand name
ALFERON N), interferon beta-1A (e.g., available under the brand
name AVONEX), interferon beta-1B, interferon gamma immunoregulatory
antibodies that bind to or react with one of the following
antigens: CD4, gp39, B7, CD19, CD20, CD22, CD401, CD40, CD40L and
CD23, rituximab (e.g., available under the brand name RITUXAN), any
chemical or radiopharmaceutical linked or conjugated antibodies
that bind to or react with one of the following antigens: CD4,
gp39, B7, CD19, CD20, CD22, CD401, CD40, CD40L and CD23), and the
like);
[0077] nicotine;
[0078] sympathomimetics (e.g., trimethaphan, clondine, reserpine,
guanethidine, and the like);
[0079] antihistamines (e.g., available under the brand name
BENADRYL, diphenhydramine, available under the brand name ACTIFED,
and the like);
[0080] cholinergics (e.g., bethanechol, oxotremorine, methacoline,
cevimeline, and the like);
[0081] acetylcholinesterase inhibitors (e.g., edrophonium,
neostigmine, donepezil, tacrine, echothiophate,
diisopropylfluorophosphate, demecarium, pralidoxime, galanthamine,
tetraethyl pyrophosphate, parathoin, malathion, isoflurophate,
metrifonate, physostigmine, rivastigmine, abenonium acetylchol,
carbaryl acetylchol, propoxur acetylchol, aldicarb acetylchol, and
the like);
[0082] magnesium and magnesium sulfates;
[0083] calcium channel blockers (e.g., amlodipine besylate (e.g.,
available under the brand name NORVASC), diltiazem hydrochloride
(e.g., available under the brand names CARDIZEM CD, CARDIZEM SR,
DILACOR XR, TIAZAC), felodipine plendil isradipine (e.g., available
under the brand names DYNACIRC, DYNACIRC CR), nicardipine (e.g.,
available under the brand name CARDENE SR), nifedipine (e.g.,
available under the brand names ADALAT CC, PROCARDIA XL),
nisoldipine sulfur (e.g., available under the brand name SULAR),
verapamil hydrochloride (e.g., available under the brand names
CALAN SR, COVERA HS, ISOPTIN SR, VERELAN) and the like);
[0084] muscarinics (e.g., muscarine, pilocarpine, and the
like);
[0085] sodium channel blockers, (e.g., moricizine, propafenone,
encainide, flecainide, tocainide, mexiletine, phenytoin, lidocaine,
disopyramide, quinidine, procainamide, and the like);
[0086] glucocorticoid receptor blockers (e.g., mifepristone, and
the like);
[0087] peripheral andrenergic inhibitors (e.g., guanadrel (e.g.,
available under the brand name HYLOREL), guanethidine monosulfate
(e.g., available under the brand name ISMELIN), reserpine (e.g.,
available under the brand names SERPASIL, MECAMYLAMINE,
HEXEMETHONIUM), and the like);
[0088] blood vessel dilators (e.g., hydralazine hydrocholoride
(e.g., available under the brand name APRESOLINE), minoxidil (e.g.,
e.g., available under the brand name LONITEN), and the like);
[0089] central agonists (e.g., alpha methyldopa (e.g., available
under the brand name ALDOMET), clonidine hydrochloride (e.g.,
available under the brand name CATAPRES), guanabenz acetate (e.g.,
available under the brand name WYTENSIN), guanfacine hydrochloride
(e.g., available under the brand name TENEX), and the like;
[0090] combined alpha and beta-blockers (e.g., carvedilol (e.g.,
available under the brand name COREG), labetolol hydrochloride
(e.g., available under the brand names NORMODYNE, TRANDATE), and
the like);
[0091] alpha blockers (e.g., doxazosin mesylate (e.g., available
under the brand name CARDURA), prazosin hydrochloride (e.g.,
available under the brand name MINIPRESS), terazosin hydrochloride
(e.g., available under the brand name HYTRIN), and the like);
[0092] combination diuretics (e.g., amiloride
hydrochloride+hydrochlorothiazide (e.g., available under the brand
name MODURETIC), spironolactone+hydrochlorothiazide (e.g.,
Aldactazide), triamterene+hydrochlorothiazide (e.g., available
under the brand names DYAZIDE, MAXZIDE) and the like); potassium
sparing diuretics (e.g., amiloride hydrochloride (e.g., available
under the brand name MIDAMAR), spironolactone (e.g., available
under the brand name ALDACTONE), triamterene (e.g., available under
the brand name DYRENIUM), and the like); nitrates (e.g.,
L-arginine, (e.g., available under the brand names NITROGLYCERIN
DEPONIT, MINITRAN, NITROPAR, NITROCINE, NITRO-DERM, NITRO DISC,
NITRO-DUR, NITROGARD, NITROGLYCERIN, NITROGLYCERIN T/R, NITRO-TIME,
NITROL OINTMENT, NITROLINGUAL SPRAY, NITRONG, NITRO-BID,
NITROPRESS, NITROPREX, NITRO S.A., NITROSPAN, NITROSTAT,
NITRO-TRANS SYSTEM, NITRO-TRANSDERMAL, NITRO-TIME, TRANSDERM-NITRO,
TRIDIL. PENTAERYTHRITOL TETRANITRATE PERITRATE, PERITRATE S.A.
Erythrityl Tetranitrate Cardilate Isosorbide
DINITRATE/PHENOBARBITAL ISORDIL W/PB ISOSORBIDE MONONITRATE IMDUR,
ISMO, ISOSORBIDE MONONITRATE, MONOKET ISOSORBIDE NITRATE
DILATRATE-SR, ISO-BID, ISORDIL, ISORDIL TEMBIDS, ISORDIL DINITRATE,
ISORDIL DINITRATE LA, SORBITRATE, SORBITRATE SA), and the
like);
[0093] cyclic nucleotide monophosphodiesterase ("PDE") inhibitors
(e.g., vardenafil (e.g., available under the brand name LEVITRA),
sildenafil (e.g., available under the brand name VIAGRA) tadalafil
(e.g., available under the brand name CIALIS) and the like);
[0094] alcohols;
[0095] vasopressin inhibitors (e.g., atosiban (Tractocile), AVP V1a
(OPC-21268, SR49059 (Relcovaptan)), V2 (OPC-31260, OPC-41061
(Tolvaptan), VPA-985 (Lixivaptan), SR121463, VP-343, FR-161282) and
mixed V1a/V2 (YM-087 (Conivaptan), JTV-605, CL-385004) receptor
antagonists, and the like);
[0096] oxytocin inhibitors (e.g., terbutaline, ritodrine, and the
like);
[0097] glucagons like peptide 1;
[0098] relaxin hormone;
[0099] renin inhibitors (e.g., Aliskiren, and the like);
[0100] estrogen and estrogen analogues (e.g., estradiols, and the
like) and metabolites;
[0101] progesterone inhibitors;
[0102] testosterone inhibitors;
[0103] gonadotropin-releasing hormone analogues (GnRH-As);
[0104] gonadotropin-releasing hormone inhibitors (e.g., Leuprolide
Acetate, and the like);
[0105] vesicular monoamine transport (VMAT) inhibitors (e.g.,
tetrabenazine, and the like); dipeptidyl peptidase (DP) IV
inhibitors (DP4 inhibitors) (e.g., LAF237, P93/01, P32/98, valine
pyrrolidide, and the like);
[0106] melatonin; and the like;
[0107] anti-coagulants (e.g., ximelagatran (EXANTA); hirulog
(BIVALIRIDIN); abciximab (REOPRO); dipridamole (AGGRENOX);
anagrlide (AGRILYN); clopiogrel (PLAVIX); dipridamole (PERSANTINE);
eptifabatide (INTEGRILIN); ticlopidine (TICLID); tirofibam
(AGGRASTAT); ardeparin (NORMIFLO); dalteparin (FRAGMIN); dnaparoid
(ORGARIN); enoxaparin (LOVENOX); lepiudin (REFLUDAN); heparin;
warfarin; alteplase (ACTIVASE), t-PA); reteplase (RETEVASE);
streptokinase; urokinase; aminocaproic acid (AMICAR); cilostazol
(PLETAL); pentoxifylline (TRENTAL); and the like).
[0108] As noted above, one or more of the above-described a
pharmacological agents may be employed in the practice of the
subject methods and may be of particular use in modulating at least
a portion of a subject's autonomic nervous system to increase the
parasympathetic activity/sympathetic activity ratio. However, the
subject methods are not limited to the above-described active
agents as other pharmacological agents may be employed in the
practice of the subject methods. For example, the below-described
pharmacological agents may be employed in the practice of the
subject methods, where one or more of the following pharmacological
agents may be of particular use in modulating at least a portion of
a subject's autonomic nervous system to decrease the
parasympathetic activity/sympathetic activity ratio. Such may be
the case, for example, wherein the subject methods are employed to
treat certain bacterial infections, e.g., bacterial vaginosis, etc.
Other conditions that may be treated by decreasing the
parasympathetic activity/sympathetic activity ratio include, but
are not limited to: infertility, early pregnancy loss, spontaneous
abortion, subfertility, failure of implantation, amenorrhea, luteal
insufficiency, dysmenorrhea, pelvic pain, depression, bipolar
disorder, bacterial vaginosis, obesity, multiple sclerosis, and the
like.
[0109] Representative pharmacological agents (and analogs,
derivatives and salts thereof) that may be employed in the practice
of the subject methods (e.g., to modulating at least a portion of a
subject's autonomic nervous system during at least one
predetermined menstrual cycle phase of the subject to increase the
sympathetic activity/parasympathetic activity ratio) include, but
are not limited to, one of more of the following:
[0110] beta agonists (e.g., dobutamine, metaproterenol,
terbutaline, ritodrine, albuterol, and the like);
[0111] alpha agonists (e.g., selective alpha 1-adrenergic blocking
agents such as phenylephrine, metaraminol, methoxamine; prednisone
and steroids and the like, (e.g., available under the brand names
CORATN, DELTASONE, LIQUID PRED, MEDICORTEN, ORASONE, PANASOL-S,
PREDNICEN-M, PREDNISONE INTENSOL));
[0112] indirect agents that include norepinephrine (e.g.,
ephedrine, ampthetamines, phenylpropanolamines, cyclopentamines,
tuaminoheptanes, naphazolines, tetrahydrozolines, and the
like);
[0113] epinephrine and the like;
[0114] norepinephrine and the like;
[0115] acetylcholine and the like;
[0116] sodium and the like;
[0117] calcium and the like;
[0118] angiotensin I and the like;
[0119] angiotensin II and the like;
[0120] angiotensin converting enzyme I ("ACE I") and the like;
[0121] angiotensin converting enzyme II ("ACE II") and the
like;
[0122] aldosterone and the like;
[0123] potassium channel blockers and magnesium channel blockers
(e.g., valproate (sodium valproate, valproic acid), lithium, and
the like);
[0124] cocaine and the like;
[0125] amphetamines and the like;
[0126] ephedrine and the like;
[0127] terbutaline and the like;
[0128] dopamine and the like;
[0129] doputamine and the like;
[0130] antidiuretic hormone ("ADH") (also known as vasopressin) and
the like;
[0131] oxytocin (including PITOCINE) and the like; and
[0132] THC cannabinoids.
[0133] As noted above, a combination of two or more of any of the
above noted agents or like agents may be employed.
[0134] As noted above, certain embodiments may include
administering a pharmacologically effective amount of a first
pharmacological agent and a pharmacologically effective amount of
at least a second, different pharmacological agent, e.g.,
concurrently administered, where the two may differ in one or more
of a variety of aspects, e.g., dosage, type, route of
administration, etc. For example, embodiments may include
administering a first type of pharmacological agent and at least
one other type of pharmacological agent to provide an enhanced
therapeutic effect. By "enhanced therapeutic effect" is meant that
at least the initial relief of the particular condition being
treated by the first pharmacological agent employed occurs more
quickly with a combination of the first pharmacological agent and
at least one other different pharmacological agent, as compared to
the same doses of each component given alone, or that doses of one
or all component(s) are below what would otherwise be a minimum
effective dose (a "sub-MED").
[0135] Accordingly, embodiments of the subject invention includes
treating a subject for a condition by modulating at least a portion
of the subject's autonomic nervous system by administering a first
pharmacological agent together with at least one other, different
pharmacological agent. The pharmacological agents may be
concomitantly administered as described above, i.e., they may be
given in close enough temporal proximity to allow their individual
therapeutic effects to overlap. For example, embodiments of the
subject invention may include the co-timely administration of a
first pharmacological agent and at least a second, different
pharmacological agent. By "co-timely" with respect to drug
administration is meant administration of a second pharmacological
agent for the treatment of a condition while a first
pharmacological agent is still present in a subject's system at a
therapeutically effective amount. It is to be understood that in
some instances this will require sequential administration.
Alternatively, multiple routes of administration may be employed,
e.g., intravenous or subcutaneous injection of a first
pharmacological agent may be combined with oral administration of a
second, different pharmacological agent.
[0136] Embodiments may also include pharmaceutical compositions in
unit dosage forms that are useful in treating conditions by
modulating at least a portion of a subject's autonomic nervous
system and which contain a first pharmacological agent and at least
a second, different type of pharmacological agent. In other words,
a single drug administration entity or single unit dosage form may
include two or more pharmacological agents. For example, a single
tablet, solution, capsule, dragee, trocheem suppository, syringe,
transdermal patch, and the like, combining two or more
pharmacological agents would be a unit dosage form. The therapeutic
agents present in a unit dosage form may be present in amounts such
that, upon administration of one or more unit doses of the
composition, a subject may experience a longer lasting efficacy
than with the administration of either agent alone. Such
compositions may be included as part of a therapeutic package in
which one or more unit doses are placed in a finished
pharmaceutical container. Labeling may be included to provide
directions for using the composition in the treatment of a
condition by modulating at least a portion of a subject's autonomic
nervous system. The actual amounts of each agent in such
compositions will vary according to the specific compositions being
utilized, the particular compositions formulated, the mode of
application, the particular route of administration, and the like.
Dosages for a given subject can be determined using conventional
considerations, e.g., by customary comparison of the differential
activities of the subject compositions and of a known agent, or by
means of an appropriate, conventional pharmacological protocol. A
person of ordinary skill in the art will be able without undue
experimentation, having regard to that skill and this disclosure,
to determine a therapeutically effective amount of a particular
pharmacological agent for practice of this invention. For example,
embodiments may include dosages conventionally administered for the
particular pharmacological agents employed, where such dosages are
known in the art.
[0137] Accordingly, in practicing the subject methods, an effective
amount of a pharmacological agent is administered to a subject
during at least one predetermined phase of the subject's menstrual
cycle to treat a condition affecting the subject. As noted above,
the particular dosage, mode of administration, treatment times,
etc., will vary according to a variety of factors, but will
generally fall within the ranges conventionally administered for
the particular pharmacological agent employed. As noted above, the
dose of pharmacological agent will be different for different
subject, condition(s) treated, etc. Embodiments include determining
the particular condition experienced by the subject and determining
the appropriate pharmacological treatment regimen including dosage
of particular agent(s) required to modulate at least a portion of
the subject's autonomic nervous system in a manner effective to
treat that subject for the particular condition.
[0138] The following descriptions of exemplary embodiments describe
average doses and may vary. Such descriptions are for exemplary
purposes only and are in no way intended to limit the scope of the
invention. For example, the number of capsules or tablets,
teaspoonfuls of solution, and the like, administered depends at
least in part on the strength of the particular pharmacological
agent administered. Furthermore, the number of doses administered
each day, the time allowed between doses, and the length of time a
subject takes the medicine, etc., depend on the condition being
treated, i.e., the condition for which a subject is taking the
pharmacological agent. Exemplary treatment protocols are now
provided. The dose of pharmacological agent may be different for
different subject, condition treated, etc. The following
embodiments describe average doses and may vary. Such are for
exemplary purposes only and are in no way intended to limit the
scope of the invention. For example, the number of capsules or
tablets, teaspoonfuls of solution, and the like, administered
depends at least in part on the strength of the particular
beta-blocker administered. Furthermore, the number of doses
administered each day, the time allowed between doses, and the
length of time a subject takes the medicine, etc., depend on the
condition being treated, etc.
[0139] Beta-Blocker
[0140] As noted above, embodiments may include administering an
effective amount of a beta-blocker to treat a condition. Such
embodiments may include administering adult oral dosage forms
(capsules and tablets) of acebutolol ranging from about 200
milligrams (mgs.) to about 1200 mgs., e.g., from about 200 mgs. to
about 800 mgs. Such oral dosages may be administered as a single
dose one time a day, two times a day, or divided into two daily
doses for an adult, etc.
[0141] Embodiments may include administering atenolol to treat a
condition. Such embodiments may include administering adult oral
dosage forms (e.g., tablets) of atenolol (e.g., available under the
brand name TENORMIN) that range from about 25 mgs. to about 100
mgs. once a day. For example, administration may include about 50
mgs. once a day, or about 100 mgs. of atenolol once a day, or about
50 mgs. atenolol two times a day, e.g., for about six to about nine
days. Embodiments that include administering atenolol in adult
injection dosage forms may include about 5 mgs. given over 5
minutes, repeated ten minutes later. Atenolol may also be
administered intravenously in certain embodiments.
[0142] Embodiments may include administering adult oral dosage
forms (e.g., tablets) of betaxolol to treat a condition. Such
embodiments may include administering about 10 mgs. of betaxolol as
an adult dosage form once a day.
[0143] Embodiments may include administering adult oral dosage
forms (e.g., tablets) of bisoprolol (e.g., available under the
brand name ZEBETA) to treat a condition. Such embodiments may
include administering about 5 mgs. to about 10 mgs. of bisoprolol
as an adult oral dosage forms (e.g., tablets) once a day.
[0144] Embodiments may include administering adult oral dosage
forms (e.g., tablets) of carteolol to treat a condition. Adult oral
dosage forms (e.g., tablets) of carteolol may include about 0.5
mgs. to about 10 mgs. administered once a day.
[0145] Embodiments may include administering esmolol to treat a
condition via IV. esmolol may be administered via iv as follows:
loading dose of about 20-30 mg ivp over 1 minute using a 10 mg/ml
10 ml vial and maintenance dose of about 2 To 12 mg/min as titrated
to patient response and maintenance infusions may be increased by
about 2 to 3 mg/min at 10 minute intervals until the desired
response is achieved.
[0146] Embodiments may include administering adult oral dosage
forms (e.g., tablets) of labetalol to treat a condition. Adult oral
dosage forms (e.g., tablets) of labetalol may include about 100
mgs. to about 400 mgs. two times a day. Adult injection dosage
forms may include about 20 mgs., e.g., injected slowly over about
two minutes with additional injections of about 40 mgs. and about
80 mgs. given about every ten minutes if needed, up to a total of
about 300 mgs., instead as an infusion at a rate of about 2 mgs.
per minute to a total dose of about 50 mgs. to about 300 mgs.
[0147] Embodiments may include administering adult oral dosage
forms (e.g., tablets) of metaprolol to treat a condition. Adult
oral dosage forms (e.g., tablets) of metoprolol may include about
100 mgs. to 450 mgs. a day, taken as a single dose or in divided
doses. For example, embodiments may include administering about 50
mgs. about every six hours for about 24 hours or more and then
about 100 mgs. two times a day for about 1 to about 3 months or
more, e.g., from about 1 to about 3 years or more. Embodiments may
include administering long-acting adult oral dosage forms
(extended-release tablets) that may include up to about 400 mgs.
once a day. Adult injection dosage forms may include about 5 mgs.
every two minutes for about three doses.
[0148] Embodiments may include administering adult oral dosage
forms (e.g., tablets) of nadolol (e.g., available under the brand
name CORGARD) to treat a condition. Embodiments ay include
administering adult oral dosage forms (e.g., tablets) of nadolol
that may include about 40 mgs. to about 320 mgs. once a day.
[0149] Embodiments may include administering adult oral dosage
forms (e.g., tablets) of oxprenolol to treat a condition.
Embodiments may include administering adult oral dosage forms
(e.g., tablets) of oxprenolol (short-acting) that may include about
20 mgs. three times a day. Embodiments may include administering
adult long-acting oral dosage forms (extended-release tablets) that
may include about 120 mgs. to about 320 mgs. once a day.
[0150] Embodiments may include administering adult oral dosage
forms (e.g., tablets) of pentbutolol to treat a condition.
Embodiments may include administering adult oral dosage forms
(e.g., tablets) of penbutolol that may include about 20 mgs. once a
day.
[0151] Embodiments may include administering adult oral dosage
forms (e.g., tablets) of pindolol to treat a condition. Embodiments
may include administering adult oral dosage forms (e.g., tablets)
of pindolol that may include about 5 mgs. two times a day-up to
about 60 mgs. a day.
[0152] Embodiments may include administering adult oral dosage
forms (e.g., tablets) of propranolol to treat a condition.
Embodiments may include administering adult oral dosage forms
(e.g., tablets) of propranolol that may include, for regular
(short-acting) oral dosage forms (tablets and oral solution), about
80 mgs. to about 320 mgs. a day taken in two, three, or four
divided doses up to about 640 mgs./day in certain embodiments.
[0153] Embodiments may also include about 10 mgs. to about 40 mgs.
three or four times a day for an adult and about 500 micrograms
(0.5 mgs.) to about 4 mgs. per kilogram of body weight a day taken
in divided doses for children. Embodiments may include
administering long-acting adult oral dosage forms (extended-release
capsules) that may include about 80 mgs. to about 320 mgs. once a
day up to about 640 mgs. once a day. Embodiments may include
administering adult injection dosage forms that range from about 1
mg. to about 3 mgs. given at a rate not greater than about 1 mg per
minute. The dose may be repeated after about two minutes and again
after about four hours if needed. Children may be administered
about 10 mgs. to about 100 micrograms (0.01 to 0.1 mg) per kilogram
of body weight given intravenously about every six to eight
hours.
[0154] Embodiments may include administering adult oral dosage
forms (e.g., tablets) of sotalol to treat a condition. Embodiments
may include administering adult oral dosage forms (e.g., tablets)
of sotalol that may include about 80 mgs. two times a day up to
about 320 mgs. per day taken in two or three divided doses.
[0155] Embodiments may include administering adult oral dosage
forms (e.g., tablets) of timolol (e.g., available under the brand
name BLOCADREN) to treat a condition. Embodiments may include
administering adult oral dosage forms' (e.g., tablets) of timolol
that may include about 10 mgs. two times a day up to about 60 mgs.
per day taken as a single dose or in divided doses. For example, up
to 30 mgs. once a day or in divided doses.
[0156] Aldosterone Antagonists
[0157] Embodiments may include administering an aldosterone
antagonist to treat a condition in accordance with the subject
invention. For example, embodiments may include administering adult
oral dosage forms (e.g., tablets) of spironolactone that may range
from about 50 mgs. to about 400 mgs. daily. Embodiments may include
administering adult oral dosage forms (e.g., tablets) of eplerenone
that may range from about 50 mgs. to about 100 mgs. daily.
[0158] Angiotensin II Receptor Blockades
[0159] Embodiments may include administering an angiotensin II
receptor blockade to treat a condition in accordance with the
subject invention. Such embodiments may include administering an
adult oral dosage form of candesartan (e.g., ATACAND) to a subject
to treat a condition. Exemplary treatment protocols may include
administering about 2 mgs. to about 32 mgs. of candesarten daily
(i.e., for a 24 hour interval), e.g., about 16 mgs. daily.
Embodiments may include administering adult oral dosage forms of
irbersarten (e.g., AVAPRO) to a subject to treat a condition.
Exemplary treatment protocols may include administering about 75
mgs. to about 100 mgs. or more, e.g., up to about 300 mgs., of
irbersarten daily. Embodiments may include administering adult oral
dosage forms of losartan (e.g., COZAAR) to a subject to treat a
condition. Exemplary treatment protocols may include administering
about 25 mgs. to about 50 mgs. or more, e.g., 100 milligrams, of
losarten orally once daily or twice daily. Embodiments may include
administering adult oral dosage forms of telmisartin (e.g.,
MICARDIS) to a subject to treat a condition. Exemplary treatment
protocols may include administering about 20 mgs. to about 80 mgs.
of telmisartin daily. Embodiments may include administering adult
oral dosage forms of valsartan (e.g., DIOVAN) to a subject to treat
a condition. Exemplary treatment protocols may include
administering about 20 mgs. to about 80 mgs. of valsarten once
daily. Embodiments may include administering adult oral dosage
forms of eprosarten (e.g., TEVETAN) to a subject to treat a
condition. Exemplary treatment protocols may include administering
about 400 mgs. to about 800 mgs. of eprosarten once daily or twice
daily.
[0160] Angiotensin Converting Enzyme Inhibitors (ACE
Inhibitors)
[0161] Embodiments may include administering an ACE inhibitor to a
subject to treat a condition in accordance with the subject
invention. Such may include administering adult oral dosage forms
of captropil (e.g., CAPOTEN) to a subject to treat a condition.
Exemplary treatment protocols may include administering about 12.5
mgs. to about 50 mgs. of captropil over about 8 to about 12 hours.
Embodiments may include administering adult oral dosage forms of
enalapril (e.g., VASOTEC) to a subject to treat a condition.
Exemplary treatment protocols may include administering about 5
mgs. to about 20 mgs. of enalapril once daily. Embodiments may
include administering adult oral dosage forms of fosinopril (e.g.,
MONOPRIL) to a subject to treat a condition. Exemplary treatment
protocols may include administering about 10 mgs. to about 80 mgs.,
e.g., about 20 mgs. to about 40 mgs., of fosinopril daily.
Embodiments may include administering adult oral dosage forms of
lisinopril (e.g., PRINIVIL) to a subject to treat a condition.
Exemplary treatment protocols may include administering about 10
mgs. to about 80 mgs., e.g., about 20 mgs. to about 40 mgs., of
lisinopril daily. Embodiments may include administering adult oral
dosage forms of moexipril (e.g., UNIVASC) to a subject to treat a
condition. Exemplary treatment protocols may include administering
about 3.75 mgs. to about 15 mgs., e.g., 7.5 mgs. of moexipril
daily. Embodiments may include administering-adult oral dosage
forms of quinaapril (e.g., ACCUPRIL) to a subject to treat a
condition. Exemplary treatment protocols may include administering
about 10 mgs. to about 80 mgs, e.g., about 20 mgs., of quinapril
once daily. Embodiments may include administering adult oral dosage
forms of ramipril (e.g., ALTACE) to a subject to treat a condition.
Exemplary treatment protocols may include administering about 2.5
mgs. to about 20 mgs. of ramipril daily. Embodiments may include
administering adult oral dosage forms of trandolapril (e.g., MAVIK)
to a subject to treat a condition. Exemplary treatment protocols
may include administering about 1 mg. to about 4 mgs., e.g., about
2 mgs., of trandolapril daily.
[0162] Statins
[0163] Embodiments may include administering adult oral dosage
forms (e.g., tablets) of a statin to treat a condition in
accordance with the subject invention. For example, embodiments may
include administering adult oral dosage forms (e.g., tablets) of
atorvastatin (e.g., available under the brand name Lipitor) that
may range from about 0.5 mgs. to about 80 mgs. daily. Embodiments
may include administering adult oral dosage forms (e.g., tablets)
of cerivastatin (e.g., available under the brand name Baycol) that
may range from about 0.2 mgs. to about 0.3 mgs. daily. Embodiments
may include administering adult oral dosage forms (e.g., tablets)
of fluvastatin (e.g., available under the brand name lescoL) that
may range from about 20 mgs. to about 80 mgs. daily. Embodiments
may include administering adult oral dosage forms (e.g., tablets)
of lovastatin (e.g., available under the brand name Mevacor) that
may range from about 10 mgs. to about 80 mgs. daily. Embodiments
may include administering adult oral dosage forms (e.g., tablets)
of prevastatin (e.g., available under the brand name Pravachol)
that may range from about 10 mgs. to about 40 mgs. daily.
Embodiments may include administering adult oral dosage forms
(e.g., tablets) of simvastatin (e.g., available under the brand
name Zocor) that may range from about 5 mgs. to about 40 mgs.
daily.
[0164] Triglycerides Lowering Drugs
[0165] Embodiments may include administering adult oral dosage
forms (e.g., tablets) of a triglycerides lowering drug to treat a
condition in accordance with the subject invention. For example,
embodiments may include administering adult oral dosage forms
(e.g., tablets) of fenofibrate (e.g., available under the brand
name TRICOR) that may range from about 65 mgs. to about 200 mgs.
daily. Embodiments may include administering adult oral dosage
forms (e.g., tablets) of genfibrozil (e.g., available under the
brand name LOPID) that may range from about 1200 mgs. total given
as about 600 mgs. two times per day (e.g., every 12 hours).
[0166] Niacin
[0167] Embodiments may include administering niacin to treat a
condition in accordance with the subject invention. For example,
dosing may include administering by mouth about 2 mgs. to about 6
mgs. total, e.g., as given as about 1 mg. to about 2 mgs. twice per
day or three times per day.
[0168] Diabetes Agents
[0169] Embodiments may include administering a diabetes drug to
treat a condition in accordance with the subject invention. For
example, embodiments may include administering adult oral dosage
forms (e.g., tablets) of acarbose (e.g., available under the brand
name PRECOSE) that may range from about 25 mgs. to about 300 mgs.
for an eight hour interval. Embodiments may include administering
adult oral dosage forms (e.g., tablets) of glimepiride (e.g.,
available under the brand name AMARYL) that may range from about 1
mg. to about 2 mgs. daily. Embodiments may include administering
adult oral dosage forms (e.g., tablets) of glyburide (e.g.,
available under the brand names MICRONASE, DIABETA) that may range
from about 1.5 mgs. to about 5 mgs. daily. Embodiments may include
administering adult oral dosage forms (e.g., tablets) of metformin
(e.g., available under the brand name GLUCOPHASGE) that may range
from about 500 mgs. to about 850 mgs. for an 8 to 24 hour interval.
Embodiments may include administering adult oral dosage forms
(e.g., tablets) of miglitol (e.g., available under the brand name
GLYCET) that may range from about 25 mgs. to about 100 mgs. for an
8 hour interval. Embodiments may include administering adult oral
dosage forms (e.g., tablets) of pioglitazone (e.g., available under
the brand name ACTOS) that may range from about 15 mgs. to about 40
mgs. daily. Embodiments may include administering adult oral dosage
forms (e.g., tablets) of repaglinide (e.g., available under the
brand name PRANDIN) that may range from about 0.5 mgs. to about 4.0
mgs. 3 times per day. Embodiments may include administering adult
oral dosage forms (e.g., tablets) of rosiglitazone (e.g., available
under the brand name AVANDIA) that may range from about 4 mgs. to
about 8 mgs. daily.
[0170] Immunomodulators
[0171] Embodiments may include administering an immunomodulator to
treat a condition in accordance with the subject invention. For
example, embodiments may include administering interferon beta-1B
(e.g., available under the brand name BETASERON), where dosing may
include administering about 0.25 mg. subcutaneously every other
day. Embodiments may also include administering interferon alfa-2A
(e.g., available under the brand name ROFERON-A), where dosing may
include administering about 3 million units to about 36 million
units per day IM/SC to about 3 million units to about 36 million
units 3 times per week (3 million units (1 ml); 6 million units/ml
(3 ml); 0 million units/ml (0.9 ml), 3 ml); 36 million units/ml (1
ml)). Embodiments may also include administering interferon alfa-2B
(e.g., available under the brand name INTRON-A), where dosing may
include administering about 1 to about 30 million units/M2 IM/SC
three times per week (3 million units (0.5 ml); 5 million units
(0.5 ml); 10 million units (1 ml); 25 million units powder for
injection: 18 million units and 50 million units). Embodiments may
also include administering interferon alfa-2B and ribavirin
combination pack (e.g., available under the brand name REBETRON),
where dosing may include administering INTRON A at about 3 million
units subcutaneously three times per week and about 500 mgs. to
about 600 mgs. of ribavirin twice daily. Embodiments may also
include administering interferon alfa-N3 (e.g., available under the
brand name ALFERON N), where dosing may include administering about
250,000 units (0.05 ml) twice weekly (5 million units (1 ml)).
Embodiments may also include administering interferon beta-1A
(e.g., available under the brand name AVONEX), where dosing may
include administering about 30 micrograms IM once weekly
(reconstitute with 1.1 ml of diluent).
[0172] Nicotine
[0173] Embodiments may include administering nicotine to treat a
condition in accordance with the subject invention. For example,
embodiments may include administering nicotine in the form of
chewing gum, e.g., from about 2 mgs. to about 4 mgs. dosage
strength). Embodiments may include administering nicotine as an
inhalant (e.g., about 4 mgs. per cartridge), nasal spray (e.g.,
each actuation of nicotine nasal spray may deliver about 0.5 mgs.
nicotine), or as a transdermal system. For example, dosing
schedules (mg/day) of nicotine transdermal systems may include a
patch duration of about 24 hours and dosing schedule of about 7
mgs. to about 22 mgs. for about 2 to about 6 weeks; a patch
duration of about 16 hours and a dosing schedule of about 15 mgs.
for about 4 to about 12 weeks. Each dosing schedule may be followed
by a reduced dosing schedule.
[0174] Sympathomimetics
[0175] Embodiments may include administering a sympathomimetic to
treat a condition in accordance with the subject invention. For
example, embodiments may include administering trimethaphan via an
I.V., e.g., about 0.1 mgs. to about 1.0 mgs./minute, up to about 15
mgs. per minute. Embodiments may include administering by mouth
clondine at about 0.1 mgs. to about 2.4 mgs. daily. Embodiments may
include administering by mouth reserpine at about 10 mgs. to about
20 mgs. daily. Embodiments may include administering by mouth
guanethidine at about 10 mgs. to about 50 mgs. daily.
[0176] Antihistamines
[0177] Embodiments may include administering adult oral dosage
forms of an antihistamine to treat a condition in accordance with
the subject invention. For example, embodiments may include
administering adult oral-dosage forms (e.g., tablets) of BENADRYL
at about 25 mgs. to about 50 mgs. three to four times daily.
Nighttime dosage may include about 50 mgs. at bedtime.
[0178] Cholinergics
[0179] Embodiments may include administering a cholinergic to treat
a condition in accordance with the subject invention. For example,
embodiments may include administering bethanechol by mouth at about
10 mgs. to about 50 mgs. four times per day or three times per day.
Embodiments may include administering methacoline as an inhaled
aerosol at about 0.02 to about 25.0 mg/mL. Embodiments may include
orally administering about 30 mgs. cevimeline three times per
day.
[0180] Acetylcholinesterase Inhibitors
[0181] Embodiments may include administering an
acetylcholinesterase inhibitor to treat a condition in accordance
with the subject invention. For example, embodiments may include
administering about 0.1 ml. to about 0.8 ml via an I.V. edrophonium
or about 1 ml. of a 1:20000 solution (0.5 mg.) of neostigmine
intramuscularly (IM) or subcutaneously (SC). Embodiments may also
include orally administering about 5 mg of donepezil to about 10
mgs./day. Embodiments may also include administering about 1 to
about 2 g of pralidoxime, e.g., as an infusion in 100 mL of saline,
over about a 15 to 30 minute period, via I.V. About 16 mgs to about
32 mgs. of galanthamine may be administered orally twice per day.
Physostigmine may be administered intravenously or intramuscularly
e.g., about 0.5 mgs. to about 2 mgs. Rivastigmine may be orally
administered, e.g., about 3 mgs. to about 6 mgs. two times per
day.
[0182] Magnesium and Magnesium Sulfates
[0183] Embodiments may include administering magnesium to treat a
condition in accordance with the subject invention. For example, a
dose may include administering about 0.3 mEq/kg to about 1.0 meq
mg/kg daily via an I.V.
[0184] Calcium Channel Blockers:
[0185] Embodiments may include administering a calcium channel
blocker to treat a condition in accordance with the subject
invention. Embodiments may include orally administering amlodipine
besylate (e.g., available under the brand name NORVASC), e.g.,
about 5 mgs. to about 20 mgs. daily; diltiazem hydrochloride (e.g.,
available under the brand names CARDIZEM CD, CARDIZEM SR, DILACOR
XR, TIAZAC) at about 30 mgs. to about 360 mgs. four times per day
(for example 180 mgs. to about 360 mgs. divided into four times per
day); felodipine plendil at about 2.5 mgs. to about 10 mgs. daily;
isradipine (e.g., available under the brand names DYNACIRC,
DYNACIRC CR) at about 2.5 mgs. daily; nicardipine (e.g., available
under the brand name CARDENE SR) at about 20 mgs. to about 40 mgs.
three times per day; nifedipine (e.g., available under the brand
names ADALAT CC, PROCARDIA XL) at about 10 mgs. three times per
day; nisoldipine (e.g., available under the brand name SULAR) at
about 10 mgs. to about 20 mgs. daily; and verapamil hydrochloride
(e.g., available under the brand names CALAN SR, COVERA HS, ISOPTIN
SR, VERELAN) at about 40 mgs. three times per day.
[0186] Muscarinics
[0187] Embodiments may include administering a muscarinic to treat
a condition in accordance with the subject invention. For example,
embodiments may include administering about 5 mgs. of pilocarpine
by mouth to a subject four times per day, up to about 30
mgs./day.
[0188] Sodium Channel Blockers
[0189] Embodiments may include administering a sodium channel
blocker to treat a condition in accordance with the subject
invention. For example, embodiments may include administering about
150 mgs. of propafenone by mouth every 8 hours (450 mgs./day) up to
about 300 mgs. every 8 hours (90 mgs./day). Embodiments may also
include administering about 50 mgs. to about 100 mgs. of flecainide
by mouth about every 12 hours up to about 400 mgs./day. Embodiments
may also include administering about 400 mgs. to about 2400 mgs. of
tocainide by mouth about every 8 hours. Embodiments may also
include administering about 100 mgs. to about 200 mgs. of phenytoin
by mouth three times per day. Embodiments may also include
administering about 10-30 mgs of about 1% to about 2% lidocaine IM
(the maximum individual dosage typically should not exceed about
4.5 mg/kg of body weight and generally the maximum total dose
should not exceed about 300 mgs.). Embodiments may also include
administering about 150 mgs. to about 300 mgs. of dispoyramide by
mouth about every 6 hours to about every 12 hours, up to about 1600
mgs. per day. Embodiments may also include administering quinidine
(e.g., available under the brand name QUINAGLUTE) at about two
tablets (648 mgs.; 403 mgs. of quinidine base) of QUINAGLUTE by
mouth about every 8 hours.
[0190] Glucocorticoid Receptor Blockers
[0191] Embodiments may include administering a glucocorticoid
receptor blocker to treat a condition in accordance with the
subject invention. For example, embodiments may include
administering mifepristone my mouth at about 400 micrograms to
about 600 mgs.
[0192] Peripheral Andrenergic Inhibitors
[0193] Embodiments may include administering a peripheral
andrenergic inhibitor to treat a condition in accordance with the
subject invention. For example, embodiments may include
administering about 5 mgs. to about 75 mgs. of guanadrel (e.g.,
available under the brand name HYLOREL) by mouth e.g., about 5 mgs.
two times per day, about 20 to about 75 mgs. per day in divided
doses. Embodiments may also include administering about 10 mgs. to
about 50 mgs. or more per day of guanethidine monosulfate (e.g.,
available under the brand name ISMELIN) by mouth. Embodiments may
also include administering about 0.05 to about 1.5 mgs. once per
day by mouth of reserpine (e.g., available under the brand names
SERPASIL, MECAMYLAMINE, HEXEMETHONIUM). Embodiments may also
include administering about 2.5 mgs. of mecamylamine two times per
day by mouth.
[0194] Blood Vessel Dilators
[0195] Embodiments may include administering a blood vessel dilator
to treat a condition in accordance with the subject invention. For
example, embodiments may include administering about 10 mgs. to
about 50 mgs. of hydralazine hydrocholoride (e.g., available under
the brand name APRESOLINE) by mouth four times a day. Embodiments
may also include administering about 5 mgs. to about 40 mgs. of
minoxidil (e.g., e.g., available under the brand name LONITEN) by
mouth once per day.
[0196] Central Agonists
[0197] Embodiments may include administering a central agonist to
treat a condition in accordance with the subject invention. For
example, embodiments may include administering about 250 mgs. of
alpha methyldopa (e.g., available under the brand name ALDOMET) by
mouth three times per day or about 500 mgs. to about 2 grams per
day divided into 2 to 4 doses. Embodiments may also include
administering about 0.1 mgs. to about 0.6 mgs. of clonidine
hydrochloride (e.g., available under the brand name CATAPRES) by
mouth once per day. Embodiments may also include administering
about 4 mgs. of guanabenz acetate (e.g., available under the brand
name WYTENSIN) by mouth two times per day (up to about 32 mgs. per
day). Embodiments may also include administering about 1 mg. to
about 3 mgs. of guanfacine hydrochloride (e.g., available under the
brand name TENEX) by mouth once per day.
[0198] Combined Alpha and Beta-Blockers
[0199] Embodiments may include administering a combined alpha and
beta-blocker to treat a condition in accordance with the subject
invention. For example, embodiments may include administering about
100 mgs. two times per day of labetolol hydrochloride (e.g.,
available under the brand names NORMODYNE, TRANDATE) by mouth up to
about 400 mgs. per day. Embodiments may also include administering
about 3.125 mgs. two times per day of carvedilol (e.g., available
under the brand name COREG) by mouth up to about 50 mgs. per
day.
[0200] Alpha Blockers
[0201] Embodiments may include administering an alpha and
beta-blocker to treat a condition in accordance with the subject
invention. For example, embodiments may include administering about
1 mg once per day by mouth of doxazosin mesylate (e.g., available
under the brand name CARDURA) up to about 16 mgs. per day.
Embodiments may also include administering about 0.5 mgs. by mouth
of prazosin hydrochloride (e.g., available under the brand name
MINIPRESS) two or three times per day (and may include about 6 to
about 15 mgs. per day divided into 2 or 3 doses. Embodiments may
also include administering about 1 mg. of terazosin hydrochloride
(e.g., available under the brand name HYTRIN) by mouth once per
day, up to about 5 mgs. per day.
[0202] Combination Diuretics
[0203] Embodiments may include administering a combined diurentic
to treat a condition in accordance with the subject invention. For
example, embodiments may include administering about 1-2 tablets of
amiloride hydrochloride+hydrochlorothiazide (e.g., available under
the brand name MODURETIC) once per day for tablets containing 5
mgs. of anhydrous amiloride HCl and 50 mgs. of
hydrochlorothiazide). Embodiments may also include administering
about 25 mgs. to about 50 mgs. once per day by mouth of
spironolactone+hydrochlorothiazide (e.g., available under the brand
name ALDACTAZIDE). Embodiments may also include administering about
1 to 2 tablets one per day of triamterene+hydrochlorothiazide
(e.g., available under the brand names DYAZIDE, MAXZIDE) for
tablets containing 25 mgs. hydrochlorothiazide and 37.5 mgs.
triaterene.
[0204] Potassium Sparing Diuretics
[0205] Embodiments may include administering a potassium sparing
diuretic to treat a condition in accordance with the subject
invention. For example, embodiments may include administering about
5 mgs. to about 20 mgs. by mouth once per day of amiloride
hydrochloride (e.g., available under the brand name MIDAMAR).
Embodiments may also include administering about 25 mgs. to about
200 mgs. once per day by mouth of spironolactone (e.g., available
under the brand name ALDACTONE). Embodiments may also include
administering about 1 to 2 tablets once per day of triamterene
(e.g., available under the brand name DYRENIUM)) for tablets
containing 25 mgs. hydrochlorothiazide and 37.5 mgs.
triaterene.
[0206] Nitrates
[0207] Embodiments may include administering a nitrate to treat a
condition in accordance with the subject invention. For example,
embodiments may include administering isosorbide dinitrate (e.g.,
available under the brand name ISODIL) at about 50 to about 40 mgs.
orally four times per day or 40 mgs. sustained release orally every
8 to 12 hours. Embodiments may also include administering
isosorbide mononitrate (e.g., available under the brand names ISMO,
MONOKET) at about 20 mgs. orally two times per day and/or may
include administering extended release initially about 30 mgs. to
about 60 mgs. orally once per day. Maximum of about 240 mgs./day.
Embodiments may also include administering nitroglycerine ointment,
e.g., about 0.5 inches q8 h and/or about 0.5 to about 2 inches
every 4 to 6 hours, maximum 4 inches every 4 to 6 hours (0.5 inches
is about 7.5 mgs.). Embodiments may also include administering
nitrobid, e.g., orally about 2.5 mgs. to about 9 mgs. 2 to 4 times
per day. Embodiments may also include administering a nitroglycerin
patch, e.g., one patch each day applied and removed at bedtime.
[0208] Cyclic Nucleotide Monophosphodiesterase ("PDE")
Inhibitors
[0209] Embodiments may include administering a cyclic nucleotide
monophosphodiesterase ("PDE") inhibitor to treat a condition in
accordance with the subject invention. For example, embodiments may
include administering about 5 mgs. to about 20 mgs. once per day of
vardenafil (e.g., available under the brand name LEVITRA) by mouth.
Embodiments may also include administering about 10 mgs. to about
20 mgs. of tadalafil (e.g., available under the brand name CIALIS)
orally once per day. Embodiments may also include administering
about 25 mgs. to about 100 mgs. of sildenafil (e.g., available
under the brand name VIAGRA) orally once per day.
[0210] Alcohols
[0211] Embodiments may include administering an alcohol to treat a
condition in accordance with the subject invention. For example,
embodiments may include administering about 200 mgs. orally four
times per day or 0.5 to about 1.0 ml per interspace for
subarachnoid injections.
[0212] Vasopressin Inhibitors
[0213] Embodiments may include administering a vasopressin
inhibitor to treat a condition in accordance with the subject
invention. For example, embodiments may include administering about
up to about 6.75 mg administered via IV of atosiban, e.g., 300
micrograms/min to about 100 micrograms/min IV.
[0214] Oxytocin Inhibitors
[0215] Embodiments may include administering an oxytoxin inhibitor
to treat a condition in accordance with the subject invention. For
example, embodiments may include administering about 0.25 to about
IM of terbutaline, typically not more than about 0.5 mgs. within a
four hour period. Embodiments may also include administering about
50 micrograms per minute IV of ritodrine, maximum dosage of about
300 micrograms per minute.
[0216] Glucagon Like Peptide 1
[0217] Embodiments may include administering glucagon like peptide
1 to treat a condition in accordance with the subject invention.
For example, embodiments may include administering by I.V. about
200 .mu.g/kg two times per day. Embodiments may also include
administering by SQ infusion about 1.25 to about 20 .mu.g/kg.
[0218] Relaxin Hormone
[0219] Embodiments may include administering a relaxin hormone to
treat a condition in accordance with the subject invention. For
example, embodiments may include administering 1 to 2 tablets of
relaxin by mouth three times per day for tablets of
valerian/ayrvedic passion flower blend (550 mgs.)
[0220] Renin Inhibitors
[0221] Embodiments may include administering a rennin inhibitor to
treat a condition in accordance with the subject invention. For
example, embodiments may include administering Aliskiren by mouth
at about 2 mgs to about 10 mgs./day.
[0222] Estrogen and Analogues (e.g., Estradiols) and
Metabolites
[0223] Embodiments may include administering estrogen and estrogen
analogues and estrogen metabolites to treat a condition in
accordance with the subject invention. For example, embodiments may
include administering about 10 mgs. three times per day.
[0224] Gonadotropin-Releasing Hormone Inhibitors
[0225] Embodiments may include administering a
gonadotropin-releasing hormone inhibitor to treat a condition in
accordance with the subject invention. For example, embodiments may
include administering leuprolide acetate at about 65 mgs. SQ
(subcutaneous) implant.
[0226] Vesicular Monoamine Transport (VMAT) Inhibitors
[0227] Embodiments may include administering a VMAT inhibitor to
treat a condition in accordance with the subject invention. For
example, embodiments may include administering tetrabenazine by
mouth at about 150 mgs. to about 200 mgs. once per day. Embodiments
may also include administering reserpine at about 50 micrograms to
about 500 micrograms one time per day.
[0228] Melatonin
[0229] Embodiments may include administering melatonin to treat a
condition in accordance with the subject invention. For example,
embodiments may include administering melatonin by mouth at about
0.5 mgs. to about 3.0 mgs. once per day.
[0230] Testosterone Inhibitors
[0231] Embodiments may include administering a testosterone
inhibitor to treat a condition in accordance with the subject
invention. For example, embodiments may include administering
spironolactone by mouth at about 100 mgs. to about 300 mgs. in
divided doses two times per day. Embodiments may include
administering cyproterone acetate by mouth at about 100 mgs. to
about 150 mgs. once per day.
[0232] Dipeptidyl Peptidase (DP) IV Inhibitors (DP4 Inhibitors)
[0233] Embodiments may include administering a DP4 inhibitor to
treat a condition in accordance with the subject invention. For
example, embodiments may include administering LAF237 by mouth at
about 25 mgs. to about 200 mgs. per day.
[0234] Anti-Coagulants
[0235] Embodiments may include administering an anti-coagulant to
treat a condition in accordance with the subject invention. For
example, embodiments may include administering about 0.25 mg/kg
intravensou bolus of abciximab and/or a continuous intravenous
infusion of about 0.125 mg/kg/min (to a maximum of about 10 mg/min)
for a period of time, e.g., 12 hours. Embodiments may include
administering dipridamole (e.g., AGGRENOX or the like) orally,
e.g., one capsule twice daily. Embodiments may include
administering anagrlide (e.g., AGRILYN or the like) orally, e.g.,
initially 0.5 mg orally four times daily or 1 mg orally twice daily
or lowest effective dose- to a maximum 10 mg/day. Embodiments may
include administering clopiogrel (e.g., PLAVIX or the like) at 75
mg orally once daily. Embodiments may include administering
dipridamole (e.g., PERSANTINE or the like) at 75 to 100 mg orally
four times daily. Embodiments may include administering
eptifabatide (e.g., INTEGRILIN or the like) via IV at 0.5
mcg/kg/min to 180 mcg/kg or 135 mcg/kg and/or (e.g., followed by)
0.5 mcg/kg/min.times.20-24 hours. For example IV bolus of 180
mcg/kg over 1-2 minutes followed by 2 mcg/kg/min (maximum 15 mg/hr)
up to 72 hours. Embodiments may include administering ticlopidine
(e.g., TICLID or the like) at 250 mg orally twice daily.
Embodiments may include administering tirofibam (e.g., AGGRASTAT or
the like) at 0.4 mcg/kg/min to 0.1 mcg/kg/min. Embodiments may
include administering ardeparin (e.g., NORMIFLO or the like) at 50
units SC every 12 hours. Embodiments may include administering
dalteparin (e.g., FRAGMIN or the like) at 2500 units to 5000 units
SC one daily or 120 units/kg to about 10,000 SC every 12 hours.
Embodiments may include administering enoxaparin (e.g., LOVENOX or
the like) at 30-40 mg SC once daily. Embodiments may include
administering lepiudin (e.g., REFLUDAN or the like) at 0.4 mg/kg
(max weight of 110 kg) over a 15-20 seconds followed by does of
0.15 mg/kg/hr (max weight of 110 kg).times.2-10 days as needed.
Embodiments may include administering alteplase (e.g., ACTIVASE),
t-PA or the like) at 15 mg to 35 mg via IV, e.g., 15 mg via IV
bolus followed by 30-35 mg via N over about 60 minutes. Embodiments
may include administering reteplase (e.g., RETEVASE or the like) at
10.8 units IV over 2 minutes repeated in 30 minutes. Embodiments
may include administering streptokinase at 1.5 million units N over
60 minutes. Embodiments may include administering aminocaproic acid
(e.g., AMICAR or the like) at 4 to 5 grams orally or IV over 1
hour, then 1 gram as needed. Embodiments may include administering
cilostazol (e.g., PLETAL or the like) at 50 to 100 mg orally twice
daily. Embodiments may include administering pentoxifylline (e.g.,
TRENTAL or the like) at 400 mg orally three times daily with
meals.
[0236] Beta Agonists:
[0237] As described above, embodiments may include administering an
effective amount of a beta agonist to a subject during at least one
phase of the subject's menstrual cycle. Embodiments may include
administering dosages of about 0.5 to about 1.0
micrograms/kilogram/minute of dobutamine intravenously, e.g.,
dosages of about 500 micrograms/ml to about 2000 micrograms/ml may
be administered. Embodiments may include administering dosages of
terbutaline at about 0.25 mg to about 0.5 mg intramuscularly
("IM"), e.g., not more than about 0.5 mg within a four hour period.
Embodiments may include administering dosages of ritodrine at about
50 to about 350 micrograms per minute intravenously. Embodiments
may include administering dosages of albuterol via nebulizer at
about 0.5 ml of 0.5% inhalation solution with about 2.5 ml sterile
saline solution given over about 5 to about 15 minutes three to
four times per day. Embodiments may include administering dosages
of metaproterenol via nebulizer every four hours wherein a vial
containing 0.4% metaproterenol sulfate is equivalent to 0.2 ml of
metaproterenol sulfate inhalation solution 5% diluted to 2.5 ml
with normal saline.
[0238] Alpha Agonists:
[0239] As described above, embodiments may include administering an
effective amount of an alpha agonist to a subject during at least
one phase of the subject's menstrual cycle. Embodiments may include
administering dosages of phenylephrine, e.g., subcutaneously or
intramuscularly: from 1 mg to about 10 mg., wherein the initial
dose generally should not exceed 5 mg.; intravenously: from about
0.1 mg to about 0.5 mg., wherein generally the initial dose should
not exceed 0.5 mg. Injections are typically not repeated more often
than about every 10 to 15 minutes. Embodiments may include
administering dosages of metaraminol subcutaneously at about 2 to
about 10 mg for an interval of about 10 minutes.
[0240] Prednisone and Steroids:
[0241] As described above, embodiments may include administering an
effective amount of prednisone or a steroid to a subject during at
least one phase of the subject's menstrual cycle. Embodiments may
include administering dosages of prednisone or a steroid by mouth
at about 5 to about 60 mg/day, once per day. For example,
prednisone may be in the form of a solution, syrup or tablet and
doses may be given once daily or every other day and about 2.5-15
mg may be taken by a subject 2-4 times daily.
[0242] Indirect Agents that Include Norepinephrine:
[0243] As described above, embodiments may include administering an
effective amount of an indirect agents that include norepinephrine
to a subject during at least one phase of the subject's menstrual
cycle. Embodiments may include administering dosages of ephedrine
IM or IV at about 25 to about 50 mg once per day. Embodiments may
include administering dosages of phenylpropanolamine by mouth at
about 25 mg every four hours, up to about 150 mg/day. Embodiments
may include administering dosages of ampthetamine by mouth at about
2.5 mg to about 60 mg once per day.
[0244] Epinephrine:
[0245] As described above, embodiments may include administering an
effective amount of epinephrine to a subject during at least one
phase of the subject's menstrual cycle. Embodiments may include
intravenously administering epinephrine at about 0.1 to about 0.25
mg (about 1 to about 2.5 ml of 1:10,000 solution) once every 20 to
30 minutes.
[0246] Norepinephrine:
[0247] As described above, embodiments may include administering an
effective amount of norepinephrine to a subject during at least one
phase of the subject's menstrual cycle. Embodiments may include
intravenously administering norepinephrine at about 0.5 to about
1.0 mg (about 5 to about 10 ml of 1:10,000 solution) once every 5
minutes.
[0248] Potassium Channel Blockers and Magnesium Channel
Blockers:
[0249] As described above, embodiments may include administering an
effective amount of a potassium channel blocker or a magnesium
channel blocker to a subject during at least one phase of the
subject's menstrual cycle. Embodiments may include administering
lithium by mouth at about 10 to about 60 mg/kg once per day.
Embodiments may include administering valproate by mouth at about
10 to about 60 mg/kg once per day.
[0250] Acetylcholine
[0251] As described above, embodiments may include administering an
effective amount of acetylcholine to a subject during at least one
phase of the subject's menstrual cycle. Embodiments may include
administering acetylcholine in the form of eye drops at about 0.75
to about 10 milligrams/ml acetylcholine.
[0252] Cocaine:
[0253] As described above, embodiments may include administering an
effective amount of cocaine to a subject during at least one phase
of the subject's menstrual cycle. Embodiments may include
administering cocaine topically on mucus membranes, e.g., about 10%
cocaine hydrochloride.
[0254] Amphetamines:
[0255] As described above, embodiments may include administering an
effective amount of an amphetamine to a subject during at least one
phase of the subject's menstrual cycle. Embodiments may include
administering an amphetamine by mouth at about 5 to about 10 mg per
day, e.g., 10 mg/day in divided doses.
[0256] Ephedrine:
[0257] As described above, embodiments may include administering an
effective amount of ephedrine to a subject during at least one
phase of the subject's menstrual cycle. Embodiments may include
administering ephedrine sulfate injection at about 10 to about 50
mg injected subcutaneously or intramuscularly (equivalent to 0.2 to
1.0 ml of 5% solution).
[0258] Terbutaline:
[0259] As described above, embodiments may include administering an
effective amount of terbutaline to a subject during at least one
phase of the subject's menstrual cycle. Embodiments may include
administering terbutaline intramuscularly at about 0.25 mg, e.g.,
one time, and typically not more than about 0.5 mg within a 4 hour
period.
[0260] Dopamine:
[0261] As described above, embodiments may include administering an
effective amount of dopamine to a subject during at least one phase
of the subject's menstrual cycle. Embodiments may include
administering dopamine intravenously at about 2 to about 50
microgram/kg/minute, wherein each milliliter of a 40 mg/ml
preparation contains 40 mg of dopamine hydrochloride (equivalent to
32.31 mg of dopamine base). Embodiments may also include
administering levodopa (L-dopa) in combination with carbidopa taken
by mouth, e.g., about 25 mg carbidopa (up to about 2500 mg per day)
and about 100 mg levodopa one half tablet, daily. Embodiments may
also include administering bromocriptine (e.g., available under the
brand name PARLODEL) by mouth at about 1.25 to about 100 mg per
day.
[0262] Doputamine:
[0263] As described above, embodiments may include administering an
effective amount of doputamine to a subject during at least one
phase of the subject's menstrual cycle. Embodiments may include
intravenously administering doputamine at about 0.5 to about 1.0
microgram/kg/min (up to about 500 microgram/ml).
[0264] Antidiuretic Hormone ("ADH") (Also Known as
Vasopressin):
[0265] As described above, embodiments may include administering an
effective amount of ADH to a subject during at least one phase of
the subject's menstrual cycle. Embodiments may include
subcutaneously or intramuscularly administering about 5 to about 10
units of AHD two or three times per day.
[0266] Oxytocin:
[0267] As described above, embodiments may include administering an
effective amount of oxytocin to a subject during at least one phase
of the subject's menstrual cycle. Embodiments may include
intravenously administering oxytocin (e.g., available under the
brand name PITOCIN) at about 1 to about 2 mU/mm (solution of 1 ml
(10 units) combined with 1,000 ml of a non hydrating diluent).
[0268] THC Cannabinoids:
[0269] As described above, embodiments may include administering an
effective amount of THC cannibinoid to a subject during at least
one phase of the subject's menstrual cycle. Embodiments may include
administering THC cannibinoid by rectal suppository at about 2.5 mg
two times per day; or about 10 to about 20 mg one, two or three
times per day by mouth; or 1 mg intravenously, e.g., one time; or
about 200 mg once per day by mouth.
[0270] In certain embodiments, a given pharmacological agent may be
administered at or near the time of a particular phase of a
subject's menstrual cycle, i.e., in close temporal proximity to,
including during, one or more predetermined phases of a subject's
menstrual cycle. For example, embodiments of the subject methods
may include administration of a pharmacological agent to achieve a
particular parasympathetic activity/sympathetic activity ratio
during at least a portion of the menses phase and/or follicular
phase and/or the ovulation phase and/or the luteal phase. Of
interest is the administration of a pharmacological agent at least
near the time of, or during at least a portion of, the luteal phase
and/or menses phase to modulate the autonomic nervous system to
increase the parasympathetic activity/sympathetic activity ratio to
treat the condition of interest. For example, embodiments may
include determining the occurrence (predetermining the occurrence)
of one or more phases of a subject's menstrual cycle, e.g., the
luteal phase, and administering at least one pharmacological agent
to increase the parasympathetic activity/sympathetic activity ratio
during the one or more predetermined phases, e.g., during the
luteal phase, after ovulation, or at a time prior to the start of
the luteal phase and/or throughout all of or a portion of the
luteal phase. Embodiments may include determining the occurrence of
the menses phase and administering at least one pharmacological
agent to increase the parasympathetic activity/sympathetic activity
ratio during the menses phase, or at a time prior to the start of
the menses phase and/or throughout all of or a portion of the
menses phase. Similar treatment protocols may be employed for the
follicular and ovulation phases.
[0271] The luteal phase is the part of the cycle that starts at
ovulation and ends the day before a female's next period and
usually lasts between about 12 to about 16 days. As such,
embodiments of the subject invention may include administering an
effective amount of a pharmacological agent at least one time
during ovulation and/or at least one time during the luteal phase
to increase the parasympathetic activity/sympathetic activity ratio
in a manner effective to treat a condition, where embodiments may
include administration during about all of the days of a subject's
luteal phase or the late luteal phase. By "late luteal phase" is
meant the later half of the luteal phase. For example, if a
subject's luteal phase is determined to last about 14 days, the
late luteal phase may be considered to be from about day 7 to about
day 14 of the luteal phase.
[0272] As embodiments of the subject methods include administering
an effective amount of at least one pharmacological agent to a
subject during at least one predetermined menstrual phase,
embodiments of the subject methods include determining the
occurrence of the phases or at least one phase of a subject's
menstrual cycle by any suitable method, e.g., using
hormone-specific blood tests, urine tests, etc., as is known to
those of skill in the art. For example, the onset of the luteal
phase may be determined using a urine leutinizing hormone ("LH")
detection test or kit, as are known in the art, e.g., as available
under the brand names OVUQUICK ONE-STEP, CLEARPLAN EASY and
SURESTEP. Other known methods may be employed as well and include
empirical and non-empirical methods such as estimating the start,
duration and/or end of a particular menstrual cycle phase, e.g., by
a calendar method (counting days) or the like. Regardless of the
particular method employed, in certain embodiments the onset of
ovulation and/or the luteal phase and/or any other menstrual cycle
phase may be determined and one or more of the pharmacological
agents described above may be administered at or near the
predetermined start of the subject's luteal phase and/or during at
least part of a subject's determined luteal phase.
Electrical Modulation of at Least a Portion of the Autonomic
Nervous System
[0273] As described above, embodiments of the subject invention may
also include electrically modulating at least a portion of the
autonomic nervous system to increase the parasympathetic
activity/sympathetic activity ratio. By "electrically modulating at
least a portion of a subject's autonomic nervous system" is meant
altering or changing at least a portion of an autonomic nervous
system by applying electrical energy to provide a change,
alteration or shift in at least one component or aspect of the
autonomic nervous system, as will be described in greater detail
below. The electrical modulation of the autonomic nervous system
may affect central motor output and/or nerve conduction and/or
transmitter release and/or synaptic transmission and/or receptor
activation, but in any event is a change that provides an increase
in the parasympathetic activity/sympathetic activity ratio.
[0274] For example, embodiments may include electrically modulating
at least a portion of a subject's autonomic nervous system to
alter, shift or change the activity in at least one of the
sympathetic system and parasympathetic system from a first state to
a second state, where the second state is characterized at least by
an increase or decrease in the parasympathetic activity/sympathetic
activity ratio relative to the first state. Electrical energy may
be employed to increase and/or decrease activity in at least a
portion of the autonomic nervous system. For example, embodiments
may include electrically modulating at least a portion of the
autonomic nervous system to achieve one or more of the following
(but in any event to achieve a net result of an increase or
decrease in parasympathetic activity/sympathetic activity ratio,
relative to the parasympathetic activity/sympathetic activity ratio
prior to pharmacological modulation): (1) increasing activity in at
least one parasympathetic nerve fiber to achieve an increase in
activity in at least a portion of the parasympathetic system, (2)
increasing activity in at least one sympathetic nerve fiber to
achieve an increase in activity in at least a portion of the
sympathetic system, (3) inhibiting activity in at least one
parasympathetic nerve fiber to achieve a decrease in activity in at
least a portion of the parasympathetic system, and (4) inhibiting
activity in at least one sympathetic nerve fiber to achieve a
decrease in activity in at least a portion of the sympathetic
system. Certain embodiments of the subject invention may include
electrically modulating the autonomic nervous system to both
increase activity in at least a portion of the autonomic nervous
system, e.g., increase activity in at least one parasympathetic
nerve fiber, and inhibit activity in at least a portion of the
autonomic nervous system, e.g., inhibit activity in at least one
sympathetic nerve fiber, to treat a condition. Accordingly,
embodiments of the subject methods include providing electrical
energy to at least a portion of a subject's autonomic nervous
system, where such electrical energy may be excitatory (to increase
activity) or inhibitory (to decrease activity) and in certain
embodiments may be both excitatory and inhibitory energies.
[0275] As noted above, electrical modulation in accordance with the
subject invention may be performed prior to and/or at the same time
and/or subsequent to any other medical or clinical treatment regime
such as any of those described above, for example, pharmacological
modulation of at least a portion of the subject's autonomic nervous
system. In other words, the subject methods may include other,
concomitant therapies or treatments to treat the same or different
condition that do not employ electrical energy.
[0276] According to embodiments of the subject invention,
electrical modulation is accomplished by at least administering
electrical energy to a subject in a manner sufficient to treat the
subject for a condition caused, precipitated or otherwise
exacerbated, influenced or affected by the ratio of the
parasympathetic activity/sympathetic activity ratio. In other
words, activity in at least a portion of the autonomic nervous
system is at a level that is at least contributing to or otherwise
affecting or exacerbating a condition such a disease condition in
need of treatment, and as such modulation of the autonomic nervous
system may be employed to treat the condition.
[0277] Methods and devices suitable for use in electrically
modulating a portion of subject's autonomic nervous system, and
which may be employed in the practice of the subject invention, are
described in detail in copending U.S. application Ser. No.
10/661,368, entitled "Treatment of Conditions Through Electrical
Modulation of the Autonomic Nervous System", the disclosure of
which is herein incorporated by reference.
[0278] In general, modulating at least a portion of the autonomic
nervous system using electrical energy may be accomplished with the
use of an electric energy applying devices (also referred to as
electrical energy supplying or delivering devices), such as, e.g.,
described in the above-noted copending patent application. Once an
electric energy applying device is positioned in a suitable
position on or about one or more targeted areas of the autonomic
nervous system such as one or more parasympathetic nerve fibers
and/or one or more sympathetic nerve fibers, electrical energy is
applied to the area(s) (e.g., the targeted nerve fiber(s)) for a
period of time sufficient to provide the desired modulation of the
autonomic nervous system. This period of time will vary depending
on the area (e.g., the nerve fiber) being treated, the condition
being treated, the particulars of the device used, etc.
[0279] As described in greater detail below, certain embodiments
include simultaneously monitoring (i.e., in "real time") the
parasympathetic activity and/or sympathetic activity such that
electrical energy is applied until the desired increase in
parasympathetic activity/sympathetic activity ratio is observed.
Still further, in many embodiments once the desired ratio is
achieved, electrical energy may be repeatedly applied thereto one
or more times to maintain the desired state such that the subject
methods may be repeated one or more times, i.e., the subject
methods include chronic administration of electrical energy to at
least one area of the autonomic nervous system. For example, in
certain embodiments electrical energy (e.g., intermittent mild
electrical pulses) may be delivered to a given area of the
autonomic nervous system twenty-four hours a day for a period of
days, weeks, months, years or even the entire lifetime of the
subject in certain embodiments during one or more predetermined
menstrual cycle phases. For example, electrical energy may be
delivered to a given area during one or more predetermined phases
of a subject's menstrual cycle such as during a predetermined
luteal phase or the like every month for months, years or even the
entire lifetime of the subject.
[0280] During the period of time that a given area of the autonomic
nervous system is electrically modulated, the electrical energy may
be applied substantially continuously, including continuously, or
intermittently (i.e., pulsed or periodic), where in many
embodiments the electrical energy is in the form of electrical
pulses. In other words, in certain embodiments a given area of the
autonomic nervous system (e.g., a given nerve fiber) may be
continuously contacted with electrical energy during the
above-described period of time and in certain other embodiments a
given area of the autonomic nervous system (e.g., a given nerve
fiber) may be pulsed or intermittently contacted with electrical
energy during the period of time described above.
[0281] In accordance with embodiments of the subject methods to
electrically modulate at least one area of the autonomic nervous
system, once operatively positioned the electrical energy applying
device is activated to provide an electrical signal to the targeted
area such as to one or more nerve fiber(s) in a manner to increase
or decrease the parasympathetic activity/sympathetic activity ratio
at least in the particular area being contacted with electrically
energy and in certain instances in adjacent areas or in the entire
autonomic system, e.g., systemically in certain instances. For
example, many nerve fibers are in close proximity and thus
application of electrical energy to one nerve fiber may also
increase or decrease activity in one or more other nerve fibers,
e.g., nerve fibers in close proximity thereto.
[0282] In practicing the subject methods, activation of the
electrical energy supplying device directly applies the electrical
output of the device, i.e., electrical energy, to the targeted
area. For example, electrodes may be positioned to direct
electrical impulses to specific nerve fibers, etc. The exact
parameters of the protocol may vary depending on the particular
subject, condition being treated, etc. An electronic current wave
may be provided when the electrical energy is applied. In certain
embodiments, the current wave includes current waves of high
frequency, e.g., high frequency pulses, where the current wave may
also include low frequency amplitude modulation. In certain
embodiments, a plurality of high frequency bursts of current pulses
may be applied in addition to the application of underlying low
frequency continuous stimulus. Monopolar or multipolar technologies
may be employed.
[0283] For example, to increase activity in a portion of the
autonomic nervous system, voltage or intensity may range from about
1 millivolt to about 1 volt or more, e.g., 0.1 volt to about 50
volts, e.g., from about 0.2 volt to about 20 volts and the
frequency may range from about 1 Hz to about 2500 Hz, e.g., about 1
Hz to about 1000 Hz, e.g., from about 2 Hz to about 100 Hz in
certain embodiments. In certain embodiments a pure d-c voltages may
be employed. The pulse width may range from about 1 microsecond to
about 2000 microseconds or more, e.g., from about 10 microseconds
to about 2000 microseconds, e.g., from about 15 microseconds to
about 1000 microseconds, e.g., from about 25 microseconds to about
1000 microseconds. The electrical output may be applied for at
least about 1 millisecond or more, e.g., about 1 second, e.g.,
about several seconds, where in certain embodiments the stimulation
may be applied for as long as about 1 minute or more, e.g., about
several minutes or more, e.g., about 30 minutes or more may be used
in certain embodiments.
[0284] To inhibit activity or conduction in a portion of the
sympathetic nervous system, voltage or intensity may range from
about 1 millivolt to about 1 volt or more, e.g., 0.1 volt to about
50 volts, e.g., from about 0.2 volt to about 20 volts and the
frequency may range from about 1 Hz to about 2500 Hz, e.g., about
50 Hz to about 2500 Hz. In certain embodiments a pure d-c voltages
may be employed. The pulse width may range from about 1
microseconds to about 2000 microseconds or more, e.g., from about
10 microseconds to about 2000 microseconds, e.g., from about 15
microseconds to about 1000 microseconds, e.g., from about 25
microseconds to about 1000 microseconds. The electrical energy may
be applied for at least about 1 millisecond or more, e.g., about 1
second, e.g., about several seconds, where in certain embodiments
the electrical energy may be applied for as long as about 1 minute
or more, e.g., about several minutes or more, e.g., about 30
minutes or more may be used in certain embodiments.
[0285] The time period for modulating at least a portion of a
subject's autonomic nervous system using electrical energy is
analogous to that described above for pharmacologically modulating
at least a portion of a subject's autonomic nervous system.
[0286] A variety of different devices for applying electrical
energy to increase or inhibit activity in at least a portion of the
autonomic nervous system in accordance with the subject invention
may be employed as described in the above referenced, copending
U.S. application Ser. No. 10/661,368, the disclosure of which is
herein incorporated by reference. Electrical energy delivering
devices that may be used to practice the subject invention may be
positioned directly on a targeted area, e.g., positioned below the
skin of a subject directly on or adjacent a portion of the
autonomic nervous system (e.g., one or more nerve fibers) such as
an implantable device, or may be an external device (i.e., some or
all of the device may be external to the subject). In accordance
with embodiments of the subject invention, one or more electrodes
or electrical contacts may be positioned directly on or adjacent a
targeted area of the autonomic nervous system, i.e., directly on or
adjacent a portion of the parasympathetic and/or sympathetic
system, where the one or more electrodes may be surgically
implanted directly on or adjacent a targeted nerve fiber of a
subject. In further describing the subject invention, a single
electrode is described however it is to be understood that multiple
electrodes may be employed and features and characteristics of the
single electrode described herein are applicable to any other
electrodes that may be employed in the practice of the subject
invention.
[0287] Electrical energy delivering devices that may be employed in
the practice of the subject methods typically include a stimulator
(or inhibitor) such as an electrode, a controller or programmer and
one or more connectors for connecting the stimulating device to the
controller. In certain embodiments more than one electrode may be
employed. In further describing representative electrodes, such are
described in the singular, but it will be apparent that more than
one electrode may be used, where such may be the same or may be
different in one or more aspects. Accordingly, the description of a
representative electrode suitable for use in the subject methods is
applicable to other electrodes that may be employed.
[0288] The electrode employed in the subject invention is typically
controllable to provide output signals that may be varied in
voltage, frequency, pulse width, current and intensity. The
electrode is typically one that provides both positive and negative
current flow from the electrode and/or is capable of stopping
current flow from the electrode and/or changing the direction of
current flow from the electrode. For example, embodiments include
an electrode that is controllable in these respects, i.e.,
controllable in regards to producing positive and negative current
flow from the electrode, stop current flow from the electrode,
change direction of current flow from the electrode, and the like.
In certain embodiments, the electrode has the capacity for variable
output, linear output and short pulse width.
[0289] The energy source for the electrical output is provided by a
battery or generator such as a pulse generator that is operatively
connected to the electrode. The energy source may be positioned in
any suitable location such as adjacent to the electrode (e.g.,
implanted adjacent the electrode), or a remote site in or on the
subject's body or away from the subject's body in a remote location
and the electrode may then be connected to the remotely positioned
energy source using wires, e.g., may be implanted at a site remote
from the electrode or positioned outside the subject's body in
certain instances. Implantable generators analogous to a cardiac
pacemaker may be used in certain embodiments.
[0290] The electrode may be mono-polar, bipolar or multi-polar. In
order to minimize the risk of an immune response triggered by the
subject against the device and minimize damage such as corrosion
and the like to the device from other biological fluids, etc., the
electrode and any wires and optional housing materials are made of
inert materials such as for example silicon, metal, plastic and the
like. For example, a multi-polar electrode having about four
exposed contacts (e.g., cylindrical contacts may be employed.
[0291] A variety of methods may be used to endoscopically or
surgically implant the electrode on or adjacent at least a portion
of the autonomic nervous system such as on or adjacent one or more
nerve fibers of the parasympathetic nervous system and/or
sympathetic system, where such methods are known to those of skill
in the art. Because some nerve fibers may be in very close
proximity to one another within a very small area, an analogous
technique may generally be employed to provide operable placement
of the electrode on or adjacent to any targeted area of the
autonomic nervous system.
[0292] A controller or programmer is also typically included in an
electrical energy supplying device. The programmer is typically one
or more microprocessors under the control of a suitable software
program. Other components of the programmer will be apparent to
those of skill in the art, e.g., analog to digital converter,
etc.
[0293] The electric energy supplying device employed in the
practice of the subject methods may be pre-programmed for desired
parameters. In many embodiments the parameters are controllable
such that the electrode signal may be remotely modulated to desired
settings without removal of the electrode from its targeted
position. Remote control may be performed, e.g., using conventional
telemetry with an implanted electric signal generator and battery,
an implanted radiofrequency receiver coupled to an external
transmitter, and the like. In certain embodiments, some or all
parameters of the electrode may be controllable by the subject,
e.g., without supervision by a physician. For example, a magnetic
signal may be employed. In such embodiments, one or more magnets
may be employed such that upon bringing a magnet in proximity to or
away from the power source such as a pulse generator, the magnet
may be employed to interfere with the electronic circuitry thus
modulating the power--either increasing or decreasing the power
supplied depending on whether the magnet is brought in proximity or
moved away from the power source.
[0294] The present invention may be operated as an open-loop
controlled system. In an open-loop system, the physician or patient
may at any time manually or by the use of pumps or motorized
elements adjust treatment parameters such as pulse amplitude, pulse
width, pulse frequency, or duty cycle. Optionally, the present
invention may incorporate a closed-loop control system which may
automatically adjust the electrical parameters in response to a
sensed symptom or an important related symptom indicative of the
extent of the condition being treated. Under a closed-loop feedback
system to provide automatic adjustment of parameters of the
electrodes, a sensor that senses a condition of the body is
utilized. In certain embodiments, such a condition may be a
particular phase of the menstrual cycle (e.g., may sense hormonal
changes or the like). More detailed descriptions of sensors that
may be employed in the practice of the subject invention, and other
examples of sensors and feedback control techniques that may be
employed are disclosed in U.S. Pat. No. 5,716,377, which is
incorporated herein by reference.
[0295] Operative placement of a suitable electric energy supplying
device may be accomplished using any suitable technique. In
general, such placement includes localization of an area of the
autonomic nervous system, positioning the electrode on or adjacent
the area and attaching the electrode to a power source. However,
with regard to attaching the electrode to a power source, it should
be understood that electrodes may be employed which make the
implantation and/or attachment of a separate power source
unnecessary. For example, an electrode may be employed which
includes its own power source, e.g., which is capable of obtaining
sufficient power for operation from surrounding tissues in the
patient's body or which may be powered by bringing a power source
external to the patient's body into contact with the patient's
skin, or may include an integral power source, and the like. In
such instances, the surgical procedure may be completed upon
implantation of the electrode on or adjacent to the area of
interest.
[0296] An electrode introducer needle may be employed to implant
the electrode on or proximate to the area of interest. The size of
the introducer needle may vary depending on the diameter of the
electrode, etc., where in certain embodiments the electrode
introducer needle may be a 12-gauge, 14-gauge, 16-gauge, 18-gauge,
20-gauge needle or 22-gauge needle, e.g., an electrode introducer
needle available from Radionics in the Sluyter-Mehta kit as SMK 100
mm 2 mm active tip cannula. However, it should be understood that
other electrode introducer needles may be used as appropriate to
the needs and skill level of the practitioner performing the
surgical procedure.
[0297] At least one imaging apparatus such as a CT scan, MRI
apparatus, ultrasound apparatus, fluoroscope, or the like, may be
employed to monitor the surgical procedure during the localization
of a given area, e.g., to assist in determining a suitable entry
point for the insertion of the electrode.
[0298] Once the entry point is determined, the skin overlying the
entry point is shaved and prepared with antiseptic solution. A
25-gauge needle may be used to inject a subcutaneous local
anesthetic (such as, for example, 2 cc of 2% lidocaine) into the
skin and subcutaneous tissues overlying the entry point. In
addition to the local anesthetic, the patient may be given
intravenous sedation and prophylactic antibiotics prior to
commencement of the implantation procedure if desired.
[0299] The electrode introducer needle is inserted at the entry
point and advanced. The fluoroscope may be adjusted as the needle
is advanced. Once the needle is suitably positioned, the stylet is
withdrawn from the electrode introducer needle. A "test" electrode,
if employed, used to test the placement of the electrode introducer
needle may then be positioned within the central channel of the
needle. If a "test" electrode is not employed, the electrode that
is to be employed to modulate the autonomic nervous system may then
be positioned within the central channel of the needle. The
electrode may then be advanced to the distal tip of the needle to
place the electrode on or proximate to the area of interest.
[0300] In certain embodiments, the "test" electrode, if employed,
may be a radiofrequency stimulating electrode suitable to
electrically stimulate the tissue at the end of the tip of the
electrode and verify its position physiologically within the
patient, which may be a different electrode than that ultimately
implanted within the patient. A suitable radiofrequency stimulating
electrode may be 10 cm with a 2-mm non-insulated active tip. Once
the "test" electrode is inserted through the electrode introducer
needle with its electrical contacts exposed, it may then be
connected to an electrical stimulus/lesion generator for electrical
stimulation.
[0301] The frequency of stimulation may be set at any suitable
frequency, e.g., at about 50 Hz, and the voltage may be gradually
increased until the subject reports acknowledgement of application
of electrical current, e.g. reports stimulation, of or about the
area of interest of the autonomic nervous system. Repositioning of
the electrode may be performed as necessary.
[0302] If a "test" electrode is employed to test the placement of
the electrode introducer needle and as such is different from the
electrode to be employed to modulate the autonomic nervous system
(i.e., the electrode to be implanted if it is desired to implant
the electrode that will be employed to modulate the autonomic
nervous system), the "test" electrode may then be removed from the
electrode introducer needle while the needle is held firmly in
place to prevent displacement. The electrode to be implanted may
then be inserted through the central channel of the needle while
the needle is held in place at the hub. Once the electrode to be
implanted is in position, fluoroscopic imaging and electrical
stimulation may be employed to verify the correct positioning of
the needle and the electrode. Alternatively, if the electrode used
to test the placement of the electrode introducer needle is the
electrode to be implanted, the electrode may be left in the final
test position.
[0303] Once the implanted electrode is in place, the end of the
electrode that is outside the skin is carefully held in place
against the skin. The electrode introducer-needle may then be
slowly removed, leaving the implanted electrode in place. At this
point, if desired, a few small subcutaneous sutures may be placed
around the electrode to hold it in the desired position.
[0304] Once the needle has been completely removed and the
implanted electrode is in the final position, then the proximal
part of the electrode that is coming out of the skin may be secured
to the skin of the subject, e.g., by adhesive tape. Additionally, a
small incision may be made on the skin at the area the electrode
exits the body. Then several subcutaneous sutures may be placed
around the electrode to hold it in place. The distal end of the
electrode may then be connected to an extension wire or catheter,
which is tunneled to the subclavicular area, or another region
which will house the device used as an energy source for the
implanted electrode. The device or devices used to control or
stimulate the electrode may be surgically implanted in the desired
region by procedures known in the art, such as have been applied in
surgical neuromodulation therapies used to treat Parkinson's
disease.
[0305] Electrical modulation may be performed at any suitable time,
where such includes times analogous to those described above for
pharmacological modulation. For example, electrical modulation may
be performed at or near the time of a particular phase of a
subject's menstrual cycle, i.e., in close temporal proximity to,
including during, one or more predetermined phases of a subject's
menstrual cycle. For example, embodiments of the subject methods
may include electrically modulating at least a portion of a
subject's autonomic nervous system to achieve a particular
parasympathetic activity/sympathetic activity ratio (e.g., a normal
ratio) during at least a portion of the menses phase and/or
follicular phase and/or the ovulation phase and/or the luteal
phase. Of interest is electrical modulation at least near the time
of, or during at least a portion of, the luteal phase and/or menses
phases to modulate the autonomic nervous system to increase or
decrease the parasympathetic activity/sympathetic activity ratio.
For example, embodiments may include electrical modulation of at
least a portion of the autonomic nervous system to increase the
parasympathetic activity/sympathetic activity ratio during the
luteal phase, after ovulation. For example, embodiments may include
determining the occurrence of one or more phases of a subject's
menstrual cycle, e.g., the luteal phase, and applying electrical
energy to at least a portion of the autonomic nervous system to
increase the parasympathetic activity/sympathetic activity ratio
during the one or more predetermined phases, e.g., during the
luteal phase, or at a time prior to the start of the luteal phase
and/or throughout all of or a portion of the luteal phase.
Embodiments may include determining the occurrence of the menses
phase and applying electrical energy to increase the
parasympathetic activity/sympathetic activity ratio during the
menses phase, or at a time prior to the start of the menses phase
and/or throughout all of or a portion of the menses phase. Similar
treatment protocols may be employed for the follicular and
ovulation phases.
[0306] Embodiments of the subject invention may include
electrically modulating at least a portion of a subject's autonomic
nervous system at least one time during at least one predetermined
menstrual cycle phase to increase or decrease the parasympathetic
activity/sympathetic activity ratio, where embodiments may include
electrically modulating at least a portion of a subject's autonomic
nervous system during about all of the days of a subject's luteal
phase and/or menses phase. In such instances, the subject methods
typically include determining the occurrence of one or more phases
of a subject's menstrual cycle by any suitable method as described
above, e.g., using hormone-specific blood tests, urine tests, etc.,
as is known to those of skill in the art. For example, the onset of
the luteal phase may be determined using a urine leutinizing
hormone ("LH") detection test or kit, as are known in the art,
e.g., as available under the brand names OVUQUICK ONE-STEP,
CLEARPLAN EASY and SURESTEP. Other known methods may be employed as
well and include empirical and non-empirical methods such as
estimating the start, duration and/or end of a particular menstrual
cycle phase, e.g., by a calendar method (counting days) or the
like. Regardless of the particular method employed, the occurrence
of one or more menstrual cycle phases may be determined and
electrical modulation at least a portion of the subject's autonomic
nervous system as described above may be performed at or near the
determined start of the subject's determined menstrual cycle
phase.
[0307] Regardless of how the autonomic nervous system is modulated
(pharmacologically, electrically, etc.), certain embodiments of the
subject methods may also include detecting, monitoring, observing,
etc., information related to one or more aspects of the autonomic
nervous system such as a physical and/or chemical aspect, e.g.,
activity, balance, etc., in at least a portion of the autonomic
nervous system, e.g., in at least a portion of the sympathetic
nervous system and/or parasympathetic system, and evaluating this
information to determine the state of the autonomic nervous system,
e.g., the parasympathetic activity and/or sympathetic activity.
Once the state of the autonomic nervous system is determined, it
may be evaluated in regards to whether the autonomic nervous system
is in need of modulation, i.e., whether the parasympathetic
activity/sympathetic activity ratio needs to be increased to treat
a condition such that this analysis may be employed as a "trigger"
to modulating or further modulating at least a portion of the
autonomic nervous system wherein modulation may not be otherwise
performed unless the analysis determined such is necessary.
[0308] Accordingly, collecting and evaluating this type of data and
relating it to whether autonomic nervous system modulation is
required may be employed as a "trigger" to pharmacologically
modulating at least a portion of the autonomic nervous system
(e.g., performed prior to, during or following a particular
autonomic nervous system modulation protocol whether performed
using pharmacological methods, electrical energy methods or other
methods) such that such data may indicate whether, when, etc.,
modulation is required--if at all. For example, in certain
embodiments modulation of at least a portion of a subject's
autonomic nervous system may not be performed unless one or more
aspects of the autonomic nervous system are detected and indicate
such modulation is necessary. Any suitable physical and/or chemical
aspect or indicator of the autonomic nervous system may be
employed, e.g., amounts of T helper cells (Th1 and/or Th2),
conduction, catecholamine levels, heart rate variability ("HRV"),
respiratory sinus arrhythmia, action potentials, QT interval, as
well as chronotropic, inotropic, and vasodilator responses. For
example, in certain embodiments HRV measures such as low frequency
peak ("LF"), high frequency peak ("HF"), and the LF/HF ratio may be
used as indicators of different aspects of the autonomic nervous
system. Typically, in normal females, normalized units ("NU") of LF
and LF/HF ratio are higher, and NU of HF are lower, during the
luteal phase. In certain embodiments, particular hormonal levels,
e.g., associated with a particular phase of the menstrual cycle,
may be detected. In certain embodiments, detection may include
detecting the activity or function of a particular organ or system
under the control of the autonomic nervous system. Other exemplary
measurements may include, but are not limited to, plasma volume,
effective renal plasma volume, effective renal blood flow,
norepinephrine, and concentrations of
rennin-angiotensin-aldosterone system hormones, which have been
noted to be higher during the luteal phase than in the follicular
phase. Any suitable detection means may be employed to detect
relevant information about the autonomic nervous system.
[0309] In certain embodiments, a control feedback loop is provided.
For example, during or following a particular treatment regimen,
the sympathetic activity and/or parasympathetic activity may be
monitored, observed, detected, etc., e.g., by sensing conduction in
at least a portion of the sympathetic system and/or parasympathetic
system by any suitable method. Other methods that may be employed
to monitor the autonomic system include, but are not limited to,
amounts of T helper cells (Th1 and/or Th2), neurography, continuous
or serial measurements of circulating catecholamine levels,
chronotropic, inotropic, and vasodilator responses, heart rate
variability ("HRV"), particular hormonal levels, e.g., associated
with a particular phase of the menstrual cycle, post-ganglionic
action potentials, QT interval, and the like. For example, in
certain embodiments HRV measures such as low frequency peak ("LF"),
high frequency peak ("HF"), and the LF/HF ratio may be used to
monitor the autonomic nervous system, as well as, but not limited
to, plasma volume, effective renal plasma volume, effective renal
blood flow, norepinephrine, and concentrations of
rennin-angiotensin-aldosterone system hormones. For example, a
sensor suitable for detecting nerve cell or axon activity that are
related to the autonomic nervous system may be implanted in a
portion of a subject's body. A sensor may take the form of an
electrode or the like. Signals received by such a sensor may be
amplified before further processing. A sensor may also take the
form of a device capable of detecting nerve compound action
potentials or may take the form of a transducer that includes an
electrode with an ion selective coating applied which is capable of
directly transducing the amount of a particular transmitter
substance or its breakdown by-products.
[0310] Embodiments include utilizing a feedback system in such a
manner that, if the desired increase/decrease in sympathetic and/or
parasympathetic activity is not achieved, the same or a different
treatment protocol for modulating the activity of the autonomic
nervous system activity may be performed. For example, in those
instances where a different modulation protocol is performed from a
first modulation protocol, one or more of the treatment parameters
may be modified. For example, if a first modulation protocol
included pharmacological modulation, a second, different modulation
protocol may be employed, e.g., a different pharmacological agent
may be employed instead or in addition to the first, where the
differences may include dosage, type, mode of administration, etc.,
or the second protocol may include an electrical modulation
protocol. In those instances where a different protocol is
performed from a first, electrical energy modulation protocol, one
or more of the treatment parameters may be modified for a second,
different electrical modulation protocol, e.g., a different
electrical energy protocol may be employed instead of or in
addition to the first, where the differences may include voltage,
frequency, pulse width, etc., or the second protocol may include a
pharmacological modulation protocol.
[0311] Certain embodiments may include simultaneously monitoring,
detecting, observing, etc., (i.e., in "real time") the sympathetic
activity and/or parasympathetic activity such that modulation of at
least a portion of the autonomic nervous system may be performed to
treat a condition and the result of the modulation may be observed
and/or monitored, e.g., at least once, continuously or
intermittently or periodically and in certain embodiments until the
desired increase or inhibition in activity is observed or longer.
Still further, in many embodiments once the desired autonomic
nervous system modulation is achieved the same or different
modulation treatment protocol may be performed thereafter at least
one time and may be for a period of time, e.g., one or more times,
to maintain the desired state such that embodiments of the subject
methods may be repeated one or more times.
[0312] The above-described methods find use in a variety of
different applications, representative types of which are described
in greater detail below.
Utility
[0313] The subject methods find use in a variety of applications in
which it is desired to treat a subject for a condition at least
suspected of being exacerbated during at least one menstrual cycle
phase. Such conditions may be referred to as conditions that have
catamenial variations. In accordance with embodiments of the
subject invention, at least a portion of a subject's autonomic
nervous system is modulated to increase the parasympathetic
activity/sympathetic activity ratio in a manner sufficient to treat
the subject for the condition. In accordance with embodiments of
the subject invention, at least a portion of a subject's autonomic
nervous system is modulated to decrease the parasympathetic
activity/sympathetic activity ratio in a manner sufficient to treat
the subject for the condition.
[0314] The subject methods find use in the treatment of a variety
of different conditions, including, but not limited to,
cardiovascular conditions including cardiovascular disease, e.g.,
atherosclerosis, coronary artery disease, hypertension,
hyperlipidemia, eclampsia, pre-eclampsia, cardiomyopathy, volume
retention, congestive heart failure, QT interval prolongation,
aortic dissection, aortic aneurysm, arterial aneurysm, arterial
vasospasm, myocardial infarction, reperfusion syndrome, ischemia,
sudden adult death syndrome, arrhythmia, fatal arrythmias, coronary
syndromes, coronary vasospasm, sick sinus syndrome, bradycardia,
tachycardia, thromboembolic disease, deep vein thrombosis,
coagulopathy, disseminated intravascular coagulation ("DIC"),
mesenteric ischemia, syncope, venous thrombosis, arterial
thrombosis, malignant hypertension, secondary hypertension, primary
pulmonary hypertension, secondary pulmonary hypertension,
raynaud's, paroxysmal supraventricular tachycardia, and the like;
neurodegenerative conditions including neurodegenerative diseases,
e.g., Alzheimer's Disease, Pick's Disease, Parkinson's Disease,
dementia, delirium, amyotrophic lateral sclerosis, and the like;
neuroinflammatory conditions including neuroinflammatory diseases,
e.g., viral meningitis, viral encephalitis, fungal meningitis,
fungal encephalitis, multiple sclerosis, charcot joint,
schizophrenia, myasthenia gravis, and the like; orthopedic
inflammatory conditions including orthopedic inflammatory diseases,
e.g., osteoarthritis, inflammatory arthritis, regional idiopathic
osteoporosis, reflex sympathetic dystrophy, Paget's disease,
osteoporosis, antigen-induced arthritis, juvenile chronic
arthritis, and the like; lymphoproliferative conditions including
lymphoproliferative diseases, e.g., lymphoma, lymphoproliferative
disease, Hodgkin's disease, inflammatory pseudomotor of the liver,
and the like; autoimmune conditions including automimmune diseases,
e.g., Graves disease, raynaud's, hashimoto's, takayasu's disease,
kawasaki's diseases, arteritis, scleroderma, CREST syndrome,
allergies, dermatitis, Henoch-schlonlein purpura, goodpasture
syndrome, autoimmune thyroiditis, myasthenia gravis, Reiter's
disease, lupus, and the like; inflammatory conditions, e.g., acute
respiratory distress syndrome ("ARDS"), multiple sclerosis,
rheumatoid arthritis, juvenile rheumatoid arthritis, juvenile
chronic arthritis, migraines, chronic headaches, and the like;
infectious diseases, e.g., sepsis, viral and fungal infections,
diseases of wound healing, wound healing, tuberculosis, infection,
AIDS, human immunodeficiency virus, and the like; pulmonary
conditions including pulmonary diseases, e.g., tachypnea, fibrotic
lung diseases such as cystic fibrosis and the like, interstitial
lung disease, desquamative interstitial pneumonitis, non-specific
interstitial pneumonitis, lymphocytic interstitial pneumonitis,
usual interstitial pneumonitis, idiopathic pulmonary fibrosis,
pulmonary edema, aspiration, asphyxiation, pneumothorax,
right-to-left shunts, left-to-right shunts, respiratory failure,
and the like; transplant-related conditions such as transplant
related side effects such as transplant rejection,
transplant-related tachycardia, transplant related renal failure,
transplant related bowel dysmotility, transplant-related
hyperreninemia, and the like; gastrointestinal conditions including
gastrointestinal diseases, e.g., hepatitis, xerostomia, bowel
mobility, peptic ulcer disease, constipation, ileus, irritable
bowel syndrome, post-operative bowel dysmotility, inflammatory
bowel disease, typhilitis, cholelethiasis, cholestasis, fecal
incontinence, cyclic vomiting syndrome, and the like; endocrine
conditions including endocrine diseases, e.g., hypothyroidism,
hyperglycemia, diabetes, obesity, syndrome X, insulin resistance,
polycycstic ovarian syndrome ("PCOS"), and the like; genitourinary
conditions including genitourinary diseases, e.g., bladder
dysfunction, renal failure, hyperreninemia, hepatorenal syndrome,
pulmonary renal syndrome, incontinence, arousal disorder,
menopausal mood disorder, premenstrual mood disorder, renal tubular
acidosis, pulmonary renal syndrome, and the like; skin conditions
including skin diseases, e.g., wrinkles, cutaneous vasculitis,
psoriasis, and the like; aging associated conditions including
aging associated diseases, e.g., shy dragers, multi-system atrophy,
age related inflammation conditions, cancer, aging, and the like;
neurologic conditions including neurologic diseases such as
epilepsy, depression, schizophrenia, seizures, stroke, insomnia,
cerebral vascular accident, transient ischemic attacks, stress,
bipolar disorder, concussions, post-concussive syndrome, cerebral
vascular vasospasm, central sleep apnea, obstructive sleep apnea,
sleep disorders, headaches including chronic headaches, migraines,
acute disseminated encephalomyelitis ("ADEM"), and the like; Th-2
dominant conditions including Th-2 dominant diseases, e.g.,
typhilitis, osteoporosis, lymphoma, myasthenia gravis, lupus, and
the like; conditions, including diseases, that cause hypoxia,
hypercarbia, hypercapnia, acidosis, acidemia, e.g.,
ventilation/perfusion (V/Q) mismatch, Chronic Obstructive Pulmonary
Disease ("COPD"), emphysema, any chronic lung disease that causes
acidosis, acute pulmonary embolism, sudden adult death syndrome
("SADS"), chronic pulmonary embolism, pleural effusion, cardiogenic
pulmonary edema, non-cardiogenic pulmonary edema, acute respiratory
distress syndrome (ARDS), neurogenic edema, hypercapnia, acidemia,
asthma, renal tubular, asthma, acidosis, chronic lung diseases that
cause hypoxia, hypercarbia or hypercapnia, and the like; OB-GYN
conditions including OB-GYN diseases, e.g., amniotic fluid
embolism, menopausal mood disorders, premenstrual mood disorders,
pregnancy-related arrhythmias, fetal stress syndrome, fetal
hypoxia, amniotic fluid embolism, gestational diabetes, pre-term
labor, cervical incompetence, fetal distress, peri-partum maternal
mortality, peripartum cardiomyopathy, labor complications,
premenstrual syndrome, dysmenorrheal, endometriosis, fertility and
subfertility conditions such as infertility, early pregnancy loss,
spontaneous abortion, subfertility, failure of implantation,
amenorrhea, luteal insufficiency, and the like; sudden death
syndromes, e.g., sudden adult death syndrome, and the like;
menstrual related disorders, e.g., pelvic pain, dysmenorrheal,
gastrointestinal disease, nausea, and the like; peripartum and
pregnancy related conditions, e.g., peripartum cardiomyopathy, and
the like; fibrosis; post-operative recovery conditions such as
post-operative pain, post operative ileus, post-operative fever,
post-operative nausea, and the like; post-procedural recovery
conditions such as post-procedural pain, post procedural ileus,
post-procedural fever, post-procedural nausea, and the like;
chronic pain; trauma; hospitalization; glaucoma; disorders of
thermoregulation; fibromyalgia; and the like. Other conditions may
also be treated in accordance with the subject invention.
Embodiments of the subject invention include treating one or more
conditions, sequentially or at the same time, in accordance with
the subject invention.
[0315] By "treatment" is meant that at least an amelioration of the
symptoms associated with the condition afflicting the subject is
achieved, where amelioration is used in a broad sense to refer to
at least a reduction in the magnitude of a parameter, e.g.,
symptom, associated with the condition being treated. As such,
treatment also includes situations where the condition, or at least
symptoms associated therewith, are completely inhibited, e.g.,
prevented from happening, or stopped, e.g. terminated, such that
the subject no longer suffers from the condition, or at least the
symptoms that characterize the condition.
[0316] A variety of subjects are treatable according to the subject
methods. In many embodiments the subjects are "mammals" or
"mammalian", where these terms are used broadly to describe
organisms which are within the class mammalia, including the orders
carnivore (e.g., dogs and cats), rodentia (e.g., mice, guinea pigs,
and rats), and primates (e.g., humans, chimpanzees, and monkeys).
In many embodiments, the subjects are humans and particularly
female humans. While the present invention may be used for the
treatment of a human, female subject, it is to be understood that
the subject methods may also be carried-out on other female animal
subjects such as, but not limited to, mice, rats, dogs, cats,
livestock and horses, etc. Accordingly, it is to be understood that
any female subject in need of being treated according to the
subject invention is suitable.
[0317] Moreover, suitable subjects of this invention include those
who have and those who have not previously been afflicted with a
condition, those that have previously been determined to be at risk
of suffering from a condition, and those who have been initially
diagnosed or identified as being afflicted with or experiencing a
condition.
Devices and Systems
[0318] The subject invention also includes devices and systems that
may be employed in the practice of the subject methods. The subject
systems may include an effective amount of at least pharmacological
agent. The pharmacological agent may be in any suitable formulation
or form. For example, a system may include a pharmacological
composition for transdermal administration, e.g., present as an
active agent of a transdermal patch, film or the like, an oral
dosage form, injection dosage form, suppository, etc.
[0319] In certain embodiments, the subject systems may also include
suitable pharmacological agent delivery means, the particulars of
which may be dictated by the particular pharmacological agent
employed, e.g., the particular form of the agent such as whether
the pharmacological agent is formulated into preparations in solid,
semi-solid, liquid or gaseous forms, such as tablets, capsules,
powders, granules, ointments, solutions, suppositories, injections,
inhalants and aerosols, and the like, and the particular mode of
administration of the agent, e.g., whether oral, buccal, rectal,
parenteral, intraperiactivityal, intradermal, transdermal,
intracheal, intravaginal, endocervical, intrathecal, intranasal,
intravesicular, on the eye, in the ear canal, etc. Accordingly,
certain systems may include a suitable drug delivery device, e.g.,
a suppository applicator, syringe, I.V. bag and tubing, electrode,
an implantable drug delivery device, an electrostimulatory device,
and the like.
[0320] Systems may also include one or more devices for delivering,
e.g., implanting, a component such as a drug delivery device, an
electrosurgical device, and the like, to a target site of a subject
such as into the body cavity of a subject. For example, an
endoscope, introducer needle, and the like, may be provided.
Systems may also include one or more imaging or scanning
apparatuses such as a fluoroscope, CT scan, and the like.
[0321] Embodiments of the subject systems may also include an
electrical energy supplying device such that a system according to
the present invention may include at least one electrode for
electrically modulating at least a portion of a subject's autonomic
nervous system. In certain embodiments the electrical energy
supplying device may be an implantable device, or at least certain
components such as one or more electrodes, may be implantable.
Certain embodiments may include a plurality of electrodes, where
some or all may be the same or some or all may be different. For
example, at least a first electrode may be provide for electrically
stimulating at least a portion of the autonomic nervous system and
at least a second electrode may be provided for inhibiting activity
in at least a portion of the autonomic nervous system. In certain
embodiments, a "test" electrode, as described above, may be
included in a system. As noted above, such "test" electrodes may be
a radiofrequency controlled electrode. Still further, one or more
electrodes may be included in a system which, instead of or in
addition to delivering electric impulses to at least a portion of
the autonomic nervous system, delivers an autonomic nervous system
pharmacological agent to at least a portion of the autonomic
nervous system, e.g., may be used to deliver a pharmacological
agent. Included may be an energy source such as a battery or
generator, where in certain embodiments the energy source may be
implantable, and may also include one or more leads or wires for
coupling the one or more electrodes to an energy source.
[0322] A system for use in practicing the subject methods may also
include a suitable detector for detecting one or more physical
and/or chemical aspects related to the autonomic nervous system.
The detector at least includes data gathering means. Also provided
may be data analysis means where such may be a separate component
from or integral with data gathering means, but in many embodiments
is operatively coupled to data gathering means, e.g., integral
with. In use, data related to one or more aspects of the autonomic
nervous system may be collected by data gathering means and
forwarded to data analysis means which executes steps necessary to
process and evaluate the collected data and determine whether at
least a portion of the autonomic nervous system is in need of
modulation. Such evaluation may include comparing data to reference
values, etc. For example, reference values may represent normal
parasympathetic activity/sympathetic activity ratios, as described
above, such as parasympathetic activity/sympathetic activity ratios
of healthy, like women in a particular menstrual cycle phase and/or
parasympathetic activity/sympathetic activity ratios of the subject
during a particular menstrual cycle phase, typically one in which
the condition of interest is not exacerbated or, if the phase is
the same phase in which the condition is observed to be
exacerbated, there is no observable exacerbation at the time the
ratio is observed for use as a reference data point.
[0323] When present, a detector (or data evaluation means if
separate) may be operatively coupled to one or more other elements
of a given drug delivery means and/or electrical energy supplying
device such that results of the determinations of autonomic
modulation may automatically trigger (or cease) activation of drug
delivery and/or electrical energy to the autonomic nervous system.
Suitable detectors include any detector capable of gathering
information about the autonomic nervous system and includes both
invasive, minimally invasive and non-invasive detectors where in
certain embodiments a detector may be an implantable detector.
Suitable detectors include, but are not limited to, those capable
of collecting data regarding nerve conduction, circulating
catecholamine levels, heart rate variability ("HRV"), respiratory
sinus arrhythmia, post-ganglionic action potentials, QT interval,
and the like and include, but are not limited to, MRI apparatuses,
CT apparatus, hormone level detectors, neurography apparatuses,
cardiovascular monitors, sensors including electrodes, etc.
Computer Readable Mediums and Programming Stored Thereon
[0324] Any part of the subject methods, e.g., detection, analysis
and activation/termination of drug delivery and/or electrical
energy including selecting suitable drug delivery parameters and/or
electrical parameters, may be performed manually or automatically.
For example, the subject invention may include suitable computing
means such as suitable hardware/software for performing one or more
aspects of the subject methods. For example, one or more aspects of
the subject invention may be in the form of computer readable media
having programming stored thereon for implementing the subject
methods. Accordingly, programming according to the subject
invention may be recorded on computer-readable media, e.g., any
medium that can be read and accessed directly or indirectly by a
computer. Such media include, but are not limited to, computer disk
or CD, a floppy disc, a magnetic "hard card", a server, magnetic
tape, optical storage such as CD-ROM and DVD, electrical storage
media such as RAM and ROM, and the hybrids of these categories such
as magnetic/optical storage media. One of skill in the art can
readily appreciate how any of the presently known computer readable
mediums may be used to provide a manufacture that includes a
recording of the present programming/algorithm for carrying out the
above-described methodology. Thus, the computer readable media may
be, for example, in the form of any of the above-described media or
any other computer readable media capable of containing
programming, stored electronically, magnetically, optically or by
other means. As such, stored programming embodying steps for
carrying-out some or all of the subject methods may be transferred
to a computer-operated apparatus such as a personal computer (PC)
or the like, by physical transfer of a CD, floppy disk, or like
medium, or may be transferred using a computer network, server, or
other interface connection, e.g., the Internet.
[0325] For example, the subject invention may include a computer
readable medium that includes stored programming embodying an
algorithm for carrying out some or all of the subject methods,
where such an algorithm is used to direct a processor or series of
processors to execute the steps necessary to perform the task(s)
required of it and as such in certain embodiments the subject
invention includes a computer-based system for carrying-out some or
all of the subject methods. For example, such a stored algorithm
may be configured to, or otherwise be capable of, directing a
microprocessor to receive information directly or indirectly from
data gathering means (i.e., information collected by data gathering
means about the autonomic nervous system) and process that
information to determine the state of the autonomic nervous system,
e.g., the activity level of the parasympathetic system and/or the
sympathetic system and even whether the autonomic nervous system
requires modulation and, if so, the specifics of the modulation
that may be required, e.g., to treat a condition. The result of
that processing may be communicated to a user, e.g., via audio
and/or visual means, e.g., the algorithm may also include steps or
functions for generating a variety of autonomic nervous system
profile graphs, plots, etc.
[0326] The algorithm may be configured to, or otherwise be capable
of, directing a microprocessor to activate, i.e., turn "on" and
"off" a drug delivery device, e.g., an implantable or external drug
delivery device and/or an electrical energy supplying device for
applying energy to at least a part of the autonomic nervous system,
e.g., in response to the above-described determination of the state
of the autonomic nervous system. For example, if it is determined
that sympathetic and/or parasympathetic activity needs to be
increased or decreased, the processor may direct a drug delivery
device to provide the appropriate amount of drug or otherwise
execute a suitable drug treatment regime to result in the desired
action. Likewise, in embodiments employing electrical modulation,
if it is determined that sympathetic and/or parasympathetic
activity needs to be increased or decreased, the processor may
direct an electrical energy supplying device to provide the
appropriate electric impulse or otherwise execute a suitable
electric energy treatment regime to result in the desired
action
[0327] The subject invention may also include a data set of known
or reference information stored on a computer readable medium to
which autonomic nervous system data collected may be compared for
use in determining the state of the autonomic nervous system. The
data may be stored or configured in a variety of arrangements known
to those of skill in the art.
Kits
[0328] Also provided are kits for practicing the subject methods.
The subject kits may vary greatly in regards to the components
included. Embodiments may include one or more pharmacological
agents and/or electrical energy supplying devices. In those
embodiments that include one or more pharmacological agents, the
amount of the pharmacological agents provided in a kit may be
sufficient for a single application or for multiple applications.
Accordingly, in certain embodiments of the subject kits a single
dosage unit of at least one pharmacological agent may be present
for a single application.
[0329] In certain other embodiments, multiple dosage units of one
or more pharmacological agents may be present in a kit for multiple
applications. In those embodiments having multiple dosage units,
such may be packaged in a single container, e.g., a single tube,
bottle, vial, and the like, or one or more dosage units may be
individually packaged such that certain kits may have more than one
container of a pharmacological agent or of different
pharmacological agents.
[0330] A kit may include a monthly pack that includes daily
discrete or continuous unit doses wherein the total number of daily
units present in the monthly pack and may be equal to the total
number of days of a month or the days of the menstrual cycle, e.g.,
a monthly pack may include a minimum of about 30 to about 90 days,
e.g., about 30 to about 84 days. The pack may include, for example
daily unit doses in the form of oral dosage forms such as tablets,
capsules and the like. The monthly pack may be a two or more stage
pharmaceutical pack, e.g., containing at least about 30 daily unit
doses in two stages. In its first stage, such a pack may include a
first pharmaceutical agent or placebo, wherein the first stage
includes a minimum of about 25 and a maximum of about 77 daily
discrete or continuous doses, e.g., equal to the number of days of
one or more particular menstrual cycle phases. The second stage may
include a second pharmaceutical agent equal to the number of days
of one or more particular menstrual cycle phases (e.g., the luteal
phase and/or menses phase), e.g., 5, 6 or 7 daily discrete or
continuous unit doses. The first and second pharmaceutical agents
may differ in one or more respects, e.g., they may be different
pharmaceutical agents (different types), they may be the same
pharmaceutical agent but may differ in dose of active agent, etc.
More stages may be included in certain embodiments. Accordingly,
the monthly pack may include a number of pills to be administered
by a subject each day of the month or of the menstrual cycle
wherein the pack is configured to include certain pills to be
administered to a subject on certain days or during certain
menstrual cycle phases, where the type, dosage, etc. of the pills
of the pack may vary.
[0331] Suitable means for delivering one or more pharmacological
agents to a subject may also be provided in a subject kit. The
particular delivery means provided in a kit may be dictated by the
particular pharmacological agent employed, as describe above, e.g.,
the particular form of the agent such as whether the
pharmacological agent is formulated into preparations in solid,
semi-solid, liquid or gaseous forms, such as tablets, capsules,
powders, granules, ointments, solutions, suppositories, injections,
inhalants and aerosols, and the like, and the particular mode of
administration of the agent, e.g., whether oral, buccal, rectal,
parenteral, intravaginal, endocervical, intrathecal, intranasal,
intravesicular, on the eye, in the ear canal, intraperiactivityal,
intradermal, transdermal, intracheal, etc. Accordingly, certain
systems may include a suppository applicator, syringe, I.V. bag and
tubing, electrode, transdermal patch or film, etc.
[0332] Kits may also include diagnostic or detection tests, for
detecting the occurrence or onset of a particular phase of a
subject's menstrual cycle, e.g., by determining certain hormone
levels, including relative hormone levels. For example, a urine
leutinizing hormone ("LH") detection test or kit or the like may be
present in a kit, where such urine LH detection kits are known in
the art, e.g., OVUQUICK ONE-STEP, CLEARPLAN EASY and SURESTEP brand
detection tests.
[0333] Kits may include an electrical energy supplying device, as
described above. Accordingly, subject kits may include an energy
supplying device such that they may include at least one electrode
for electrically modifying at least a portion of a subject's
autonomic nervous system in accordance with the subject invention,
as described above. In certain embodiments, the energy supplying
device provided in a kit is an implantable device, or at least
certain components such as one or more electrodes, may be
implantable. Certain kits may include a plurality of electrodes,
where some or all may be the same or some or all may be different.
For example, certain kits may include at least a first electrode
for electrically modulating activity at least a portion of the
sympathetic system and at least a second electrode for electrically
modulating activity in at least a portion of the parasympathetic
system. In certain embodiments, a subject kit may include a "test"
electrode, as described above such as a radiofrequency controlled
electrode. Still further, one or more electrodes may be included in
a kit which, instead of or in addition to delivering electric
impulses to at least a portion of the autonomic nervous system,
delivers an autonomic nervous system pharmacological agent to at
least a portion of the autonomic nervous system. Kits according to
the subject invention typically also include an energy source such
as a battery or generator, where in certain embodiments the energy
source may be implantable, and may also include one or more leads
or wires for coupling the one or more electrodes to an energy
source.
[0334] Devices for delivering, e.g., implanting, an electrical
energy supplying device and/or a drug delivery device to a target
site of a subject such as into the body cavity of a subject may
also be included in the subject kits. For example, an endoscope,
introducer needle, and the like may be provided.
[0335] The subject kits may also include instructions for how to
practice the subject methods. For example, instructions may include
how to administer the one or more pharmaceutical agents provided in
the kit to treat a subject for a condition by pharmacologically
modulating at least a portion of the subject's autonomic nervous
system. Instructions may include how to use an energy supplying
device provided in the kit to treat a subject for a condition by
electrically modulating at least a portion of the subject's
autonomic nervous system. The instructions are generally recorded
on a suitable recording medium or substrate. For example, the
instructions may be printed on a substrate, such as paper or
plastic, etc. As such, the instructions may be present in the kits
as a package insert, in the labeling of the container of the kit or
components thereof (i.e., associated with the packaging or
sub-packaging) etc. In other embodiments, the instructions are
present as an electronic storage data file present on a suitable
computer readable storage medium, e.g. CD-ROM, diskette, etc. In
yet other embodiments, the actual instructions are not present in
the kit, but means for obtaining the instructions from a remote
source, e.g. via the interne, are provided. An example of this
embodiment is a kit that includes a web address where the
instructions can be viewed and/or from which the instructions can
be downloaded. As with the instructions, this means for obtaining
the instructions is recorded on a suitable substrate.
[0336] Some or all components of the subject kits may be packaged
in suitable packaging to maintain sterility. In many embodiments of
the subject kits, the components of the kit are packaged in a kit
containment element to make a single, easily handled unit, where
the kit containment element, e.g., box or analogous structure, may
or may not be an airtight container, e.g., to further preserve the
sterility of some or all of the components of the kit.
[0337] It is evident from the above discussion that the above
described invention provides methods, system and kits for treating
a subject for a condition that is at least suspected of being
exacerbated during one or more menstrual cycle phases, e.g., a
condition that has catamenial variations. As such, the subject
invention represents a significant contribution to the art.
[0338] All publications and patent applications cited in this
specification are herein incorporated by reference as if each
individual publication or patent application were specifically and
individually indicated to be incorporated by reference. The
citation of any publication is for its disclosure prior to the
filing date and should not be construed as an admission that the
present invention is not entitled to antedate such publication by
virtue of prior invention.
[0339] Although the foregoing invention has been described in some
detail by way of illustration and example for purposes of clarity
of understanding, it is readily apparent to those of ordinary skill
in the art in light of the teachings of this invention that certain
changes and modifications may be made thereto without departing
from the spirit or scope of the appended claims.
* * * * *