Note: Descriptions are shown in the official language in which they were submitted.
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PREVENTION AND TREATMENT OF MIGRAINE AND OTHER RECURRENT
HEADACHES USING LEUKOTRIENE LTD4 RECEPTOR BLOCKER DRUGS
BACKGROUND OF THE INVENTION
This invention is in the field of pharmacology, and relates to drugs that can
help
reduce the frequency, duration, and/or severity of certain types of headaches
classified as
"recurrent primary headaches" (including migraine headaches and cluster
headaches). This
treatment involves daily or other chronic administration of certain types of
"leukotriene
antagonist" drugs which can suppress activation of the "D4" subtype of
receptor that is
normally activated by leukotrienes. Several such leukotriene D4 antagonist
drugs are
known; previously, they have been used for treating asthma, as discussed
below.
Migraine headaches (also referred to simply as migraines, for convenience) and
cluster headaches are discussed in numerous journal articles and in various
full-length
medical texts, such as Headache in Clinical Practice (edited by S. Silberstein
et al., Oxford
Univ. Press, 1998); Headache Class~cation and Epidemiology by J. Olesen (Raven
Press
1994), and Headache Disorders: A Management Guide for Practitioners, by A.
Rapoport
and F. Sheftell (W.B. Saunders, Philadelphia, 1996). In addition, various
definitions,
categories, and diagnostic standards have been approved and issued by the
International
Headache Society (IHS), and were published as a supplement to the journal
Cephalalgia in
1988.
Migraines and cluster headaches are important, well-known, and extensively
studied
medical problems, and they can be regarded as "recurrent primary headaches".
They are
recurrent, since they recur with sufficient frequency to seriously interfere
with the health
and quality of life of a patient, to a point of requiring and demanding
medical attention (as
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opposed to just taking an over-the-counter analgesic and lying down dll the
pain decreases).
They are "primary" headaches since they usually arise as a primary condition,
independently of other causative conditions such as tumors, sinus or other
infections,
bleeding problems, etc.
A third major category of recurrent primary headaches is often referred to as
"tension" (or "tension-type") headaches. Although these can often be resolved
in many
patients if the source of the tension can somehow be eliminated or
substantially lessened,
that approach may require a major lifestyle change for the patient, and is
often impractical
or impossible for patients who cannot escape from the demands imposed by
stressful work,
family, or other situations. Accordingly, recurrent tension headaches must
often be treated
as a medical problem using drug intervention, usually in combination with
training in
relaxation and stress management techniques. In addition, many researchers and
physicians
believe that tension headaches and migraine headaches exist on a continuum,
and involve
the same or overlapping neurobiological mechanisms. It should also be noted
that various
drugs (including anti-inflammatory drugs, such as certain types of
prostaglandin antagonists)
that are effective (in at least some patients) in treating migraine headaches
are also effective
in treating tension headaches as well. Because of their similarities and
overlapping factors,
it is believed by the Applicant that tension headaches may be susceptible to
effective
treatment, in at least some sufferers, using LTD4 receptor blocker drugs as
disclosed
herein.
There are at least three "aspects" or "traits" of primary recurrent headaches
that are
important in this invention, since these traits can provide quantifiable
evidence of whether a
treatment is or is not effective in controlling such headaches. Those three
aspects are: (1)
frequency, which is usually evaluated over a span of time, such as number of
such
headaches per week, per month, or per year; (2) duration, which evaluates
(usually in
hours) how long a headache lasts, from the time it begins to develop into a
migraine or
cluster headache, until it has been resolved; and, (3) severity (also referred
to as intensity),
which is based on subjective estimates of the severity or intensity of pain or
other side
effects (such as nausea) being suffered by patients during such headaches.
If a preventive drug treatment can significantly reduce any of these three
aspects, it
can be regarded as effective and beneficial, since it can substantially
improve the quality of
life for such patients. For obvious reasons, an ideas preventive treatment
would reduce all
three aspects; and, indeed, the preventive treatment disclosed herein does
indeed appear to
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accomplish that ideal goal, in at least some patients, based on an initial
open-label trial.
However, simultaneously reducing all three aspects of headaches is not
essential to
providing useful, effective, beneficial relief from severe headaches. A
treatment which can
reduce any one (or two) of those goals is effective and useful from a medical
perspective,
and will be enthusiastically welcomed by sufferers of migraine and/or cluster
headaches
(and by their families and friends).
Migraines are more common than cluster headaches, and have been studied more
extensively. In addition, a better and more effective set of drugs have been
developed to
treat migraines, than cluster headaches. For those reasons, the discussion
below focuses
mainly on migraines, rather than cluster headaches. However, because of
various
physiological and pharmacological factors, and because of the highly positive
results
observed so far in initial tests on migraine sufferers, it is believed by the
Applicant that
chronic treatment with leukotriene D4 (LT-D4) receptor blocker drugs, as
disclosed herein,
is also likely to provide significant benefits to at least some patients who
suffer from cluster
headaches, or from other types of recurrent primary headaches that do not
respond
adequately to other previously-known treatments.
It should also be recognized that migraines are often "triggered" or
aggravated by
certain factors, which vary widely among different patients. In some patients,
migraines are
triggered by eating certain foods, such as chocolate, red wine, MSG,
artificial sweeteners,
or certain types of cheese. In some patients, migraines can be triggered by
perfumes or
other compounds that generate odors. In women, migraines often accompany
menstruation.
Accordingly, if a preventive drug treatment can reduce the susceptibility of a
patient
to severe headaches by one or more triggering factors, that drug treatment is
effective and
useful. However, susceptibility factors are regarded herein as being fully
included within
the three factors listed above, since a treatment which reduces a patient's
susceptibility to
one or more triggering factors will reduce the frequency, duration, and/or
severity of
severe headaches suffered by that patient.
LACK OF EFFECTIVE PREVENTIVE TREATMENTS
Drug treatments for migraine headaches have improved substantially during the
past
few years, with the widespread introduction and use of drugs known as
"triptans". These
include sumatriptan (sold under tradenames such as IMITREX and IMIGRAN by
Glaxo-
Wellcome, and also used to treat cluster headaches), naratriptan (sold under
the tradenames
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AMERGE and NARAMIG, also by Glaxo-Wellcome), zolmitriptan (sold under the name
ZOMIG, by Zeneca Pharmaceuticals), and rizatriptan (sold under the name
MAXALT, by
Merck). All of these are available as tablets for oral ingestion; in addition,
for patients who
suffer from nausea, several of these drugs are also available in other forms,
such as
subcutaneous injectable formulations, nasal sprays, and wafers or troches
designed to
dissolve in the mouth.
The primary mode of action of all of these "triptan" drugs is believed to
involve
selective activation of certain serotonin receptors subtypes, primarily SHT-1B
receptors
(which are present on blood vessels) and SHT-1D receptors (which are present
on nerve
cell terminals, both peripherally and in the CNS).
Serotonin is the common name for 5-hydroxytryptan, abbreviated as 5-HT. Inside
CNS tissue (primarily the brain and spinal cord), 5-HT is a neurotransmitter
molecule
which is generally inhibitory, since it suppresses (rather than activates)
nerve signals in
neurons. In vascular tissue, sumatriptan and other "triptan" drugs generally
cause
constriction of blood vessels in the cerebral region, and help to reverse
neurogenic
inflammation around those blood vessels during migraine attacks.
In general, triptan drugs and other therapies that are suited for treatment of
acute
migraine headaches that have already emerged) cannot be used as chronic
preventive
treatments, for a number of reasons. One of the main reasons is that chronic
administration
of acute-care drugs (such as triptan drugs) to migraine patients often drives
a patient into a
state where the patient suffers "rebound" headaches and/or chronic headaches.
Indeed,
chronic administration of triptan drugs has been observed to generate
"transformed"
migraine headaches which occur daily. This is discussed in sources such as
Neurologic
Clinics: Advances in Headache (N.T. Mathew, editor; WB Saunders, Philadelphia,
PA,
199'n.
Triptan drugs also pose a risk of adverse cardiovascular events, such as heart
attack,
stroke, etc., so they are contraindicated in patients suffering from heart
disease, stroke,
uncontrolled hypertension, basilar or hemiplegic migraine, and in people
taking various
other drugs, such as monoamine oxidase inhibitors. Accordingly, before triptan
drugs can
be prescribed safely, the diagnosing physician must do a risk factor analysis
for various
potential cardiovascular disorders, especially among patients who may be
overweight or
who smoke, or who suffer from high cholesterol, inadequate exercise levels,
hypertension,
a family history of heart disease or stroke, etc. Clearly, the risks involved
in any such
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analysis would increase substantially if a doctor or patient were tempted to
use triptan drugs
as a chronic treatment.
Regrettably, standard preventive pharmacologic treatments (involving, for
example,
aspirin, acetaminophen, ibuprofen, ergotamine or its derivatives, etc.) simply
does not work
in the large majority of migraine patients. Migraine patients who take such
drugs on a daily
basis usually observe no significant reduction in the frequency, duration, or
severity of their
headaches. In addition, most of these drugs suffer from toxicity syndromes,
when used at
the dosage rates that migraine and cluster sufferers are tempted to use them
for preventive
purposes. Ulcers and other gastrointestinal bleeding and "8th nerve" toxicity
often result
when aspirin is used chronically and at unusually high dosages; hepatotoxicity
can result
from acetaminophen overuse; and various types of kidney damage can arise from
overuse of
these and other types of over-the-counter analgesics (it has been estimated
that 10 % of all
end-stage kidney disease is secondary to the overuse of over-the-counter non-
steroidal
medications). Addiction also may occur with prescription pain-killers such as
butalbital
products (Fiorinal, Fioricet, Esgic, etc.) or opiates (Percocet, Percodan,
Codeine, Stadol,
etc.).
In addition to those problems, prior efforts at chronic preventive treatments
for
migraine or cluster headaches also frequently resulted in undesired side
effects such as
fatigue, decreased energy, depression, weight gain, decreased libido, dry
mouth, cardiac
arrhythmias, hair loss, tremors, hepatotoxicity, etc. Most such efforts do not
maintain their
efficacy over sustained periods of time, and a number of such therapies
require periodic
monitoring of blood (including complete blood count (CBC), platelet counts,
blood urea
nitrogen levels, creatinine, and cholesterol levels), as well as tests to
ensure that liver
and/or kidney functioning has not been impaired.
In view of the important advances and options offered by the recent
development of
triptan drugs, it is widely agreed among headache specialists that preventive
therapies have
not kept pace with advances in acute therapy. All of the previously known
preventive
strategies (with the possible exception of very recent discoveries using
injections of diluted
botulin toxin) are associated with potentially serious limitations, adverse
events, and side
effects, all of which makes their use unattractive to doctors and patients.
Even when a
preventive therapy is deemed to be suitable for testing in a specific patient,
the results
usually show, at best, only about a SO% decrease in frequency and intensity,
in about half
of the patients tested on such treatment regimens.
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In general, the best preventive approach that treating physicians can take
under the
prior art involves efforts to control any potential triggering factors (such
as careful
screening of the patient's diet and environment to identify triggering
factors, so the patient
can take extra precautions to avoid them), and treatment of any concomitant
medical
problems that may help trigger migraines. For example, anti-depressants are
often
prescribed for patients whose migraines appear to be triggered or aggravated
by depression,
and beta-blockers (which help regulate heartbeat rates) are prescribed for
patients whose
migraines appear to be triggered by fluctuations in blood pressure or
heartbeat. Beta-
blockers are the most commonly prescribed treatment that might be regarded as
a
preventive treatment for migraine. However, beta-blockers are contraindicated
in patients
with asthma, and there is a high correlation between asthma and migraines;
roughly 20% of
asthmatic patients suffer from migraines.
For various similar reasons, there also are no truly effective strategies for
preventing
cluster headaches.
In summary, there is a severe and very serious lack of effective and adequate
preventive treatments to reduce the frequency, duration, and/or severity of
migraine or
cluster headaches. Accordingly, there is a major medical need for effective
preventive drug
treatments that can be used in a chronic and long-term manner to prevent
migraine or
cluster headaches (rather than just for treating them once they have
commenced), and to
reduce their duration and severity when they do arise.
In addition, there is also an important medical need for improved drug
treatments
that can decrease the amount of pain and suffering caused by migraine or
cluster headaches,
once they begin. One such form of treatment would involve administration of a
drug that
can help reduce migraine symptoms in patients who are not adequately helped by
the triptan
class of drugs. Another such treatment would involve coadministration of two
completely
different types of drugs, which would work by completely different and
independent
mechanisms, to provide better pain relief than either class of drug can
provide by itself.
BACKGROUND INFORMATION ON LI~T"~KOTRI~NES
Since this invention involves certain types of drugs that act as "leukotriene
antagonists", this section provides background information on leukotrienes,
and on drugs
used to reduce leukotriene activity in asthma patients.
Leukotrienes are naturally-occurring molecules that function as inter-cellular
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messengers in mammals. There are several subtypes, referred to by designations
such as
LTA4, LTB4, LTC4, LTD4, and LTE4, as discussed below. All of these types of
leukotriene molecules are formed from arachidonic acid, a molecule with 20
carbon atoms
that contains four internal double bonds near the center of the chain, and a
carboxylic acid
group at one end. Arachidonic acid is continuously synthesized at cell
membranes, by
cleavage of certain types of phospholipids. This cleavage reaction is
catalyzed by
phospholipase enzymes.
Free arachidonic acid is then converted into any of four different types of
compounds, which are leukotrienes, prostaglandins, prostacyclins, and
thromboxanes. All
four of these types of compounds are called "eicosanoids".
Prostaglandins, prostacyclins, and thromboxanes all contain cyclic structures,
and
are created when "cyclooxygenase" enzymes (often abbreviated as COX enzymes)
generate
cyclic structures from the carbon atoms in arachidonic acid. Recently-
commercialized
"COX inhibitor" drugs such as celecoxib (sold by a Monsanto-Pfizer consortium
under the
trademark CELEBREX) and rofecoxib (sold by Merck under the trademark VIOXX)
are of
great interest, both for inhibiting arthritis pain that cannot be treated
adequately by other
drugs, and possibly for helping treat (or reduce the risk of) certain types of
cancer,
including colon cancer.
Unlike the other three classes of eicosanoids, leukotrienes do not involve
cyclooxygenase enzymes; instead, leukotrienes are created from arachidonic
acid by a
completely different enzymatic pathway. In this pathway, the double bonds in
arachidonic
acid are rearranged to create a "conjugated triene" structure, with three
double bonds that
alternate with single bonds; it is this structure which gives leukotrienes
their "tri-ene"
name.
LTA4 has an epoxide structure which is relatively reactive and unstable;
accordingly, LTA4 serves mainly as a precursor, during the synthesis of the
other
leukotrienes. LTB4 is generated when the epoxide form is been hydrolyzed into
a di-
hydroxy compound. LTC4, LTD4 and LTE4 are all modified by the addition of
cysteine,
an amino acid that contains a relatively reactive sulfhydryl group (-SI-~ at
the end of a
spacer chain; accordingly, these "cysteinyl leukotrienes" are often referred
to as "cysLT"
compounds. The structures of all of these leukotrienes are known, and are
illustrated in
numerous reference works, including the Merck Index.
All of the eicosanoid compounds (including leukotrienes) tend to aggravate
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inflammatory, pain, and fever responses, and they have been the targets of
extensive
research on anti-inflammatory and analgesic drugs. For example, anti-
inflammatory steroids
such as cortisone function by suppressing the phospholipase enzymes that
generate
arachidonic acid from membrane phospholipids. Pain-killers such as aspirin and
ibuprofen
act by blocking (to some extent) the cyclooxygenase enzymes that control the
conversion of
arachidonic acid to prostaglandins, prostacyclins, and thromboxanes.
Leukotrienes have been recognized as inflammatory agents since the early
1980's.
Articles from that period which focus on specific cellular activities of the
various
leukotrienes include Smith et al 1980, Ford-Hutchison et al 1980, Bray et al
1981, Lewis
1981, Gimbrone et al 1984, and Levine et al 1984 (complete citations to
articles are
provided below). Review articles from that period include Bray 1983 and Piper
1984.
In particular, leukotrienes are extremely potent broncho-constrictors. They
range
from roughly 100 to 1000 times more potent than histamine in reducing the
internal
diameters of bronchial passageways. For this reason, leukotriene antagonists
are highly
useful in combatting asthma.
There are also several types of leukotriene receptors, as described in
articles such as
Metters 1995 and Nicosia et al 1999. It should be noted that cross-affinities
exist between
various leukotrienes and leukotriene receptors, as well as between leukotriene
antagonist
drugs and leukotriene receptors. For example, Aharony 1998 reports that both
zafirlukast
and montelukast appear to block LTD4 and LTE4 receptors, but do not appear to
block
LTC4 receptors.
Leukotriene Biosynthesis Inhibitors
A substantial number of US patents were issued in the 1980's and early 1990's,
claiming that certain compounds known as "leukotriene biosynthesis inhibitors"
could be
used to prevent and/or treat migraine headaches. Such patents that were
assigned to the
Warner-Lambert company include US 4,602,023 (Kiely et al 1986); 4,775,677
(Connor et
al 1988); 4,786,755 (Kiely et al 1988); 4,810,716 (Connor et al 1989);
4,868,195
(Carethers et al, 1989); 4,868,199 (Carethers et al 1989); 4,868,200
(Carethers et al 1989);
4,868,205 (Carethers et al 1989); and 5,142,095 (Connor et al 1992).
US patents assigned to Merck Frosst Canada on leukotriene biosynthesis
inhibitors
include US 5,081,138 (Gillard et al 1992); 5,093,356 (Girard et al 1992);
5,102,881
(Zamboni et al 1992); 5,190,968 (Gillard et al 1993); 5,204,344 (Prasit et al
1993);
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5,221,678 (Atkinson et al 1993); 5,225,421 (Gillard et al 1993); 5,232,916
(Zamboni et al
1993); 5,252,585 (Frenette et al 1993); 5,254,567 (Down et al 1993); 5,272,145
(Prasit et
al, 1993); 5,273,980 (Frenette et al 1993); 5,294,798 (Gillard et al 1994);
5,308,850
(Gillard et al 1994); 5,334,719 (Frenette 1994); 5,380;850 (Prasit et al
1995); and
S 5,389,650 (Frenette et al 1995).
Still other drugs which reportedly can inhibit the synthesis of LT molecules
include
BAYx100S (see Hamilton et al 1997 and Dahlen et al 1997), MK-886 (Friedman et
al
1993), MK-OS91 (Diamant et al 1995), ZD2138 (Nasser et al 1994), and zileuton,
also
known as A-64077 (Knapp 1990 and Hui et al 1991).
In addition, various published articles report physiological correlations
between
migraine headaches and leukotriene concentrations in the blood. These include
Parantainen
et al 19$6, Gazzaniga et al 1987, Moskowitz 1990, and LaMancusa et al 1991.
Despite the large amount of work that went into those research and patenting
efforts,
' none of those compounds (to the best of the Applicants' knowledge and
belief) were e~rer
IS approved or commercialized for use in preventing or treating migraines.
The reasons for the failure of numerous obviously interested companies to
commercialize a potentially huge product is rarely published; accordingly,
observers can
only assume that the very large numbers of leukotriene biosynthesis inhibitors
patented by
Warner Lambert and Merck Frosst Canada either were not effective in treating
migraine, or
provoked intolerable side effects when administered at the dosages necessary
to reduce the
severity or frequency of migraines. Although no one outside those companies
can know
with certainty why they did not succeed in using leukotriene biosynthesis
inhibitors to
prevent or treat migraines, it is highly relevant and worth noting that if a
leukotriene
biosynthesis inhibitor is administered to a patient, the direct result will be
to reduce the
2S ability of the leukotriene generating system to help handle the biochemical
load of
arachidonic acid that is being generated continuously inside any patient.
Since the
leukotriene system normally handles and disposes of a significant fraction of
the arachidonic
acid which is continuously being generated by cellular processes inside a
patient, one can
assume that if the leukotriene synthesis system is suppressed, the quantity of
arachidonic
acid that normally passes through the Ieukotriene system will be forced to
find other
metabolic pathways for processing and eventual disposal. Since arachidonic
acid is normally
converted into four types of eicosanoids (prostaglandins, prostacyclins,
thromboxanes, and
leukotrienes), a drug-induced suppression of leukotriene production will
necessarily shift a
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patient's biochemical equilibrium toward the production of more
prostaglandins,
prostacyclins, and/or thromboxanes. That is highly important, since each of
those three
classes of compounds can trigger potentially serious problems.
It also should be noted that the leukotriene biosynthesis inhibitor with the
most
S extensive record of widespread public use is zileuton, which is sold as an
anti-asthmatic
drug by Abbott Laboratories (N. Chicago, Illinois) under the trademark ZYFLO.
A search
of the National Library of Medicine database "MEDLINE" indicated that not a
single
article has ever been published on the use of zileuton for treating headache.
It appears likely that one of the reasons zileuton has never been studied to
evaluate
its potential for use in preventing migraine or other severe recurrent
headaches is that it
reportedly causes headaches, as a common unwanted side effect among people who
take
zileuton to treat asthma. The Physician's Desk Reference (52nd edition, 1998;
this same
information is also reprinted in the "package inserts" that are sold with the
drug) reports
that when zileuton was taken 4 times daily at 600 mg in various clinical
trials, nearly a
quarter (24.6 % ) of all users reported headaches as an unwanted side effect.
That result
needs to be put into perspective by pointing out that in the same clinical
trials, almost
exactly the same percentage (24.0 % ) of the control (placebo-treated) group
from the tested
population of asthma sufferers reported headaches as an unwanted side effect,
when they
took a harmless placebo drug. Nevertheless, it should not be surprising that
the makers of
zileuton did not choose to test it as a potential preventive or treating agent
for headaches,
when large numbers of tested patients reported that they got headaches shortly
after they
took the drug. It also must be noted that the frequency of reported headaches
did indeed
increase, rather than decrease, when patients were treated with zileuton; even
though the
increase was small and not statistically significant, it was nevertheless an
increase. That
result teaches directly away from the current invention.
Unless and until some company with a history of research on leukotriene
biosynthesis inhibitors is able to actually show that some particular
leukotriene biosynthesis
inhibitor is indeed a safe and effective treatment for migraine or cluster
headaches, the
reported high incidence of headaches as an unwanted side effect of leukotriene
biosynthesis
inhibitor treatment, and the total absence of any publicly reported follow-up
research which
proves or implements the speculative claims made in the biosynthesis inhibitor
patents listed
above, offer powerful and even compelling evidence that leukotriene
biosynthesis inhibitors,
as studied in the prior art, have not yet been developed into any sort of
effective treatment
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or preventive agent for migraine or cluster headaches.
Leukotriene Receptor Blockers
In the 1980's and 1990's, various drugs were developed which suppress the
effects
of leukotriene molecules in blood by binding to and occupying leukotriene
receptors. on the
surfaces of various cells, rather than by suppressing the synthesis of
leukotrienes. In
general, these types of receptor blockers occupy leukotriene receptors on a
"competitive"
basis, thereby rendering the receptors unable to bind with naturally occurring
leukotriene
molecules; however, receptor "antagonists" do not triggering the same type or
level of
cellular response which is triggered by natural leukotriene molecules.
Receptor blockers are often referred to as "receptor antagonists", or simply
as
"antagonists" for convenience. However, the term "antagonist" used in
pharmacology
includes any compound which opposes and reduces the effects of some other
compound.
Therefore, the term "leukotriene antagonist" includes drugs that act as
leukotriene
biosynthesis inhibitors, since they can oppose and reduce the effects of
leukotrienes.
Accordingly, a more specific term, "leukotriene receptor blocker" is used
herein to refer to
compounds which suppress the effects of leukotriene molecules by means of an
action
involving binding to a leukotriene receptor rather than an enzyme involved in
synthesizing
leukotriene molecules.
The unwanted side effects caused by the leukotriene D4 receptor blockers which
were selected for commercialization apparently are quite low, and at least two
drugs in that
category have become highly successful and widely-used chronic treatments for
asthma,
since they can help suppress the bronchial and alveolar constrictions that
cause or aggravate
asthma attacks. One of these drugs is zafirlukast, is sold under the trademark
ACCOLATE
by Zeneca Pharmaceuticals (Wilmington, DE); it is also referred to in various
articles as
ICI 204,219 (e.g., Taylor et al 1991, Dahlen et al 1991). Zafirlukast is one
of a large
number of chemical analogs listed in US patent 4,859,692 (Bernstein et al
1989).
The other widely used LTD4 receptor blocker is montelukast, sold under the
trademark SINGULAIR by Merck and Company (West Point, PA). Montelukast is one
of
numerous analogs listed in US patent 5,565,473 (Belley et al 1996).
Montelukast and zafirlukast are both known to block LTD4 receptors.
Montelukast
is described in the Merck Index (12th edition, 1996) as a "selective
leukotriene D4 receptor
antagonist", while zafirlukast is described in that same reference as a
"leukotriene D4
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receptor antagonist".
As used herein, the phrases "LTD4 receptor blocker" (or antagonist) or
"leukotriene
D4 receptor blocker" (or simply "D4 blocker" or "D4 antagonist") all refer
interchangeably
to a drug that can reduce the activity of the LTD4 class of leukotriene
molecules, by means
of binding reactions involving leukotriene receptors. However, this does not
require that
any such blocker must be highly selective, and must act only at receptors that
interact with
LTD4. For example, montelukast and zafirlukast each reportedly have some level
of
activity at both LTD4 and LTE4 receptors (Aharony 1998).
Montelukast and zafirlukast are very complex molecules, and are structurally
similar
to each other, as can be seen by comparing the molecular structures
illustrated in reference
works such as the Merck Index. Each of these drugs apparently was developed by
taking a
portion of a leukotriene molecule and bonding it to a different type of
molecule (Bernstein
1998), thereby creating a chimeric molecule that binds to LTD4 receptors, but
without
triggering the cellular response normally induced by natural LTD4 molecules.
Various other LT receptor blockers have also been reported, including ONO-1078
(Taniguchi et al 1993), LY293111 (Evans et al 1996), BAYx7195 (Boulet et al
1997),
pranlukast (Hamilton et al 1998), and various N-carbamoyl analogs of
zafirlukast (Brown et
al 1998). All of these LT receptor Mockers are believed to help control and
suppress
asthma attacks by competitively binding to and occupying one or more types of
leukotriene
receptors on bronchial cells and various types of blood cells. The effects of
these drugs on
asthma sufferers are discussed in various articles such as Busse 1996 (a
review article) and
other articles cited therein, and in a number of articles published after that
review, such as
Evans et al 1996, Roquet et al 1997, Boulet et al 1997, Dahlen et al 1997, and
Hamilton et
al 1997 and 1998.
Montelukast and zafirlukast are both sold in pill form, and can be taken every
day
for long periods of time. Rather than creating tolerance or dependency
problems, these
drugs appear to help suppress and reduce ongoing asthma problems, when taken
chronically, by helping suppress the hypersensitive immune or allergic
responses that often
grow cumulatively worse in people who suffer from unwanted and excessive
activity of the
allergic or other immune systems.
As noted above, neither montelukast nor zafirlukast (nor any other leukotriene
receptor blockers) have previously been used to treat or prevent migraine or
cluster
headaches. When montelukast and zafirlukast were tested in asthma patients
(their most
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obvious potential use, based on the knowledge that leukotrienes are very
potent
bronchoconstrictors), headaches were reported as one of the most common and
frequent
side effects. During clinical trials of montelukast, as reported in the
packaging insert
currently sold with montelukast (reprinted in the Physicians Desk Reference;
also available
on the Internet), nearly one-fifth (18.4%) of the nearly 2000 asthma patients
who were
tested reported that they suffered from headaches when they took montelukast.
Similarly,
during clinical trials of zafirlukast, 12.9% of the more than 4000 asthma
patients who were
tested reported that they suffered from headaches when they took zafirlukast.
in both cases,
the percentage of patients who complained of headaches were higher than the
percentage of
control patients who complained of headaches after taking a placebo.
Clearly, those results teach directly away from the subject invention. In the
face of
results which clearly showed that headaches were a common complaint of asthma
patients
who took either zafirlukast or montelukast, and which also showed that
headache
complaints were higher in treated populations than in placebo-treated control
populations, it
is not surprising that the makers of montelukast and ~rlukast did not choose
to test those
drugs as potential preventive or treating agents for headaches.
To the best of the Applicant's knowledge and belief, none of the leukotriene
antagonist drugs which are commercially available (including zafirlukast and
montelukast)
have ever previously been used, or even tested, to prevent or treat migraine
or cluster
headaches.
Due to the lack of any adequate and effective level of success among
previously
known attempted treatments for migraine or cluster headaches, there remains a
pressing,
widespread, and severe need for a treatment that can be used, on a chronic and
long-term
basis, to prevent migraine and/or cluster headaches from occurring, and to
reduce their
severity when they do occur. This is a serious and important medical need
which has been
acutely known for decades, by the millions of people who suffer from the
excruciating pain
of migraine and cluster headaches, and by the tens of thousands of physicians
and
researchers who have been looking, for decades, for such a treatment, without
success.
One object of this invention is to disclose and provide a method for long-term
and
chronic yet safe administration of a drug which can prevent migraine or
cluster headaches
(i.e., which can reduce their frequency in a patient who suffers from such
headaches).
Another object of this invention is to disclose and provide a method for long-
term
and chronic administration of a drug that can reduce the duration and/or
severity of
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migraine or cluster headaches, when they do arise.
Another object of this invention is to disclose and provide a method for
treating
migraine headaches among patients who do not adequately respond to "triptan"
drugs such
as sumatriptan, naratriptan, zolmitriptan, and rizatriptan.
Another object of this invention is to disclose and provide a method for
preventing
and treating migraine headaches among patients who are highly susceptible to
"triggering"
factors (such as perfume, or certain foods), to reduce their susceptibility to
acute headaches
when they occasionally encounter their triggering factors,
Yet another object of this invention is to disclose and provide a method for
coadministering two different types of drugs, which work by completely
different and
independent mechanisms, to provide better pain relief fvr migraine and cluster
headaches
than either drug can provide by itself.
These and other objects of the invention will become more apparent through the
following summary and description of the preferred embodiments.
~LlMMg.,~Y OF THE INVENTION
Receptor blocker (antagonist) drugs which can suppress the binding of the D4
class
of leukotriene molecules to leukotriene receptors can reduce the frequency and
severity of
certain types of severe headaches referred to herein as "recurrent primary
headaches",
including migraine and cluster headaches. Various LTD4 receptor blockers are
commercially available, including montelukast and zafirlukast.
In the past, these drugs have been used to treat asthma. However, during the
human
clinical trials in which montelukast and zafirlukast were tested on asthma
patients,
headaches were one of the most commonly reported side effects of each of those
two drugs.
Accordingly, they apparently were never subsequently tested as potential
preventive agents,
to prevent or reduce migraine or cluster headaches. Despite that reported side
effect in
asthma patients, montelukast and zafirlukast both have been shown to be
generally safe,
well-tolerated, and free of serious side effects, even when used every day
over a continuous
period of years.
It has recently been discovered that, in at least some patients who suffer
from acute
recurrent migraine headaches, LTD4 receptor blockers apparently can greatly
reduce the
frequency, duration, and/or severity of such headaches, even among patients
who did not
respond adequately to any previously known medical treatment. Accordingly,
LTD4 blocker
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drugs appear to provide an important and highly useful medical treatment to
reduce the
frequency, duration, and/or severity of migraine headaches, cluster headaches,
and possibly
other types of recurrent primary headaches, using dosage forms such as pills
that can be
taken every day without causing tolerance, dependence, or other adverse
effects.
Results obtained to date also indicate that LTD4 receptor blockers can also be
used
in acute treatments for migraine or cluster headaches that have already
emerged, or which
are showing onset symptoms. In treating acute or onset headaches, an LTD4
blocker drug
can be used (i) in combination with a "triptan" drug such as sumatriptan,
naratriptan,
zolmitriptan, or rizatriptan; (ii) in patients who do not respond adequately
to triptan drugs
and who need alternate treatment; and {iii) as substitutes or alternatives for
triptan drugs, to
avoid their overuse among patients who suffer from frequent acute headaches.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGURE 1 is a graph depicting a major drop in the reported frequency of
"severe"
migraine headaches in an open-label clinical trial of montelukast among long-
term migraine
sufferers. 53 % of the treated patients showed a greater than 50 % reduction
(random
probability less than 0.025) in the frequency of severe attacks, with 41 % of
the treated
patients showing a greater than 60 % reduction of severe migraine headaches.
FIGURE 2 is a bar graph depicting changes in the mean number of migraine
headaches per month, divided into "severe", "moderate", and "mild" categories.
There was
a large decrease in the reported "severe" headaches, and a smaller decrease in
the
frequency of "moderate" attacks. The small increase in the number of "mild"
attacks
indicated that daily montelukast treatment helped reduce the intensity of
migraine headaches
from "severe" to "mild" levels.
pESCRIP1'ION OF THE PREFERRED EMBODIMENTS
This invention relates to the use of drugs known as "leukotriene D4 receptor
blockers" (also referred to as LTD4 blockers) for preventing or treating
recurrent primary
headaches {which especially includes acute and severe migraine or cluster
headaches). In
one embodiment, this invention discloses a method of treating a patient who
suffers from
such recurrent primary headaches, comprising periodic administration (such as
daily
ingestion) of at least one LTD4 receptor blocker drug, using a chronic dosage
regimen
which is therapeutically effective in reducing at least one aspect of
recurrent primary
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headaches in such patient.
In an alternate preferred embodiment, which does not depend on or require an
analysis of the particular medical status or response of any specific
individual patients, this
invention discloses a method of preventive treatment to mitigate recurrent
primary
headaches, among a population of patients who suffer from such headaches. The
preventive
treatment comprises periodic administration of at least one LTD4 receptor
blocker drug, at
a chronic dosage regimen which has been statistically shown, in human clinical
trials, to be
effective in reducing the frequency, duration, and/or severity of recurrent
primary
headaches.
In other alternate preferred embodiments, this invention discloses methods of
treating acute headaches, either during their onset (approach) phases, or
after they have
become full-blown, acute, severe headaches, comprising the step of
administering at least
one LTD4 receptor blocker drug to a patient who is either experiencing the
onset symptoms
of an acute headache, or suffering from an acute headache that has already
emerged. In
either of these forms of treatment, the LTD4 receptor blocker can be co-
administered with
a triptan drug, or with any other prescribed analgesic.
Various LTD4 receptor blocker drugs are known; as noted above, the two best-
known such drugs are zafirlukast, (sold under the trademark ACCOLATE) and
montelukast
(sold under the trademark SINGULAIR). Although both are widely used for
treating asthma
patients, to the best of the Applicant's belief, neither of these drugs was
ever previously
used, or even tested, as a,potential preventive or treatment agent to help
control the
recurrent headaches that torment and often incapacitate patients who suffer
from severe and
acute migraine or cluster headaches. Apparently, the complete lack of interest
in this type
of use against severe headaches arose from the fact that headaches were the
most common
unwanted side effects that were complained of by asthma patients, who were
tested using
these drugs in early clinical trials.
Other LT receptor blocker drugs have also been reported in the literature
(citations
are provided above), including pranlukast, BAYx7195, LY293111, ONO-1078, and
various
analogs of zafirlukast as reported in Brown et al 1998. Any of these compounds
can be
tested for use as disclosed herein to treat recurrent primary headaches, using
no more than
routine experimentation.
In addition to claiming certain specific drugs in an exemplary list (i.e.,
zafrlukast,
montelukast, pranlukast, BAYx7195, LY293111, and ONO-1078), any desired salt
or
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analog of any such drug can also be used, provided that it is both
pharmaceutically
acceptable, and therapeutically effective in mitigating migraine headaches
when taken on a
daily basis. Numerous such salts and chemical analogs have already been
disclosed in the
U.S. patents cited above and in various other published locations.
In addition, other drugs are known which inhibit the biosynthesis of
leukotrienes.
Such drugs include BAYx1005, MK-886, MK-0591, ZD2138, and zileuton, as well as
numerous other drugs disclosed in the US patents cited above which are
assigned to Warner
Lambert or to Merck Frosst Canada. As mentioned above, the various US patents
on those
drugs claimed that they could be used to treat or prevent migraines; however,
to the best of
the Applicants' knowledge and belief, none of those drugs has ever been used
or even
tested as headache treatments, and those speculative claims were contradicted
by reports
showing that in clinical trials of zileuton, headaches were one of the most
frequent
unwanted side effects. Accordingly, since the mechanisms involved in
leukotriene
biosynthesis inhibition appear to be somewhat promising despite the apparent
prior failures,
a relatively low dosage of any such leukotriene biosynthesis inhibitor can be
tested in
combination with an LTD4 receptor blocker drug, to determine whether the
combination of
both drugs will be more effective than the LTD4 receptor Mocker drug alone at
preventing
or treating migraines without causing severe unwanted side effects.
It should also be noted that many of the leukotriene biosynthesis inhibitors
listed
above or disclosed in the various patents cited above were initially created
by bonding a
first portion, derived from a Ieukotriene molecule, to a second portion
derived from an
entirely different type of molecule, thereby creating a molecular chimera.
Such chimeras
are deliberately designed to bind and cling to (and competitively occupy)
proteins which
normally react with natural leukotrienes (catalytic enzymes, in the case of LT
biosynthesis
inhibitors; cell receptors, in the case of LT receptor blockers).
Accordingly, it is likely that at least some of the LT biosynthesis inhibitors
disclosed
in the above-cited patents are likely to also bind to LTD4 receptors. Such
competitive
binding can be evaluated easily, using simple in vitro binding assays.
Accordingly, any such
compound which can function as a bi-functional agent, to both inhibit LT
biosynthesis and
bind to D4 leukotriene receptors, can be evaluated as disclosed herein, to
determine
whether it can serve as an effective preventive treatment for migraine and/or
cluster
headaches.
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OVERVIEW OF CLINICAL TRIAL
Initial results which were gathered in an "open-label" trial involving 17
patients, as
described in more detail below, strongly indicate that LTD4 blocker drugs are
effective in
reducing the frequency, duration, and/or severity of migraine headaches, among
at least
some patients who are susceptible to such headaches. All 17 patients completed
the study,
which consisted of a 2-month period to establish baseline values (including
frequency and
severity of migraine headaches), followed by a 3 month treatment phase using
montelukast.
The treatment was quite well tolerated; no adverse events were reported by any
of the
patients.
Fifty-three percent of patients who suffered from severe migraine attacks
showed a
greater than 50 % reduction (probability less than < 0.025 percent) in the
frequency of
severe attacks, with 41 % of such patients showing a greater than 60 %
reduction in severe
attacks. These results are shown in Fig. 1.
Because of the way the data were processed and analyzed, relatively small
increases
were seen in occurrence rates for "moderate" or "mild" migraine headaches.
These
increases represent a substantial decrease in the severity of reported
headaches, many of
which moved out of the "severe" category and into the "moderate" category (as
well as out
of the original "moderate" category and into the "mild" category). All
patients who
responded to the drug rated the drug as excellent.
This Applicants do not claim or assert that all patients who suffer from
migraine or
cluster headaches will benefit from treatment using an LTD4 receptor blocker.
Nevertheless, this invention discloses that at least some such patients will
benefit
substantially from daily or other chronic administration of an LTD4 receptor
blocker drug.
Such treatment can reduce, in at least some patients, at least one and usually
two (or even
all three) of the three main quantifiable traits of recurrent severe headaches
(i.e., the
frequency, duration, and/or severity of such headaches).
In one preferred embodiment, an LTD4 blocker drug is administered in oral
form.
A "unit dosage" form with a predetermined quantity of the drug (such as a
tablet, capsule,
or other pill) is generally preferred, but other oral forms (such as syrups)
can be used if
desired. The drug is administered at a suitable dosage rate (such as one or
two pills per
day) on a chronic and long-term basis (such as for months at a time). When
administered in
such manner, the drug can help prevent and/or reduce the frequency of migraine
and/or
cluster headaches (and possibly other types of severe recurrent primary
headaches as well),
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and can help reduce the duration and/or severity of such headaches if and when
they do
occur.
As used herein, terms such as "preventing" and/or "treating" headaches are
used
broadly. "Preventing" headaches refers to a treatment which reduces the
occurrence or
frequency of migraine or cluster headaches (which typically can be expressed
in terms such
as the average number of headaches per month, or per year). "Treating"
headaches is a
broader term, and includes a drug treatment that can effectively reduce the
frequency of
such headaches, the duration of such headaches, or the severity of such
headaches (which
includes a reduction in pain intensity, a reduction in side effects such as
nausea, and other
such effects that would be regarded as beneficial by a migraine sufferer).
As used herein, any reference to "treating" migraine or cluster headaches
using an
LTD4 blocker drug also includes the use of such drugs to increase the potency
or efficacy
of other drugs (such as aspirin, acetaminophen, ibuprofen, naproxen,
sumatriptan,
ergotamine, or other analgesics) in treating migraine or cluster headaches.
As used herein, all references to "headache" refer to migraine headaches
and/or
cluster headaches, as those terms are used and interpreted by physicians who
specialize in
treating such headaches, and as defined in the medical textbooks cited above.
It is
recognized by the Applicants that treatment using an LTD4 blocker drug may be
able to
also help reduce the frequency or severity of other types of headaches as well
(especially
including certain types of severe recurrent headaches such as tension
headaches, which for
various reasons are not classified as migraine or cluster headaches). However,
this current
patent application does not cover or claim the use of LTD4 blocker drugs as a
general
treatment for any and all types of headaches.
Instead, this current application is limited to the use of LTD4 blockers as
agents for
reducing the frequency, duration, and/or severity of "recurrent primary
headaches" (which
especially includes migraine and cluster headaches), since there is a major
and pressing
need for such treatment. Prior to this discovery, there have been no adequate
dnag
treatments that can accomplish those goals in treating either migraine or
cluster headaches.
A new drug treatment that can achieve those results would be an extraordinary
blessing and
relief, for the millions of people who suffer from severe and often
debilitating migraine
and/or cluster headaches.
One of the primary advantages of using an LTD4 blocker drug on a chronic basis
to
help prevent migraine or cluster headaches is that such drugs apparently do
not create any
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problems of tolerance or dependency. Instead, based on their results in
treating asthma, it
appears that these drugs are likely to help suppress, control, and reduce,
over the long
term, various types of gradually cumulative problems which are characteristic
of overly-
sensitized immunological activity, in which a patient's immune or allergic
system keeps
getting primed, triggered, or otherwise perturbed in ways which disrupt its
desired "stand-
by" status, and which generate repeated episodes of unwanted activity,
inflammation, and
other problems.
If such results continue to be evidenced by chronic daily treatments which
last for
years without interruption, it appears that LTD4 blocker drugs may offer an
ideal approach
to a long-term preventive ("prophylactic") treatment to reduce the number of
episodes of
acute migraine or cluster headaches, and to reduce the number of "early onset"
episodes
which indicate the approach of a migraine or cluster headache in ways that
require
immediate medical intervention, using sumatriptan or other powerful
analgesics, to prevent
or reduce the onset or severity of a full-blown acute attack.
SHORT-TERM TREATMENT FOR EMERGENT HEADACHES
In another preferred embodiment, LTD4 blockers can also be used for short-term
treatment of a migraine and/or cluster headache that has akeady commenced,
either during
the early-onset stage, or after it has become a full-blown acute headache.
In this mode of treatment, an LTD4 Mocker can be administered on its own, or
in
conjunction with any other type of analgesic (such as aspirin, acetaminophen,
ibuprofen, or
naproxen) or acute migraine treatment (such as ergotamine or a triptan drug).
It is believed
that, by helping reduce and suppress the activity of leukotrienes at LTD4
receptors, such
drugs can provide a form of treatment which can act in an additive and
possibly synergistic
manner, to increase and improve the efficacy, speed, and other beneficial
results of other
types of analgesic drugs that are used to treat migraine or cluster headaches.
In addition, it is believed that LTD4 blocker drugs may be able to offer
substantial
pain relief and other benefits to migraine patients who are not adequately
responsive to
triptan drugs, ergotamine, or other analgesics (such as aspirin,
acetaminophen, ibuprofen,
or naproxen). Roughly 30% of patients who are suffering from severe migraine
headaches,
and who are treated by a specific triptan drug, do not receive adequate relief
from that
drug. When this occurs, other triptans are usually tested. Although a
different triptan drug
may help, a residual group of about 10 to 20 % of all migraine patients do not
respond
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adequately to any of the known triptan drugs. Patients who are non-responsive
to triptan
drugs, and patients who have numerous and frequent attacks (such as about 5
per month or
more), are especially promising candidates for treatment using LTD4 blockers,
either alone
or in conjunction with a triptan drug or any other know n analgesic.
Although orally ingestible formulations are generally preferred for such use,
injectable formulations can also be used, especially for very severe headaches
and/or in
people suffering from nausea and/or vomiting, who may be unable to keep down
an
ingested oral formulation. Alternately, rectal suppositories, percutaneous
patches, or other
modes of administration can also be used by people suffering from nausea
and/or vomiting.
It should be noted that the actions of leukotrienes and leukotriene
antagonists tend to
vary substantially, in sometimes inconsistent ways. For example, in some
situations,
leukotrienes cause vasoconstriction (i.e., narrowing of blood vessels), as
described in
Broughton-Smith 1989 and Menger 1994. But in other situations, leukotrienes
appear to
cause vasodilatation which is the opposite effect. As examples of this
apparent
inconsistency, the abstract of Ortiz et al 1995 opens with, "Cysteinyl-
leukotrienes cause
contractions and/or relaxations of human isolated pulmonary vascular
preparations", and
closes with, "The mechanical effects of LTD4 on human pulmonary vasculature
are
complex and are mediated via at least two types of cysteinyl-ieukotriene
receptors. "
Similarly, the abstract of Ford-Hutchinson et al 1986 states, "[leukotrienes]
may have
important cardiovascular actions through mechanisms involving either
vasoconstriction or
indirect vasodilatation. "
These apparently inconsistent and paradoxical activities of LT's seem to
mirror, in
some respects, certain paradoxical aspects of migraine headaches, which
typically involve
vasoconstriction during the early stages, followed by the opposite activity,
vasodilation
(which may be an overcompensating response), during the later stages.
DOSAGES AND MODES OF ADMINISTRATION
The preferred dosages for any LTD4 receptor blocker selected for use as
disclosed
herein will depend on various factors, including the age and body weight of a
patient taking
the medication, etc. In general, one of the primary initial goals of such drug
therapy is to
establish a daily oral dosage, so that a single convenient "unit dosage"
formulation (usually
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a pill, such as a tablet, capsule, etc.) can be taken by a patient each day.
The dosage levels
that have already been established for the anti-asthma formulations of
zafirlukast
("ACCOLATE", which normally is taken twice a day) and montelukast
("SINGULAIR",
which normally is taken once a day) offer a good starting point for evaluating
preferred
dosages that will have maximum beneficial effects in preventing migraine
headaches.
Evaluative tests to optimize the daily dosages for various patients with
particular migraine
patterns or seventies can be carried out using no more than routine
experimentation.
It should also be noted that capsules tend to be well suited for providing a
plurality
of microencapsulated quantities of an LTD4 receptor blocker drug. Different
formulations
and thicknesses for the microencapsulating material can be used, to provide an
array of tiny
pellets that will provide a sustained-release formulation, in a single
enclosing capsule that
can be taken once a day.
If desired, other types of oral formulations (such as syrups or other liquids,
lozenges, troches, etc.) can be developed, and may be well-suited for patients
who suffer
from nausea. Various types of non-oral formulations (including injectable
formulations,
nasal sprays, rectal suppositories, transdermal patches, etc.) can also be
developed; such
non-oral formulations may be preferred for acute treatment of migraines or
cluster
headaches that have already commenced, especially for patients who suffer from
nausea
during such headaches.
As another optional approach, an LTD4 blocker can be incorporated into a
single
tablet, capsule, or other formulation with one or more other drugs, to provide
additive or
synergistic treatment of migraines, either on a chronic preventive basis, or
on an acute
treatment basis.
Similarly, two or more LT antagonist drugs can be provided in a single
formulation,
if desired. For example, an LTD4 receptor blocker can be used along with a
leukotriene
biosynthesis inhibitor and/or a second LT receptor blocker which blocks a
different type of
LT receptor.
It should be noted that the currently available LTD4 receptor blockers,
zafirlukast
("ACCOLATE") and montelukast ("SINGULAIR"), typically require about 4 weeks
(and
sometimes more) of daily oral ingestion of tablets before noticeable effects
are seen in
reducing the frequency of asthma attacks. However, the articles cited above,
reporting the
testing of various LT antagonist drugs on asthma patients, indicate that such
agents exert a
variety of physiological effects within 24 hours of administration. It also
should be
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recognized that after this new use (i.e., using LT receptor blockers to
prevent or treat
migraine and cluster headaches) is recognized and evaluated by the medical
community, it
is likely that formulations (including IV or intramuscular injectable
formulations, nasal
sprays, etc.) can be developed which will not suffer from a prolonged lag time
before they
become effective in reducing the frequency of migraine headaches. Such non-
oral
formulations can be used for any desired period of time; for example, they can
be used as
initial treating agents, to quickly establish a desired level of the drug in
circulating blood.
Subsequent use of more convenient oral tablets or capsules can be used
thereafter, to
sustain the desired levels of a LTD4 receptor blocker drug in the blood.
LABELLED PACKAGES IN COMBINATION WITH LTD4 BLOCKERS
This invention also discloses an article of manufacture, comprising a LTD4
receptor
blocker inside a labelled package which encloses and protects the drug,
wherein the labelled
package indicates to physicians and purchasers that the D4 blocker drug inside
the package
is effective, if taken on a daily or other chronic basis, in reducing migraine
headaches (or,
alternately or additionally, one or more other types of recurrent primary
headache), in at
least some patients who suffer from such headaches.
This type of article of manufacture, where the label is an essential element
of the
claimed item, and wherein the label cannot be separated, excised, or divorced
from the
drug contained inside the package, reflects the fact that under the laws which
apply to drugs
sold for human use, the drug and its labelled package are regarded as a single
indivisible
and integral item of commerce. It is illegal to sell such drugs, no matter how
safe or
effective they may be, unless they are packaged and labelled in a manner that
has been
approved by the Food and Drug Administration, in the United States (or by
similar agencies
in other countries).
Preferably, the drug inside the labelled package should be orally ingestible,
for
convenience of use. Even more preferably, the orally ingestible formulation
should be a
"unit dosage form", such as a tablet, capsule, or other pill which has a pre-
measured
quantity of the drug in each pill.
Exam In a 1 _gpen-Label Triai_
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An open-label clinical trial was organized and conducted at The New England
Center for Headache (Stamford, Connecticut), which specializes in treating
severe
headaches, including migraine headaches. Seventeen adult patients, all of whom
suffered
from "migraine without aura" as defined by International Headache
Societyz° (gIS) criteria,
were selected to participate. Each patient went through a 2-month baseline
evaluation,
followed by a 3-month trial period using daily ingestion of montelukast (an
LTD4 receptor
blocker) in tablet form. Fourteen females and 3 males, between the ages of 14
and 64
(mean age 45.5) were inducted into the study. The mean for "years suffering
from
migraine" was 24.6, with a range of 5 to 54 years. Although most (n=12) had
occasional
episodes of episodic tension-type headache (ETTHA), any patients with chronic
tension-type
headache were excluded. Inclusion criteria included diagnosis of IHS migraine
without
aura, the ability of patients to differentiate migraine from E'TTHA, and
willingness to keep
accurate headache calendars for the two-month baseline period and the three-
month
treatment phase. Patients with chronic tension-type headache, transformed
migraine,
analgesic/ergot/triptan overuse, or failure on two or more previous trials on
preventive
agents were excluded from the study. No changes in concomitant prophylactic
regimens
{n =11 of the 17 total) were allowed during the baseline (BL) period or during
montelukast
treatment.
In general, patients were selected only if they had not responded in an
adequate and
satisfactory manner to other treatments for migraine. Patients were not
selected if they had
totally failed to respond to any other preventive medications; accordingly,
those who were
selected generally comprised: (i) "partial responders" who were already
receiving some
form of preventive treatment when they entered the study, but who were still
experiencing a
sufficient number of migraine attacks to warrant further steps to improve
their treatment;
and, (ii) patients who had elected not to be on other preventive medications,
because of side
effects such as fatigue, weight gain, dry mouth, sexual dysfunction, etc. All
patients who
were chosen for the study, and who were informed of the drug that would be
used in the
study, were happy to take montelukast on a daily basis, in view of its very
low level of side
effects.
Each selected patient went through a 2-month "baseline" period. During that
period
{and also during the 3-month trial period), no medications, hormones, or other
medical
treatments were altered. Upon being selected, each patient was required to
keep a
"headache calendar" for at least two months prior to entering the trial, in
order to establish
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WO 00/21536 PCT/US99/23932
baseline or "control" data which could be compared to the results of the trial
period. Daily
administration of montelukast, in 10 mg tablets taken once per day, began
after the 2-month
baseline period had been completed by a patient. Patients who typically awoke
with
migraine attacks were dosed at bedtime. Patients who ieported that their
attacks typically
occurred during the afternoon or evening were dosed accordingly.
During the baseline period and the study period, the frequency, severity, and
duration of migraine attacks were recorded on a calendar or log book, by each
study
participant. All patients who did not show a decrease of at least 50% in
frequency of
attacks within 2 months after commencing montelukast treatment at 1 tablet/day
had their
dosages increased to 2 tablets per day, and were evaluated 4 and 8 weeks
later.
In addition, patients who reported specific sensitivity to perfume as a
migraine
triggering factor were evaluated for reduced sensitivity to perfume
triggering.
The trial was conducted as a prospective, "open label" trial. As such,
blinding
procedures were not used to conceal which drug a patient was taking; instead,
each patient
was informed of exactly what drug he or she would receive during the trial.
As shown in Fig. 2, the mean number of monthly attacks that were categorized
as
"severe", in baseline patients before montelukast treatment began, was 2.7$
(range 0 to
4.5). This frequency level was reduced by more than half {p < .025) by
montelukast
treatment, to a mean value of 1.31 severe attacks per month. Percentage
reductions for
individual patients are displayed in Fig. 1; these data indicate that more
than half of the
patients (53 % ) patients showed a reduction of more than 50 % in the
frequency of severe
attacks, with 41 % of patients showing a greater than 60 % reduction in
frequency.
Despite the shift of substantial numbers of headaches out of the "severe"
category
and into the "moderate" category, there was nevertheless a reduction in the
total number of
reported "moderate" attacks as well, as shown in Fig. 2. The mean number of
"moderate"
attacks per month reported by patients during the baseline periods was 5.5,
with a range of
1 to 9. This mean value decreased to 4.68 among treated patients. Although
this numerical
difference was not statistically significant on an absolute basis, it was in
fact highly
significant, since the overall frequency dropped even though several patients
reported
increases in the number of "moderate" headaches they suffered, as their
headaches shifted
out of the "severe" category and into the "moderate" category. In addition,
even when
patients were included whose attacks had decreased from "severe" to "moderate"
levels,
70 % of all reporting patients reported a decrease in the number of moderate
headaches they
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WO 00/21536 PCT/US99/23932
suffered.
For similar reasons, the number of "mild" headaches that were reported
increased
slightly, from a pre-treatment baseline level of 1.53 to a treatment level of
2.02. This
reflects the fact that a number of patients reported a substantial decrease in
the intensity of
S their headaches, from "severe" or "moderate" levels during the pretreatment
baseline
period, to "mild" levels during treatment.
A total of 4 of the 17 patients were escalated from 10 mg once daily, to 10 mg
twice daily, during the study (2 patients shifted after 1 month, and 2
patients shifted after 2
months). All 4 of these patients experienced a reduction in the frequency of
"severe"
attacks for the remaining 1 or 2 months of their treatment period. Several
other patients
were eligible for a dosage increase, but they declined, in view of their
satisfaction with
what appeared to them to be a substantial and highly welcome reduction in the
severity of
their attacks.
None of the patients reported any adverse effects; in specific, none of the
tested
patients reported any increase in headache frequency or severity.
Two of the 17 patients (regarded as "non-responders") reported no change in
frequency or severity levels for their migraine attacks.
Of the remaining 15 patients, 13 had a 33 % or greater reduction in the
frequency of
severe attacks. All 13 of those patients rated the treatment as "excellent",
and were highly
reluctant to terminate the treatment when their test period ended.
Additional and larger trials (including double-blinded placebo-controlled
trials) can
be carried out, using any selected type or formulation of an LTD4 blocker, on
any type,
class, or group of recurrent severe headaches, as necessary to evaluate such
formulation
and to obtain governmental approval to label that drug formulation for sale
and use as a
safe and effective treatment for such headaches.
Thus, there has been shown and described a new and useful method for treating
patients who suffer from recurrent severe headaches, including migraine
headaches and
cluster headaches. Although this invention has been exemplified for purposes
of illustration
and description by reference to certain specific embodiments, it will be
apparent to those
skilled in the art that various modifications, alterations, and equivalents of
the illustrated
examples are possible. Any such changes which derive directly from the
teachings herein,
and which do not depart from the spirit and scope of the invention, are deemed
to be
covered by this invention.
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