Title: Migraine and
United States Patent: 7,396,649
Issued: July 8, 2008
Philip-John (Hollywood, GB), Lundy; Fionnuala Teresa (Belfast, GB), Shaw;
Christopher (Comber, GB)
Assignee: Philip-John Lamey
Appl. No.: 10/257,435
Filed: April 17, 2001
PCT Filed: April 17, 2001
PCT No.: PCT/GB01/01683
371(c)(1),(2),(4) Date: February
PCT Pub. No.: WO01/79270
PCT Pub. Date: October 25,
Master of Science in Law
The present invention related to the use
of Cystatin in predicting onset of migraines. The invention also relates
to the use of Cystatin as a vasodilatory agent. The invention also relates
to antagonists to Cystatin for use in treating and preventing and treating
Description of the
The present invention relates to a novel
biochemical marker associated with migraine and a method of predicting
forthcoming migraine attacks. The invention also relates to a novel
vasodilatory agent and to the use of a peptide to develop an antimigraine
The molecular basis of migraine was previously unknown. Work in this area
began with the clinical observation that most migraineurs woke with a
migraine from sleep. This cast considerable doubt on the previously
described relationship between migraine and so called trigger factors such
as the ingestion of cheese, chocolate, citrus fruits and red wine for two
reasons: firstly, the time scale was too long as patients normally sleep
for 6-8 hours and yet a pharmacological effect of an ingredient of these
substances should produce and effect within 1-2 hours and secondly,
critical evaluation of the evidence for these factors actually triggering
true migraine is weak.
In view of these observations, investigations were carried out regarding
factors during sleep which could conceivably trigger attacks of migraine.
The resulting research identified tooth clenching as the major problem and
this led to an appliance being described which obviated tooth clenching
during sleep and in turn prevented attacks of migraine. Indeed following
one year of treatment with such a device, around 85% of migraineurs suffer
no further attacks.
Whilst deciding how long a patient had to wear the appliance in order to
permanently alleviate their migraine, it became clear that a three month
period was too short. Indeed all patients who discontinued their attacks
by that time will experience an attack of migraine within ten days of
stopping appliance therapy. In essence the appliance could therefore be
used as a mechanism to trigger migraine in those individuals.
In a first aspect the present invention aims to provide a product to
predict the onset of migraine.
The invention provides a method of predicting the onset of migraine
attack, through the detection of elevated levels of salivary peptide
Following the establishment of a patient's normal Cystatin levels,
variations of this level can serve as an indication of an impending attack
According to the present invention there is provided a method for
predicting potential migraine attacks, the method comprising the steps of
establishing a normal level of Cystatin SN for an individual and
subsequently testing for variations thereof wherein elevated levels of
Cystatin SN indicate the on set of a migraine attack.
Elevated levels of Cystatin SN will preferably be at least three time the
Prediction of a migraine attack will enable an individual to commence
treatment of the attack before onset therefore minimising any ill-effects
or to plan ahead accordingly.
The method may extend to detecting levels of other members of the Cystatin
The detection method may look for the amino acid sequence which is known
for Cystatin SN. The invention further provides a device for use in
detecting elevated levels of Cystatin SN.
In one embodiment the device uses antibodies to Cystatin SN.
The device may be in the form of a dipstick.
The device may indicate changes of the level of Cystatin SN by colour
The invention may comprise use of an anti-sense RNA to the mRNA for
The invention comprises the use of the amino acid sequence of Cystatin SN
in the elucidation of the or a nucleic acid sequence in the development of
a test for elevated expression of Cystatin SN.
The invention provides such a test for detection of levels of expression
of the Cystatin SN gene.
Data undertaken blindly on saliva samples from migraineurs and non-migraineurs
has for the first time identified a reliable biochemical marker for
migraine. To date no other substance has been so strongly linked to the
Presently there are no reliable markers for migraineurs nor biochemical
predictive markers of attacks for an impending attack of migraine.
By having a model to trigger migraine attacks, the present inventors were
able to identify a peptide in saliva which appears to be associated with
migraines. The identified peptide was partially sequenced and the sequence
was shown to be homologous with the known sequence of salivary peptide
The present inventors have found that levels of Cystatin SN are about ten
times higher in migraineurs than non-migraineurs and levels rose markedly
in the 24 hours before a migraine attack.
As this molecule is intimately linked with migraine attack, it can be
concluded that its release as a result of tooth clenching may be the main
factor responsible for attacks of migraine.
The amino-acid sequence of the identified peptide accords with that of the
full sequence of Cystatin SN. This molecule offers for the first time the
opportunity to reliably predict the onset of migraine attacks within a 24
hour period and as such has important implications for the management of
migraineurs. FIG. 1 (SEQ ID NO.: 1, see Original Patent) show the full
amino-acid sequence of the Cystatin molecule.
As the full structure of Cystatins are known and the levels which are
normally present in migraineurs are known as opposed to non-migraineurs,
then a saliva based recording technique can be developed which quantifies
the amount of Cystatin present in saliva. Such a technique would give the
advantage that an individuals "baseline" Cystatin level could be
established, and from this level changes associated with the subsequent
development of an attack could be monitored, thus allowing forthcoming
migraines to be predicted.
It is a further object of the present invention to provide a new
According to another aspect of the present invention there is provided a
novel vasodilatory agent, wherein said novel, vasodilatory agent is or is
based on the peptide Cystatin.
Studies linking the release of Cystatin SN with the onset of a migraine
attack have shown that migraine attacks are related to profound
vasodilation. The effectiveness of Cystatin SN as a vasodilator has been
tested in vitro in an animal model system. This has shown that even crude
extracts of saliva from migraineurs are vasodilatory and therefore it
would be anticipated that refined preparations would show an even greater
The invention further provides a method of controlling the degree of
vascular tone by means of supplementing rational levels of Cystatin in the
Preferably said vasodilatory agent may be administered as a potential
application to a number of vasodilatory cardiovascular problems.
Preferably the invention will not be limited solely to Cystatin SN with
any suitable peptide of the Cystatin group of peptides or synthetic
versions or derivatives thereof being suitable for use.
The invention further provides use of Cystatin or a similar peptide in the
preparation of a medicament for the treatment of vasodilatory problems.
By similar peptide is meant a peptide having a similar sequence which is
prepared from nature or made synthetically or an active fragment thereof.
An active fragment will have vasodilatory activity.
Preferably, said Cystatin would include the amino-acid sequence: I I P G G
I Y N A D L N D E W V Q R A L H F A I S E Y N [SEQ ID NO.:2]
The amino-acid sequence of Cystatin is shown in FIG. 1 (SEQ ID NO.: 1).
Peptides being at least 60% homologous across the sequence should also be
The invention also provides a cDNA sequence which can be expressed to
produce Cystatin or a similar peptide for use as a vasodilator.
The cDNA sequence may be used in the preparation of a medicament for the
treatment of vasodilatory problems.
There are a number of conditions in which vasoconstriction produces a
disease process such as ischaemic heart disease and peripheral vascular
disease. The initial administration of Cystatin SN to in vivo and in vitro
animal systems would allow careful evaluation of the degree of
vasodilation caused by Cystatin SN and therefore its potential
Cystatin SN occurs naturally in low amounts in non-migraineurs. The levels
of systemic circulation are likely to control the degree of vascular tone
in vasodilation and therefore this could be supplemented by exogenous
emission of Cystatin SN.
The present invention characterises the relationship between Cystatin SN
as a vasodilatory neuro-peptide and its potential application to a number
of vasodilatory cardiovascular related problems.
As Cystatin SN is a naturally occurring substance, the clinical response
should be beneficial, but requires evaluation in a model system,
particularly model systems which look at intra-cranial vasodilation.
Although the inventors do not wish to be bound by any particular theorem,
the invention would be put into practice by using molecular techniques
which involve cloning the substance and producing large volumes of it.
Following this, the relative vasodilatory effect of the peptide versus
other similar peptides would be tested in in vitro animal model systems.
At the same time baseline levels of Cystatin SN both in saliva and in
serum would be evaluated in migraineurs and non-migraineurs with this,
followed by the administration of Cystatin SN perhaps initially by means
of topical application to assess its vasodilatory effect. These effects
would be further analysed both from a laser doppler point of view and also
using the technique of thermographic imaging which allows non-invasive
assessment of the degree of local vasodilation produced by the substance.
It is a further object of the present invention to provide a novel therapy
for use in migraine management or prevention.
Migraine is currently managed in a number of ways. Although patients are
often advised to avoid the so called trigger factors as detailed above, it
is the inventor's opinion that this rarely solves the problem. Drug
therapy is a standard way of managing migraine attacks and by and large
there are two main drug therapies employed. One type of treatment
comprises the administration of prophylactic drugs which can involve drugs
such as beta-blockers which are given on an everyday basis, but the
rationale and evidence that these are effective is not strong. The other
way in which drugs can be used to treat an attack is through treating the
attack at the acute stage. The problem with treatment at this stage, is
that by definition the patient has to suffer an attack before acute drug
therapy can be introduced. Therefore although acute drug therapy has some
merit in reducing the severity of attacks, it is unable to prevent the
frequency of attacks by its very nature of administration.
There are several disadvantages to current drug therapies. Firstly, the
evidence for prophylactic anti-migraine drug therapy being effective is
not strong and secondly the role of acute drug treatment suffers from the
limitation that the patient has to actually suffer an attack before by
definition they can be treated. An additional disadvantage is that in
approximately 50% of such cases, treatment with the so called triptan
drugs, patients suffer a rebound headache within 24 hours.
The present inventors have shown that the substance Cystatin SN is
intimately linked to attacks of migraine. This offers the opportunity to
investigate the mechanism by which Cystatin SN causes attacks of migraine
and therefor offers new drug possibilities as an agent for developing a
drug against Cystatin SN or its receptor or increasing drug metabolism or
excretion or allowing current drug therapies, some of which are not
presently indicated for use in the treatment of migraine, to be given at
an earlier stage when they perhaps would be effective.
As there are no current reliable biochemical markers for migraine and
there is some doubt as to the mechanism by which even acute migraine drug
therapy is effective and as such the present invention in conjunction with
the identification of the Cystatin SN molecule offers a different
mechanism to prevent migraine attack.
The present invention thus provides the use of a Cystatin molecule in
developing a treatment for migraine wherein the treatment is based on an
antagonist of cystatin.
According to the present invention there is provided a method of treating
or preventing onset of migraine attack, the method comprising the step of
administering an antagonist to the molecule Cystatin.
Further, said method may extend to preventing migraine attack through the
administration of an antagonist against any member of the family
comprising Cystatin molecules.
Preferably the antagonist will be directed against the known amino acid
sequence of Cystatin SN.
The invention also provides the use of Cystatin in the preparation of an
antagonist thereto for the preparation of a treatment for migraine
The invention thus provides an antagonist to Cystatin.
The invention further provides the use of an antagonist to Cystatin in the
preparation of a medicament for the treatment of migraine.
The invention also provides a cDNA clone for expression and production of
Cystatin for use in the preparation of an antagonist thereto.
The amino-acid sequence of Cystatin is shown in FIG. 1 (SEQ ID NO.: 1).
Although the inventors do not wish to be bound by any particular theorm,
the present invention may have the use and advantages as described below.
Prophylactic drug therapy is not effective and as such was not considered
to be a fruitful avenue to pursue in terms of the mechanism of the drugs
currently against Cystatin SN. However, detailed studies by the inventors
on the effects of Cystatin SN on blood vessels have shown a relationship
to angiotensin converting inhibitors. Interestingly, we note from our
literature searches that these drugs are frequently associated with
attacks of migraine. It is therefore proposed to either administer current
acute phase therapies in a different way following a known prediction of
an attack, or alternatively to look at other drugs which are effective
against antiogtensin converting enzymes and then therefore Cystatin SN.
Clinical trials would be required to test the efficacy of current triptan
drug therapies against levels of Cystatin SN to show whether there was any
specific mode of action directed against Cystatin SN levels or
alternatively whether there is any indirect action. This work would
establish whether the effect of these drugs is truly via an effect on
antagonism to Cystatin SN. The apparently very long half-life of Cystatin
SN may also partly explain why in approximately 50% of the patients who
treat their migraine during the acute phase with triptan suffer a rebound
Although the particular description above and associated experimental work
relates to Cystatin, potentially any member of the Cystatin family may
show linked effects to the onset of migraine and as such an antagonist
against these would also be appropriate.
Claim 1 of 5 Claims
1. A method of monitoring an individual
to predict potential migraine attacks, the method comprising the steps of:
establishing a level of Cystatin SN for an individual at a first time
point, and then testing for variations of the level of Cystatin SN at a
later time point, wherein an elevated level of Cystatin SN at the later
time point relative to the level of Cystatin SN at the first time point is
predictive of the onset of a migraine attack.
If you want to learn more
about this patent, please go directly to the U.S.
Patent and Trademark Office Web site to access the full