TITLE: METHOD FOR TREATING MIGRAINE HEADACHES

FIELD OF THE INVENTION

[001 ] This invention relates to a procedure for treatment of migraine headaches.

BACKGROUND TO THE INVENTION

[002] Migraine headaches have been a problem for mankind since time immemorial.

Such headaches can last for hours and less commonly for several days. Migraine headaches can be quite severe and incapacitating.

[003] The exact cause of migraine headaches is unknown, but various hypotheses include: vascular instability, autonomic nervous system dysfunction, and dietary incompatibilities. Numerous treatments exist including serotonin agonists, NSAIDS, ergot alkaloids, narcotics, beta-adrenergic receptor blockers (beta blockers) amongst others. Typically, most of such pharmaceuticals are administered orally.

[004] A number of pharmaceuticals have been employed in the past for the treatment of migraine including beta-blocking agents intended to prevent a migraine from arising. Once a migraine has commenced, generally other drugs have been employed to ameliorate the severity of the attack. A disadvantage of the prophylactic use of beta-blocking agents is that such drugs are typically administered on a regular basis as a constant drug therapy even in the absence of indications that a migraine is developing. This is an inconvenience for patients. In some cases, side effects develop from the administration of drugs on this basis.

[005] In view of the severe burden that migraine headaches impose on individuals, any procedure for the amelioration of the severity of such event would be useful.

[006] In some patients, a warning of an impending migraine event occurs in the form of an "aura" involving modifications to vision, topical tingling or through an unarticulated intuition. US patent 5,242,949 (to Goldberg et al.) describes the treatment of migraine through the administration of a beta-adrenergic blocking agent as soon as practical when it is determined that a migraine event is likely to occur. According to this reference, the blocking

agent, which can include Timolol (or its salts), is preferably administered nasally in an aqueous solution. Further, Goldberg et al, indicate that the blocking agent must be maintained at an appropriate blood concentration of for at least two hours after the onset of aura.

[007] Timolol maleate, also called "Timolol", is a non-selective beta-adrenergic receptor blocking agent. In an oral form ( e.g. Blocadren*), it is used to treat high blood pressure and prevent heart attacks, and occasionally as a prophylactic agent to prevent migraine headaches. In an ophthalmic solution ( e.g., Timoptic*) it is used to treat open-angle and occasionally secondary glaucoma by reducing aqueous humour production through blockade of the beta adrenergic receptors on the ciliary body epithelium. Timoptic* ophthalmic solution is supplied as a sterile, isotonic, buffered, aqueous solution of timolol maleate in two dosage strengths; Timoptic* 0.25% and Timoptic* 0.5%, containing 2.5mg/ml and 5mg/ml respectively. Timoptic* is applied topically as an eye drop.

[008] Timolol maleate eye drops have been prescribed as a prophylactic treatment against migraine headaches according to a report by Doctors M. Etemadifar and M. R. Abedi of the Department of Neurology, Isfahan University of Medical Science, Isfahan, Iran entitled "The preventive role of Timolol in treatment of migraine headaches", Journal of Research and Medical Sciences, VoI 10, No 5, Sept & Oct 2005. Administered in the form of a 0.5% water-based eyedrop solution, employed twice a day, this article reports success in terms of the prophylactic effect of such treatment. According to the protocol for this migraine treatment, Timolol drops were administered twice a day, one drop in the eye on the same side as the side where pain was typically occurring in the form of a headache.

[009] According to the report from this trial, the frequency of attacks per month dropped from 13.1 to 3.4 and the duration of attacks dropped from 16.4 to 2.1 hours. At the same time, the degree of severity of headaches experienced during the trial was shown to be markedly reduced.

[0010] Timolol eye drops were being administered topically in this trial as a prophylactic procedure. Accordingly, patients experienced repeated exposure to this pharmaceutical and were burdened with the constant chore of administering the drug according to a

predetermined time schedule. It would be desirable to develop a treatment for migraine that is not subject to these prophylactic inconveniences. The present invention addresses such an objective.

[001 1] The invention in its general form will first be described, and then its implementation in terms of specific testing will be detailed hereafter. These embodiments are intended to demonstrate the principle of the invention, and the manner of its implementation. The invention in its broadest and more specific forms will then be further described, and defined, in each of the individual claims which conclude this Specification.

SUMMARY OF THE INVENTION

[0012] According to the invention in one aspect, a person expecting to suffer from a migraine attack is treated by the administration of a therapeutically effective amount of a pharmaceutically acceptable solution of a beta adrenergic blocking agent, more particularly Timolol maleate, or ocularly compatible salts thereof, in the form of eye drops delivered topically during the interval beginning from the time and within the first 30 minutes thereafter when a patient first senses the onset, or potential onset, of a migraine headache. The preferred 30 minute treatment window commences at the first indication of an impending migraine attack whether in the form of an actual headache experience or an aura-like anticipatory experience. The administration of this active ingredient within this time window has been found to be effective in stopping the development of a migraine headache or reducing the intensity of migraine headaches.

[0013] It is predicted that all beta adrenergic blocking agents in drop form, including compositions having non-interfering components, will be effective if used in accordance with the procedure of the invention. Table 1 summarizes brand names comprising beta adrenergic blocking agents that will be effective if used in accordance with the procedure of the invention.

Table 1 - Brands and composition

Brand Composition

Betoptic* betoxolol

Betagan* levobunolol

Teoptic* metipranolol levobetaxolol carteolol

Cosopt* timolol and dorzolamide

Combigan* timolol and brimonidine

Xalacom* timolol and latanoprost

Duotrav* timolol and travoprost

* Trade-mark

[0014] According to a further preferred aspect of the invention, an optically compatible, e.g. 0.25% to 0.5%, aqueous solution of Timolol maleate is administered topically in the form of drops, the preferred dosage being one to two drops per eye and the preferred treatment being directed to both eyes.

[0015] According to another aspect of the invention, such drops may be administered repeatedly, between intervening intervals and preferably on half hour intervals, during the first two hours from the onset of a migraine headache.

[0016] It is believed and predicted that this effect, to a greater or lesser degree, but still to a therapeutically effective level, will be associated with all beta adrenergic blocking agents administered in a similar manner.

[0017] The foregoing summarizes the principal features of the invention and some of its optional aspects. The invention may be further understood by the description of the specific tests which follow.

[0018] Wherever ranges of values are referenced within this specification, sub-ranges therein are intended to be included within the scope of the invention unless otherwise indicated. Where characteristics are attributed to one or another variant of the invention, unless

DESCRIPTION OF SPECIFIC TESTS

[0019] At a general ophthalmology clinic, five patients with a long history of recurrent migraines were recruited to participate in a voluntary test. These patients did not have glaucoma. They were asked to treat future migraines with one drop of Timoptic* 0.5% ophthalmic solution, applied topically to both eyes at the onset of migraine or the aura of migraine, within 30 minutes of the first such indication of migraine. That is, the drops were to be delivered within the first 30 minutes thereafter when the patient first senses the onset, or potential onset of a migraine. Such administration of drops was to be repeated every half hour for up to two hours if the migraine persisted. The patients were not to use any other prophylactic or spontaneous treatment for migraine.

Patient 1 Female 49

History of migraines with classis visual aura 10 migraines over the study period. 9 migraines were stopped by one application of drops during the aura.

Patient 2 Female 21 History of migraines with classic visual aura

4 migraines over the study period. All responded to one application of drops at the onset of aura.

Patient 3 Male 51

History of migraines with classic aura.

2 migraines during study period. One migraine stopped with one application of drops. The second required a second application.

Patient 4 Female 47

History of classic migraines with aura, tension headaches, and hormonal headaches Fifteen migraines during the study period. The migraines were aborted 10 times.

Patient 5 Male 38

History of classic migraines with aura. 6 migraines during the study period. All responded to one application of drops.

All patients continue using the treatment.

[0020] Although the drug administered in the these tests was Timolol maleate marketed under the trade brand: "Timoptic*", the effect is not believed to be specific to this brand. It is believed and predicted that this effect, to a greater or lesser degree, but still to a therapeutically effective level, will be associated with all beta adrenergic blocking agents administered in a similar manner. Furthermore, it is believed and predicted that this effect will similarly be associated with the topical use of any of the brands/compositions listed in Table 1.

CONCLUSION

[0021] The foregoing has constituted a description of specific embodiments showing how the invention may be applied and put into use. These embodiments are only exemplary. The invention in its broadest, and more specific aspects, is further described and defined in the claims which now follow.

[0022] These claims, and the language used therein, are to be understood in terms of the variants of the invention which have been described. They are not to be restricted to such variants, but are to be read as covering the full scope of the invention as is implicit within the invention and the disclosure that has been provided herein.