Title: Use of valproic acid analog for the treatment and
prevention of migraine and affective illness
United States Patent: 6,268,396
Inventors: Nau; Heinz (Hannover, DE); Leahy; Emer (Tarrytown,
NY); O'Connell; Alan (Babylon, NY)
Assignee: American Biogenetic Sciences, Inc. (Copiague,
Appl. No.: 337986
Filed: June 22, 1999
This invention relates to a method for the treatment and prevention of
migraine and affective illness by administering a therapeutically
effective amount of the valproic acid analog 2-n-propyl-4-hexynoic acid.
The compound 2-n-propyl-4-hexynoic acid is an effective anti-migraine and
anti-affective illness drug with greatly reduced adverse effects including
neurotoxicity and teratogenic potential compared to valproic acid. This
invention thus provides an improved method for treating and preventing
migraine and affective illness.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to the use of the valproic acid analog
2-n-propyl-4-hexynoic acid as a treatment and prevention for migraine and
This invention provides a method of treating and preventing migraine or
affective illness in individuals by administering 2-n-propyl-4-hexynoic
acid. The synthesis and desirable metabolic properties of
2-n-propyl4-hexynoic acid are fully disclosed in U.S. Pat. No. 5,786,380
(Examples 7-8 and 10-11) which is incorporated herein by reference in its
entirety. Mammals, and in particular humans, who would benefit from this
method of treatment include those exhibiting, or at risk for exhibiting,
any type of recurring headaches, especially vascular headaches and those
which are moderate or severe. Individuals suffering from migraine are
expected to benefit from administration of 2-n-propyl-4-hexynoic acid. The
method of the invention comprises administering to an individual a
therapeutically effective amount of 2-propyl-4-hexynoic acid which is
sufficient to reduce or prevent migraine or affective illness.
In contrast to valproic acid, the compound for use with this invention
exhibits greatly reduced adverse effects and teratogenicity, and has a
longer duration of activity.
The data presented here show that like valproic acid,
2-n-propyl-4-hexynoic acid is expected to be effective against amygdala
kindled seizures. Furthermore, it exhibits adverse effects only at the
highest dose tested and those effects are much milder compared to that of
valproic acid. Therefore, 2-propyl-4-hexynoic acid provides an improved
method for the treatment and prevention of migraine and affective illness.
The compound 2-propyl-4-hexynoic acid is effective for the treatment of
acute mania with bipolar disorder. Typical manic symptoms include pressure
of speech, motor hyperactivity, reduced need for sleep, flight of ideas,
grandiosity, poor judgement, aggressiveness, and possible hostility.
The compound 2-propyl-4-hexynoic acid is also effective for the prevention
and treatment of migraine headaches.
It will be apparent to those skilled in the art that the compound
2-propyl-4-hexynoic acid for use with this invention may exist in
enantiomeric forms. Pure enantiomers may be resolved from the racemate by
methods well known in the art. Alternatively, enantiomeric forms may be
prepared by chiral synthesis. Individual R and S enantiomers, racemates
and non-racemic mixtures of enantiomers of 2-n-propyl-4-hexynoic acid are
all within the scope of this invention. When the individual enantiomers
are used, the S enantiomer of 2-n-propyl-4-hexynoic acid is preferred if
one needs to take advantage of the apparent higher pharmacokinetic profile
of the S enantiomer. However, if maximal avoidance of teratogenic side
effects is required, then the R enantiomer is the preferred form.
The dose of the compound used in the treatment of such disease will vary
in the usual way with the seriousness of the disorder, the weight and
metabolic health of the sufferer. The preferred initial dose for the
general patient population will be determined by routine dose-ranging
studies, as are conducted for example during clinical trials.
Therapeutically effective doses for individual patients may be determined
by titrating the amount of drug given to the individual to arrive at the
desired therapeutic or prophylactic effect while minimizing side effects.
Dosages may be similar to those used with valproic acid, however, they may
be adjusted appropriately, based on the potencies and kinetic parameters
disclosed herein or as determined by routine methods. A preferred initial
dose for this compound, may be estimated to be between about 1 and 60
mg/kg/day, more preferably between 10-20 mg/kg/day. The preferred plasma
concentration for patients taking 2-n-propyl-4-hexynoic acid is between
Administration of the compounds of this invention may be by any method
used for administering therapeutics, such as for example oral, parenteral,
intravenous, intramuscular, subcutaneous, or rectal administration.
This invention also provides pharmaceutical compositions for the treatment
of migraine. In addition to comprising the compound 2-n-propyl-hexynoic
acid or a salt or pro-drug thereof, the pharmaceutical composition may
also comprise additives such as preservatives, excipients, fillers,
wetting agents, binders, disintegrants, buffers, and/or carriers. Suitable
additives may be for example magnesium and calcium carbonates,
carboxymethylcellulose, starches, sugars, gums, magnesium or calcium
stearate, coloring or flavoring agents, and the like. There exists a wide
variety of pharmaceutically acceptable additives for pharmaceutical dosage
forms, and selection of appropriate additives is a routine matter for
those skilled in art of pharmaceutical formulation.
The compositions may be in the form of tablets, capsules, powders,
granules, lozenges, suppositories, reconstitutable powders, or liquid
preparations such as oral or sterile parenteral solutions or suspensions.
In order to obtain consistency of administration it is preferred that a
composition of the invention is in the form of a unit dose. Unit dose
forms for oral administration may be tablets, capsules, and the like, and
may contain conventional excipients such as binding agents, for example
syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; and
carriers or fillers, for example lactose, sugar, maize-starch, calcium
phosphate, sorbitol or glycine. Additives may include disintegrants, for
example starch, polyvinylpyrrolidone, sodium starch glycolate or
microcrystalline cellulose; preservatives, and pharmaceutically acceptable
wetting agents such as sodium lauryl sulphate.
In addition to unit dose forms, multi-dosage forms are also contemplated
to be within the scope of the invention. Delayed-release compositions, for
example those prepared by employing slow-release coatings,
micro-encapsulation, and/or slowly-dissolving polymer carriers, will also
be apparent to those skilled in the art, and are contemplated to be within
the scope of the invention.
The solid oral compositions may be prepared by conventional methods of
blending, filling, tabletting or the like. Repeated blending operations
may be used to distribute the active agent throughout those compositions
employing large quantities of fillers. Such operations are conventional in
the art. The tablets may be coated according to methods well known in
normal pharmaceutical practice, for example with an enteric coating.
Oral liquid preparations may be in the form of, for example, emulsions,
syrups, or elixirs, or may be presented as a dry product for
reconstitution with water or other suitable vehicle before use. Such
liquid preparations may contain conventional additives such as suspending
agents, for example sorbitol syrup, methyl cellulose, gelatin,
hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, and
hydrogenated edible fats; emulsifying agents, for example lecithin,
sorbitan monooleate, or acacia; non-aqueous vehicles (which may include
edible oils), for example almond oil or fractionated coconut oil, oily
esters such as esters of glycerine, propylene glycol, or ethyl alcohol;
preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic
acid; and if desired conventional flavoring or coloring agents.
For parenteral administration, fluid unit dosage forms are prepared
utilizing the compound and a sterile vehicle, and, depending on the
concentration used, can be either suspended or dissolved in the vehicle.
In preparing solutions the compound can be dissolved in water or saline
for injection and filter sterilized before filling into a suitable vial or
ampoule and sealing. Advantageously, additives such as a local anaesthetic,
preservative and buffering agent can be dissolved in the vehicle. Suitable
buffering agents are, for example, phosphate and citrate salts. To enhance
the stability, the composition can be frozen after filling into the vial
and the water removed under vacuum. Parenteral suspensions are prepared in
substantially the same manner, except that the compound is suspended in
the vehicle instead or being dissolved, and sterilization cannot be
accomplished by filtration. The compound can be sterilized by conventional
means, for example by exposure to radiation or ethylene oxide, before
being suspended in the sterile vehicle. Advantageously, a surfactant or
wetting agent is included in the composition to facilitate uniform
distribution of the compound.
Claim 1 of 10 Claims
What is claimed is:
1. A method of treating and/or preventing migraine in a mammal, comprising
administering to said mammal a therapeutically effective amount of
2-n-propyl-4-hexynoic acid or a pharmaceutically compatible salt thereof,
wherein the form of the 2-n-propyl-4-hexynoic acid is chosen from the
racemate, a single enantiomer, or a non-racemic mixture of enantiomers.
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