Note: Descriptions are shown in the official language in which they were submitted.
2127573
Niacin-Calcium-Caffeine-Acetylsalicylic-Acid
With Tryptophan Treatment For Migraines
The present invention of a novel composition relates to a treatment for
alleviating migraine headaches. Although two of the five components, namely,
acetylsalicylic acid and caffeine, are already used for treating headaches,
it is the addition of the other agents that relates to the novel composition
for use in alleviating mi~raine headaches.
Several medicinal treatments for migraines are known, although none
claims effectiveness with all migraine patients. One medication called
10 sumatriptan, a serotonin type lD receptor agonist, has been reported
effective in aborting migraines in 70% to 80% of migraineurs (Ferrari &
Saxena, 1993; Pearce, 1992). Sumatriptan has been reported to cause rebound
migraine headaches within 48 hours after use in one-third to 42% of patients
(Ferrari & Saxena, 1993; Pearce, 1992). Sumatriptan has been reported to
cause adverse effects on the heart by constricting coronary arteries and
occasionally causing cardiac ischemia in some patients, a serious side effect
(Ferrari & Saxena, 1993). The current high cost was reported as one of the
limits to sumatriptan's use (Pearce, 1992).
Other migraine medication can cause paresthesia, pain and weakness in the
20 extremities, specifically ergotamine with caffeine, tradename "Cafergot"
(Compendium of Pharmaceuticals and Specialties, 1993). Others contain
addictive substances such as a barbiturate or a narcotic, and may cause
physical dependency. For example, the migraine medication tradename
"Fiorinal" contains acetylsalicylic acid, caffeine, and the barbiturate
butalbital; "Fiorinal-C" contains acetylsalicylic acid, caffeine, butalbital,
and the narcotic codeine. The medication tr~d~n; e "Tylenol #3" contains
caffeine, acetaminophen, the narcotic codeine, and is used for headache pain
(Compendium of Pharmaceuticals and Specialties, 1993).
-- 1 --
2127573
-
Physiologic events occurring during migraine attacks include but are not
limited to the following: falling blood levels of serotonin (Anthony & Lance,
1971; Anthony & Lance 1989); vascular dilatation (Dalessio, 1979; Ferrari and
associates, 1991); inflammatory response in intracranial structures (Pearce,
1992); and in some not all migraines, an increasing release of histamine
still rising 24 hours after onset (Anthony & Lance, 1971).
Migraine medications containing substances that affect blood vessel
tone, such as vasoconstriction, could be expected to alleviate the migraine
feature of vasodilatation and/or irregularities of vasodilatation and
10 vasoconstriction. Migraine medications cont~ining substances that enhance
serotonergic functioning might be expected to alleviate the migraine feature
of falling blood levels of serotonin and/or the vascular sequelae caused by
diminished serotonin blood levels. Most migraine medications individually
influence only one or two of the first three physiologic events mentioned.
One medication that does influence these three physiologic features is
sumatriptan (Ferrari & Saxena, 1993), but it can cause rebound headaches and
other side effects.
The inventor hypothesized that extant agents ~nown to influence these
three physiologic features of migraines might be useful in treating
20 migraines. The inventor, a researcher who had already published several
studies involving serotonin, theorized that:
to reverse a decreasing blood level of serotonin, L-trYPtoPhan, a
precursor of serotonin, can be used;
to restore serotonin's influence in regulating blood vessel tone,
reversing the decreasing blood level of serotonin is required, and
acetYlsalicYlic acid can displace tryptophan from binding proteins,
thereby freeing up more tryptophan for serotonin synthesis (Chafetz,
1990, p. 61).
-- 2 --
2127S73
f~,
to facilitate tryptophan's conversion to serotonin instead of conversion
to kynurenines and/or nicotinic acid, niacin, which is also called
nicotinic acid, is effective because it is a feedback regulator for
the kynurenine pathway of tryptophan metabolism, and it reduces the
amount of tryptophan converted to kynurenines (Lapin, 1991).
to reduce vasodilatation, agents with vasoconstricting properties such
as caffeine (Leonard et al., 1987) or calcium (Guyton, 1986, p. 243)
are useful;
to reduce vasodilatation, avoiding food and drink high in potassium, a
mineral that causes vasodilatation (Guyton, 1986, p. 243), is a
logical proscription;
to reduce an inflammatory response, ascetYlsalicYlic acid can be used.
Except for the amino acid L-tryptophan, which requires a medical
prescription, the other agents require no prescription, are commonly
available and, at low doses, no serious risks are reported (Compendium of
Pharmaceuticals and Specialties, 1993; Hendler, 1990).
The first time this hypothesized combination of five agents was tested,
it terminated the migraine with no side effects or rebound headache. The
inventor was the first subject, thereby ensuring no one was put at undue
20 risk. Two and a half years of data have been collected on the first subject.
That evidence and subsequent data on others indicate that the hypothesized
composition alleviates migraines within 30 to 60 minutes and does not cause
recurring headaches 24 or 48 hours later. Apart from occasional flushing
of the face and/or upper body lasting 15 to 30 minutes, no side effects have
been reported in the small number of migraineurs who have tried this
treatment to date. These subjects had had migraines for at least 8 years,
have a family history of migraines, and previously had debilitating
migraines necessitating retreat to bed. Further studies are in progress.
-- 3 --
21275~3
This novel composition overcomes disadvantages posed by previous
treatments because, at worst, only minor side effects are listed in the
standard medication reference (Compendium of Pharmaceuticals and Specialties,
1993) for low doses of these common agents, and low-to-very-low doses are
used. This is consistent with the evidence so far. Apart from occasional
flushing, a "harmless" response to niacin (Stern et al., 1991, p. 66), no
side effects have been reported by migraineurs who tried this over a period
of 1 - 2 1/2 years. No rebound headaches 24 hours later have occurred during
that time period either. The caffeine component entails only low doses. The
10 other four agents are not known to have addictive properties.
Another advantage is that the cost of these common agents is rather
modest, and only a small fraction of the cost of the currently most effective
migraine treatment, sumatriptan. This could mean that migraine sufferers on
low incomes could more easily avail themselves of this approach. The novel
composition is used only when needed. This contrasts with preventative
migraine medications which are ta~en daily, thereby incurring the cost of
daily medication plus concomitant ris~ of side effects with long-term use.
This novel treatment has been repeatedly effective at the doses listed.
The invention consists of the following agents and directions for use:
100 milligrams vitamin B3 niacin;
500 lligrams calcium carbonate;
64 milligrams caffeine;
650 lligrams acetylsalicylic acid;
500 ll;grams amino acid L-tryptophan, which requires a prescription;
ta~en orally with 120 ll;litres of milk when one realizes one has a
migraine or awa~es with a migraine; all can be repeated four hours later
if migraine symptoms return, up to two repeats;
once ta~en, high-potassium foods are to be avoided for several hours.
-- 4 --
2127573
-
The standard practice of avoiding consumption of hot liquids in the hour
after taking niacin, applies because of the possibility of flushing (Stern et
al., 1991). The standard practice of ta~ing food or drin~ with niacin or
tryptophan is met with the small consumption of milk. However, the
composition works when ta~en with water if one is in a situation without mil~
immediately available.
Doses of 1 gram L-tryptophan have also been found effective, but this is
the suggested upper range Per intake because single doses higher than 1 gram
approach a "loading dose" of tryptophan. Loading doses activate the enzyme,
10 tryptophan pyrrolase, that routes tryptophan down the ~ynurenine pathway away
from conversion to serotonin (Gal & Sherman, 1980). Doses of caffeine could
range up to 100 lligrams per inta~e and still obtain benefit.
A subcombination of the novel combination, consisting of all the agents
minus the L-tryptophan, has been found to provide some benefit. Preliminary
evidence suggests that this subcombination halts a migraine from worsening
but symptoms present before intake may linger a few hours before
disappearing. This contrasts with recovery 30 to 60 minutes after inta~e
that has been found when all five agents are used.
Some migraine episodes have a concomitant strong release of histamine
20 that continues to increase 24 hours after onset (Anthony & Lance, 1971).
Not all migraineurs have seasonal allergies, but migraineurs who do have a
sensitivity to pollens might have this escalating-histamine variation when
exposed to certain plant substances. Migraineurs sensitive to rapid
barometric pressure changes, might have the escalating-histamine migraine
version when travelling by airplane or during fast weather changes. If
benefit were not obtained with the novel composition, the addition of a
histamine type 1 receptor bloc~er, such as a non-sedating 12-hour
antihistamine terfenadine, has been effective.
-- 5 --
2127573
All five agents have been in use with humans for decades or longer, yet
there are no reports of these five being combined therapeutically. Niacin
alone for migraines has been mentioned anecdotally (Hendler, 1990, p. 60).
Caffeine and/or acetylsalicylic acid are common co-agents in migraine
medication. But no other migraine medication includes tryptophan or calcium.
For these reasons, the inventor regards this novel composition as an
unobvious choice of agents to combine. All but L-tryptophan are readily
available in tablet form--at these doses--not requiring a prescription;
L-tryptophan requires a prescription in Canada.
No one has previously reported combining these five common agents
intentionally or serendipitously for a treatment effect. Numerous scientists
have striven to create effective migraine treatment, and current research
focuses on designing new drugs, not on using extant agents in new
combinations. The idea to combine these five agents was done by the inventor
first hypothesizing what might correct three physiologic features of
migraines, then by testing the hypothesis on a migraine subject who happened
to be the inventor. The first time this hypothesized combination was tried,
it terminated the first of many migraines with no side effects or rebound
headache; this occurred February 27, 1992. This novel treatment is the
20 outcome of scientific hypothesis-testing, not of serendipity or an "obvious"
combining of agents.
References to publications cited herein follow.
Anthony, M. & Lance, J.W. (1971) Histamine and serotonin in cluster headache.
Archives of Neurolo~Y 25, 225-231.
Anthony, M. & Lance, J.W. (1989) Plasma serotonin in patients with chronic
headaches. Journal of Neurolo~Y, Neurosur~erY. and PsYchiatrY 52, 182-184.
Chafetz, M.D. (1990) Nutrition and Neurotransmitters~ The Nutrient Bases of
Behavior. Prentice Hall: Englewood Cliffs, New Jersey.
-- 6 --
2127573
-
Canadian Pharmaceutical Association. (1993) ComPendium of Pharmaceuticals and
SPecialties. TwentY-Ei~hth Edition. Canadian Pharmaceutical Association:
Ottawa, Canada.
Dalessio, D. (1979) Classification and mechanism of migraine. Headache 19,
114-119.
Ferrari, M.D. & Subcutaneous Sumatriptan International Study Group. (1991)
Treatment of migraine attacks with sumatriptan. New En~land Journal of
Medicine 325, 316-321.
Ferrari, M.D. & Saxena, P.R. (1993) Clinical and experimental effects of
sumatriptan in humans. Trends in Pharmacolo~ical Sciences 14, 129-133.
Gal, E. & Sherman, A.D. (1980) L-kynurenine, its synthesis and possible
regulatory function in brain. Neurochemical Research 5, 223-229.
Guyton, A.C. (1986) Textbook of Medical PhYsiolo~Y. Seventh Edition.
W.B. Saunders: Toronto, Canada.
Hendler, S.S. (1990) The Doctors' Vitamin and Mineral EncYcloPedia. Simon &
Schuster: New York, N.Y.
Lapin, I.P. (1991) Kynurenines and seizures. EPilePsia 22, 257-265.
Leonard, T.K., Watson, R.R. & Mohs, M.E. (1987) The effects of caffeine on
various body systems: a review. Journal of the American Dietetic
Association 87, 1048-1053.
Pearce, J.M.S. (1992) Sumatriptan: efficacy and contribution to migraine
me~h~n; ~. Journal of Neurolo~Y. Neurosur~erY. and PsYchiatrY 55,
1103-1105.
Stern, R.H., Spence, D., Freeman, D.J., Parbtani, A. (1991) Tolerance to
nicotinic acid flushing. Clinical Pharmacolo~Y and TheraPeutics 50, 66-70.
