Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1998-09-04
2001-05-29
Criares, Theodore J. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06239178
ABSTRACT:
TECHNICAL FIELD
This invention relates to a method of treating the symptoms of headache, migraine headache or recurring vascular disorders in a mammal, which conditions are indicated by low blood urea levels.
BACKGROUND ART
In humans, vascular disorders include headaches including wine headaches, migraine headaches and associated conditions. Typically migraines are a headache which can be characterised by a prodromal aura, unilateral onset, photophobia, severe pain, and autonomic disturbances during the acute phase, which may last for hours or days.
According to recent International Headache Society definitions, migraine can be divided into two broad clinical groups; migraine with typical aura and migraine without typical aura. The commonest clinical group being migraine without aura. Most patients with this form of migraine are women and many experience menstrual attacks. Migraine sufferers are acutely aware of their unpredictable unreliability and frequently avoid making social arrangements that they are scared they may be unable to fulfil, and on numerous occasions, rather than to be seen to let their colleagues down, many migraine sufferers prefer to tough it out and turn up at work, but often do not perform very competently.
Generally, the tendency to have migraine attacks is inherited and sufferers vary in the frequency of their attacks. Many have only one or two attacks a year and these usually result in a temporary social or work hiccup. Perhaps 10-15% of women experience one or more attacks per month and because of their unpredictability and the resulting unreliability, or reduction in competence of the sufferer, this group of patients experience substantial disruption to their activities.
There are two main forms or treatments used to counter the attacks. One is to take regular medication, trying to prevent the occurrence of the more severe unpleasant type of attack. The other is trying to treat such attacks as they occur, using either simple pain killers or specific anti-migraine treatments which are directed at the actual migraine process, attempting to stop individual attacks as soon as possible after onset.
OBJECTS OF THE INVENTION
It is a first object of the present invention to reduce the symptoms of headache including wine and migraine headache in humans.
It is a further object of the invention to provide a method of determining the cause of migraine in humans.
DISCLOSURE OF THE INVENTION
The present inventor has surprisingly found that many more than the expected number of human migraine sufferers have a low level of blood urea and therefore this blood condition is a marker for prospective migraine sufferers. Furthermore, migraine headaches are surprisingly thought to be a cause of erratic form in racehorses and greyhounds. Wine is also known to trigger biochemical reactions within the human body and it is thought that these reactions can be to some extent reversed, thereby at least reducing the symptoms.
According to a first aspect of this invention there is provided a method of reducing the symptoms of headache including wine and migraine headache in mammals said method comprising the step of reducing the concentration of arginine and as a consequence nitric oxide in the blood of the mammal and its arteries.
The method involves administering to a mammal a substance selected from the group consisting of:
(a) a substance which acts on the urea cycle to interfere with by reducing or preventing the production of arginine;
(b) an inhibitor of an enzyme which leads to an increase in nitric oxide levels;
(c) a substance which acts to remove ammonia from a mammal's body;
(d) a substance which reduces ammonia absorption by the mammal's body;
(e) an activator of arginase or inhibitor of arginine;
mixtures thereof and of other kinds of similar substances.
The concentration of arginine is usually reduced by activators of arginase or inhibitors of arginine. Typically any substance which acts on the urea cycle to interfere with by reducing or preventing the production of arginine, or acts to remove ammonia from a mammal's body, or reduces ammonia absorption by the mammal's body, or acts on the levels of nitric oxide in a mammal's body, mixtures thereof or of other kinds of similar substances may be used to reduce the concentration of arginine and nitric oxide. Other methods of reducing arginine and nitric oxide blood concentrations include blood transfusions so as to give blood, plasma or the like, and haemodialysis. The concentration of arginine and nitric oxide is usually reduced to a substantially normal level/concentration or within a substantially normal range/concentration in the blood of the mammal. A normal level/concentration of blood urea is normally indicative of a normal level/concentration of arginine and nitric oxide in the blood.
Examples of arginase activators and examples of inhibitors of arginine are hormones such as glucocorticoid and testosterone, possibly including adjusting physical stress levels experienced by the mammal.
Examples of substances which act on the urea cycle include inhibitors of the urea cycle such as excess levels of arginine: inhibitors of enzymes which lead to increased levels of nitric oxide such as inhibitors of arginosuccinase, arginosuccinic acid synthetase, carbamylphosphate synthetase, N acetylglutamate synthetase, arterial nitric oxide synthase; inhibitors of omithine transcarbamylase; gene replacement therapy for the defective gene which encodes for arginase, arginosuccinase, arginosuccinic acid synthetase, carbamylphosphate synthetase, N acetylglutamate synthetase, arterial nitric oxide synthase, ornithine transcarbamylase; substances which reduce the overall protein load, in particular reducing the amount of dietary arginine, aspartic acid and glutamic acid; substances which decrease the susceptibility of arginase to inhibition by extraneous substances including proline and branched chain amino acids or by changes in oestrogen and glucocorticoid levels or changes in the levels of the hormones involved in the menstrual cycle.
Examples of substances which act to remove ammonia from a mammal's body include antibiotics which reduce the production of gastrointestinal ammonia such as neomycin, or compounds such as sodium benzoate and phenyl acetate.
Examples of substances which reduce ammonia absorption by the mammal's body include charcoal and lactulose.
Examples of substances which act on the levels of nitric oxide in a mammal's body include inhibitors of nitric oxide production such as immunosuppresive agents like corticosteroids, azathioprine, antihymocyte globulin or cyclosporin.
This invention particularly relates to reducing the symptoms of headache including migraine and wine headaches in mammals by administering to the mammal an inhibitor of arginosuccinase.
The arginosuccinase inhibitors used for this treatment are typically N3 or N2 and N3 substituted arginines which include the following:
N3-(1-carboxy-2-methoxycarbonyl-ethyl)-L-arginine
N3-(1-carboxy-2-propoxycarbonyl-ethyl)-L-arginine;
N3-(1-carboxy-2-isobutoxycarbonylethyl)-L-arginine;
N3-(1-carboxy-3-N-ethylpropanamide)-L-arginine:
N3-(1,2-dimethoxycarbonylethyl)-L-arginine;
N3-(2-carboxy-1-methoxycarbonyl-ethyl)-L-arginine;
N3-(2-carboxy-1-propoxycarbonyl-ethyl)-L-arginine;
N3-(2-carboxy-2-isobutxycarbonylethyl)-L-arginine;
N3-(2-carboxy-1-N-ethylmethamidethyl)-L-arginine;
N3-(1-carboxy-2-nitroethyl)-L-arginine;
N2-methyl-N3-(L-1,2-dicarboxy-ethyl)-L-arginine;
N2-dimethyl-N3-(1,2-dicarboxy-ethyl)-L-arginine:
N2-propyl-N3-(1,2-dicarboxy-ethyl)-L-arginine;
N2-isobutyl-N3-(1,2-dicarboxy-ethyl)-L-arginine, and
N2-ethylamino-N3-(1,2-dicarboxy-ethyl)-L-arginine.
An investigation into the cause of migraine headaches indicates the arginase enzyme as a likely site of a defective enzyme in migraine, the mechanism being the unfettered production of arginine, thereby driving the production of the dilating and pain producing chemical nitric oxide.
While several studies have shown infusions of arginine have not produced migraine in e
Criares Theodore J.
Ladas & Parry
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