Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1996-11-12
2001-07-24
Fay, Zohreh (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
06265441
ABSTRACT:
The present invention relates to the use of a NO scavenger or an inhibitor or antagonist in the prophylactic or acute treatment of migraine or other vascular headaches in mammals including humans.
Many theories for the causation of migraine have been proposed and some have been reviewed.
It has been known for a century that nitroglycerin or glyceryl trinitrate may induce headache. Glyceryl trinitrate, which may be regarded as a prodrug for nitric oxide, induces a mild to moderate headache in healthy subjects. The present inventor and co-workers have previously made an investigation (Olesen et al., NeuroReport 4, 1027-1030 (1993)) to study whether migraine patients are more sensitive to nitric oxide than non-migrainous subjects, and it was found that glyceryl trinitrate-induced headache was significantly more severe in migraine sufferers, lasted longer and fulfilled diagnostic criteria for migraine more often. However, it has not hitherto been recognized that migraine as distinct fom headache in general is induced by glyceryl trinitrate and histamine, nor that they do so by activating the nitric oxide-cyclic guanylate monophosphate (cGMP) pathway and that this pathway could play a central role in the pathophysiology of migraine or other vascular headaches, as explained in more detail below.
The vascular pathophysiology of migraine has been evaluated in considerable detail. The migraine aura is throught to be caused by a cortical spreading depression (a slowly spreading depolarization of neurones and glial cells), and the pain is probably due to depolarization of perivascular nerve terminals cortically and/or around the large basal cerebral and extracerebral arteries. However, these findings do not explain the pain in migraine without aura. On the basis of animal experiments, it has been suggested that migraine pain is due to perivascular neurogenic inflammation around dural and meningeal arteries. This process is known to be associated with liberation of neuropeptide transmitters from perivascular trigeminal nerve endings.
During migraine attacks, concentrations of substance P (the primary mediator of neurogenic inflammation) remain normal in the external jugular venous blood whereas concentrations of calcitonin gene-related peptide (CGRP) are increased. However, substance P and CGRP are not likely to be the primary chemical mediators of migraine pain, since neither substance causes significant pain when injected into the temporal muscle and CGRP does not cause a headache when infused intravenously in humans. Although these substances could be nociceptive when released locally in high concentrations, it appears that other molecules may be more important.
Nitric Oxide and Pain
Nitric oxide (NO) has a large number of effects throughout the human body. It is a free radical which is highly reactive and is a molecular effector of activated-macrophage-induced cytotoxicity. Furthermore, it is the most important of the endothelium-derived relaxing factors. After its formation, NO diffuses into vascular smooth muscle where it activates soluble guanylate cyclase. This results in the formation of cGiW which, in turn, relaxes the muscle and dilates the blood vessels. Nitric oxide synthase catalyses the synthesis of NO from L-arginine, and this enzyme is present in nerve fibres surrounding cerebral blood vessels in animals and humans. However, the effect of nitric oxide formed in these nerves is unknown. Nitric oxide is also found in the CNS and has been shown to play an important role in the central processing of painful stimuli, it facilitates the transmission of noxious impulses from the periphery to the thalamus and the neocortex and, therefore, enhances pain.
The present inventor has now found that the nitric oxide-cyclic GNP pathway plays a central role in the pathophysiology of vascular headaches. In particular the present invention can be expressed in three parts as follows:
1. Activation of the nitric oxide-cyclic GMP pathway causes migraine in migraineurs cluster headache in cluster headache sufferers and non-specific vascular headache in others.
2. Drugs which are effective in the treatment of migraine and other vascular headaches and which are not general analgesics exert their activity by inhibiting one or more steps in the nitric oxide-cyclic GMP pathway or by exerting effects which antagonize the effects of products of this pathway.
3. Substances which cause vascular headache do so by stimulating one or more steps in the nitric oxide-cyclic GMP pathway or by exerting effects which are agonistic to those of one or more steps in this pathway.
More particularly the said investigations described below indicate that NO scavengers or inhibitors or antagonists can be used for the treatment of migraine or other vascular headaches.
Accordingly, the present invention provides the use of a NO scavenger or of an inhibitor or antagonist for an enzyme, coenyme, cofactor or other factor in, or product of, the nitric oxide-cyclic GMP pathway, for the production of a pharmaceutical composition for the prophylactic or acute treatment of migraine or other vascular headaches in mammals.
Suitably, the active principle used accordingly to the invention is a NO synthase inhibitor or a guanylate cyclase inhibitor. Furthermore, the active principle used according to the invention may suitably be a cGMP antagonist, an antagonist to a cGMP dependent protein kinase, or a NO scavenger.
Furthermore, the present invention provides a method for the prophylactic or acute treatment of migraine or other vascular headaches in mammals, which comprises administering to said mammal an effective amount for said treatment of a NO scavenger or of an inhibitor or antagonist for an enzyme, coenzyme, cofactor or other factor in, or product of, the nitric oxide-cyclic GMP pathway.
Suitably the NO synthase inhibitor used according to the invention is an arginine derivative such as those described in U.S. Pat. No. 5,028,627 and preferably it is L-NMMA, i.e. L-NG-monomethylarginine.
L-NMMA is available from Sigma Chemical Company Limited, Fancy Road, Poole, Dorset BH17 7NH, England.
In this connection it should be mentioned that the NO synthase inhibitor used according to the invention is intended for inhibition of one or more of the NO synthase enzymes known.
Suitably the guanylate cyclase inhibitor used according to the invention is methylene blue.
Suitable NO scavengers include transition metal complexes as described in International Patent Application W094/26263, for example Ferrioxamine B and Diethylenetriaminepentaacetic acid, Iron (III).
Many NO synthase inhibitors, for example L-NMMA, are capable of forming salts. Thus, the present invention includes NO synthase inhibitors in the form of salts, in particular acid addition salts.
Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable although salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Thus, preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, succinic, oxalic, fumaric, maleic, oxaloacetic, methanesulphonic, ethanesulphonic, p-toluenesulphonic, benzenesulphonic and isethionic acids. Salts of the compounds of NO synthase inhibitors can be made by reacting the appropriate compound in the form af the free base with the appropriate acid.
Whilst it may be possible for the NO synthase inhibitors to be administered as the raw chemical, it is preferable to present them as a pharmaceutical formulation. According to a further aspect, the present invention provides a pharmaceutical formulation comprising the NO synthase inhibitor or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers therefor and optionally one or more other therapeutic ingredients. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulat
Bacon & Thomas
Fay Zohreh
LandOfFree
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