Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-03-02
2001-10-02
Weber, Jon P. (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S579000
Reexamination Certificate
active
06297281
ABSTRACT:
The invention relates to a pharmaceutical composition comprising, as active ingredient, at least one substance inhibiting NO synthase and at least one substance trapping reactive forms of oxygen, and optionally a pharmaceutically acceptable carrier. The invention also relates to a product comprising at least one substance inhibiting NO synthase and at least one substance trapping reactive forms of oxygen as a combined product, in a separate form, of these active ingredients.
A pharmaceutical composition and a product according to the invention are advantageous in the treatment of pathological conditions where nitrogen monoxide and reactive forms of oxygen are involved, and particularly:
cardiovascular and cerebrovascular disorders including, for example, atherosclerosis, migraine, arterial hypertension, septic shock, cardiac or cerebral infarcts of ischaemic or haemorrhagic origin, ischaemia and thrombosis;
disorders of the central or peripheral nervous system such as, for example, neurodegenerative diseases including, in particular, cerebral infarct, senile dementia including Alzheimer's disease, Huntington's chorea, Parkinson's disease, Creutzfeld-Jakob disease, diseases due to prions, amyotrophic lateral sclerosis and also pain, cerebral trauma or trauma of the spinal cord, addiction to opiates, alcohol and habit-forming substances, erectile dysfunction and reproductive disorders, cognitive disorders, encephalopathy, depression, anxiety, schizophrenia, epilepsy, sleep disorders, eating disorders (anorexia, bulimia);
proliferative and inflammatory disorders such as, for example, atherosclerosis, pulmonary hypertension, glomerulonephritis, portal hypertension, psoriasis, osteoarthritis and rheumatoid arthritis, fibrosis, amyloidosis, inflammation of the gastrointestinal system (colitis, Crohn's disease) or of the pulmonary system and air passages (asthma, sinusitis);
diarrhoea, vomiting including that of autacoid origin, radioactive irradiation, solar radiation (UVA, UVB);
organ transplants;
autoimmune and viral diseases such as, for example, lupus, AIDS, parasitic and viral infections, diabetes, multiple sclerosis, myopathy;
cancer; and
all pathological conditions characterised by the production or dysfunction of nitrogen monoxide and/or reactive forms of oxygen.
In all these pathological conditions, there is experimental evidence showing the involvement of nitrogen monoxide or reactive forms of oxygen (Kerwin et al., Nitric oxide: a new paradigm for second messengers, J. Med. Chem. 38, 4343-4362, 1995; Halliwell B., Gutteridge J M C., Free radicals in biology and medicine, 2nd ed., Oxford, Clarendon Press, 1989). This is the case, in particular, with the experimental cerebral infarct which illustrates the invention (Buisson et al., The neuroprotective effect of a nitric oxide inhibitor in a rat model of focal ischemia., Br J Pharmacol. 106, 766-767, 1992; Nowicki et al., Nitric oxide mediates neuronal cell death after focal cerebral ischemia in the mouse, Eur. J. Pharmacol. 204, 339-340, 1991; Zhao et al., Delayed treatment with the spin trap -phenyl-N-tert-butyl nitrone (PBN) reduces infarct size following transient middle cerebral artery occlusion in rats, Acta. Physiol. Scand., 1994; Schulz et al., Improved therapeutic window for treatment of histotoxic hypoxia with a free radical spin trap, J. Cereb. Blood Flow Metab. 15, 948-952 (1995)). In this context, the medicaments that can inhibit the formation of nitrogen monoxide or reactive forms of oxygen may bring beneficial effects. No combination of these two active ingredients, namely an NO synthase inhibitor and a trap of reactive forms of oxygen has been produced. As is set out in the experimental part, these two active ingredients act in a synergistic manner. In fact, these two active ingredients administered in subactive doses (i.e. doses which do not, by themselves, produce a therapeutic effect), produce a highly significant therapeutic effect when they are combined.
The advantage of this combination is to reduce considerably the doses of each of the active ingredients and thus to reduce considerably their undesirable effects whilst gaining therapeutic efficacy. This invention is illustrated particularly well in an experimental pathological model of neurodegeneration: cerebral ischaemia with reperfusion.
The invention provides, therefore, a pharmaceutical composition comprising, as active ingredient, at least one substance inhibiting NO syntase and at least one substance trapping reactive forms of oxygen, and optionally a pharmaceutically acceptable carrier.
More particularly, the invention provides a pharmaceutical composition comprising, as active ingredient, a substance inhibiting NO synthase and a substance trapping reactive forms of oxygen.
The term NO synthase inhibitor should be taken to mean any specific or non-specific inhibitor of one of the isoforms thereof whether it be constitutive (neuronal or endothelial) or inducible (Kerwin et al., Nitric oxide: a new paradigm for second messengers, J. Med. Chem. 38, 4343-4362, 1995).
The term trap of reactive forms of oxygen should be taken to mean any chemical or enzymatic substance capable of opposing or trapping the or one of the reactive forms of oxygen such as O
2
.,OH
−
, RO
2
., RO., ONO
2
−
, NO., NO
2
. or H
2
O
2
(Halliwell B., Gutteridge J M C., Free radicals in biology and medicine, 2nd ed., Oxford, Clarendon Press, 1989). These substances may be natural or synthetic and have antioxidant properties. (Santrucek and Krepelka, Antioxidants—Potential chemotherapeutic agents Drugs Future 13, 975-996, 1988; Jackson et al., Antioxidants: a biological defense mechanism for the prevention of atherosclerosis, Med. Res. Reviews 13, 161-182 (1993); Aruoma, Characterization of drugs as antioxidant prophylactics, Free Rad. Biol. Med. 20, 675-705 (1996)).
In a pharmaceutical composition according to the invention, the NO synthase inhibitor and the trap of reactive forms of oxygen may be in a separate form or a combined form forming a salt. Preferably, the salt is formed from a derivative of the substance inhibiting NO synthase containing at least one basic group, and from a derivative of the substance trapping reactive forms of oxygen containing at least one acid group. Thus, salts may be formed, according to methods known to the person skilled in the art, from NO synthase inhibitors such as, for example, amidines, guanidines, pyridines or piperidines as defined below, and traps of reactive forms of oxygen such as, for example, the phenolic acids as defined below, and more particularly 3,5-di-tert-butyl-4-hydroxybenzoic acid, caffeic acid, sinapic acid or gallic acid.
The invention also provides a product comprising at least one substance inhibiting NO synthase and at least one substance trapping reactive forms of oxygen as a combined product, in a separate form, for simultaneous or sequential use in the treatment of pathological conditions in which nitrogen monoxide and reactive forms of oxygen are involved such as cardiovascular and cerebrovascular disorders, disorders of the central or peripheral nervous system, proliferative and inflammatory diseases, organ transplants, autoimmune and viral diseases, cancer and all pathological conditions characterised by the production or dysfunction of nitrogen monoxide and/or reactive forms of oxygen.
In a pharmaceutical composition or a product according to the invention, the NO synthase inhibitor and the trap of reactive forms of oxygen may be in doses that may be identical or different. The dosages are chosen in terms of the compounds combined with suitable diluents or excipients.
The NO synthase inhibitor and the trap of reactive forms of oxygen may be administered simultaneously or sequentially by the same route of administration or by different routes, depending on whether they are in a separate or combined form. Preferably, the routes of administration are oral, parenteral or topical.
NO synthase inhibitors include compounds of the amino acid and non amino acid type. The amino acid type o
Bigg Dennis
Chabrier De Lassauniere Pierre-Etienne
Bierman, Muserlian and Lucas
Patten Patricia
Societe de Conseils de Recherches et d'Applications Scienti
Weber Jon P.
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