Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-05-03
2002-03-19
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S141000, C514S215000, C514S217000, C514S410000, C514S923000
Reexamination Certificate
active
06358941
ABSTRACT:
SUMMARY OF THE INVENTION
The present invention relates to the use of pharmaceutically acceptable cholinesterase inhibitors of the preparation of a pharmaceutical composition for the treatment or prophylaxis of arthritic disorders, including osteoarthritis, rheumatoid arthritis and other rheumatoid diseases such as Juvenile Arthritis, Systemic Lupus Erythematosis, Sjögren's Syndrome, Progressive Systemic Sclerosis, Polymyositis, Dermatomyositis, Ankylosing Spondilitis, Reiter's Syndrome, Psoriatic Arthritis, Relapsing Polychondritis, Relapsing Panniculitis, Crohn's Disease, Ulcerative Colitis, Hereditary Complement Deficiencies, Collagen Vascular Diseases, Felty's Syndrome, rheumatological manifestations associated with bacterial and viral endocarditis or myocarditis and other rheumatological manifestations such as anaemia of chronic disorders. The invention also relates to a novel method of treatment or prophylaxis of such diseases and manifestations.
Preferably, the cholinesterase inhibitors are selected from a group of nicotinic acetylcholinesterase inhibitors such as galantamine (The name of this drug was previously spelled galanthamine).
DETAILED DESCRIPTION OF INVENTION
In the present description and claims, the term “rheumatoid” covers any of a variety of disorders marked by degeneration or metabolic derangement of the connective tissue structures of the body, especially the joints and related structures, including muscles, bursae (snyovial membranes), tendons and fibrous tissue. They are attended by pain, stiffness, or limitation of motion of these parts. Rheumatoid Arthritis is a chronic, recurrent systemic inflammatory disease primarily of the joints, usually polyarticular, marked by inflammatory changes in the snyovial membranes and articular structures and by atrophy and rarefaction of the bones. In late stages deformity and ankylosis develop. Extra-articular manifestations include vasculitis, atrophy of the skin and muscle, subcutaneous nodules, lymphadenopathy, splenomegaly, leukopaenia and often chronic anaemia.
In one important embodiment of the invention, the arthritic disorder is osteoarthritis. Osteoarthritis is a chronic degenerative disease of skeletal joints, which affects specific joints, commonly knees, hips, hand joints and spine, in adults of all ages. Osteoarthritis is characterized by a number of the following manifestations including degeneration and thinning of the articular cartilage with associated development of “ulcers” or craters, osteophyte formation, hypertrophy of bone at the margins, and changes in the snyovial membrane and enlargement of affected joints. Furthermore, osteoarthritis is accompanied by pain and stiffness, particularly after prolonged activity.
The method of the invention comprises administering an effective amount of a pharmaceutically acceptable cholinesterase inhibitor to a patient in need thereof.
The method of the invention results in the treatment or prevention of one or several of the following symptoms or signs associated with the above-mentioned diseases: muscle pain, muscle weakness, muscle stiffness, joint stiffness, joint pain, joint or tissue swelling, inflammation, and extra-articular manifestation as mentioned above, including anaemia.
The invention is based on discoveries made in connection with the treatment of patients for other conditions, e.g. chronic fatigue syndrome. Surprisingly, it was found that patients who, in addition to fibromyalgia or chronic fatigue syndrome, suffered from osteoarthritis or rheumatoid arthritis, had improvement of their arthritis symptoms.
Thus, ten patients with rheumatoid arthritis were treated with galantamine. The purpose of the treatment was to treat their fatique syndrome resulting from their rheumatoid arthritis. However, it was found that not only did the ten patients improve with respect to their fatique syndrome, but also in the symptoms of their rheumatoid arthritis condition itself. They had less articular pain and the inflammatory process was less active (as evidenced by less swollen and less painful joints) while they were on treatment with galantamine.
In other studies, reported in detail below, patients suffering from rheumatoid arthritis, osteoarthritis and other rheumatoid diseases, respectively, experienced marked improvements of their conditions, e.g. with respect to tiredness, pain, stiffness and grip strength, upon treatment with galantamine.
It was also found by direct measurement that there is a considerable acetylcholinesterase activity in the snyovial fluid of patients with rheumatological conditions. This finding is new and may shed light on the clinical observations with galantamine in rheumatological patients as this acetylcholinesterase activity is believed to exert a proteolytic activity in the snyovial fluid of these patients and may be directly related to tissue damage seen in both rheumatoid diseases and in osteoarthritis.
Patients with rheumatoid diseases or other chronic diseases very often suffer from anaemia of unknown pathophysiology. It is a normochromic, normocytic or hypochromic, non-progressive anaemia—the severity being related to the severity of the chronic disease. Both the serum iron and total iron binding capacity are reduced. The serum ferritin is normal or elevated and bone marrow storage iron is normal but erythroblast iron is reduced. The pathogenesis of this anaemia appears to be related to the decreased release of iron from macrophages, reduced cell lifespan and inadequate erythropoietin response to the anaemia. This anaemia is normally only corrected by successful treatment of the underlying disease and does not respond to iron therapy despite the low serum iron.
Thus, the present invention also relates to the use of pharmaceutically acceptable cholinesterase inhibitors for the preparation of a pharmaceutical composition for treatment or prophylaxis of anaemia associated with chronic disorders.
As appears from the above, the present invention relates to the administration of a cholinesterase inhibiter. Compounds which function as cholinesterase inhibitors may be divided into several groups, namely poison gases for use in warfare, insecticides, such as malathion, and drugs. In the present context, the term “pharmaceutically acceptable” indicates that the cholinesterase inhibitors in question are tolerable for the patient.
Pharmaceutically acceptable cholinesterase inhibitors include, e.g., galantamine and galantamine derivatives, norgalantamine and norgalantamine derivatives, epigalantamine, physostigmine, tacrine and tacrine analogues, fasciculin, metrifonate, heptyl-physostigmine, norpyridostigmine, norneostigmine, and huperzine or a prodrug therefor. Some of the cholinesterase inhibitors show certain undesirable properties, such as short half life, etc. In some cases, such deficiencies can be compensated for by modifying the compound into a prodrug for the active compound, in accordance with well-known principles for prodrug construction, such as introduction of hydrophilic groups to enhance the solubility of a compound in water, thus making it possible to formulate the compound as an injection solution, an introduction of lipophilic groups such as ester groups to enhance the capability of the compound to pass membranes and other barriers of the body to enable the drug to act in the affected area.
The presently preferred cholinesterase inhibitor used according to the invention is galantamine. Galantamine is known as an acetylcholinesterase acting substantially at nicotinic receptor sites, and having a high selectivity for acetylcholinesterase as opposed to butyrylcholinesterase. A more detailed discussion of galantamine and galantamine derivatives is given below:
Galantamine is a well-known acetylcholinesterase inhibitor which is active substantially selectively at nicotinic receptor sites and has substantially little effect on muscarinic receptor sites, is capable of passing the blood-brain barrier in humans, with a good side-effect profile in therapeutically relevant dosages.
Galantamine and acid add
Murray James
Snorrason Ernir
Lillie Raymond J.
Snorrason Ernir
Truong Tamthom N.
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