Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
1999-07-30
2001-06-12
Kulkosky, Peter F. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C514S825000, C514S886000, C514S885000, C424S400000
Reexamination Certificate
active
06245340
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method of enhancing the immune response of a mammal and compositions therefor.
2. Reported Developments
Rheumatoid arthritis (hereinafter sometimes referred to as RA) is a common type of arthritis that causes inflammation in the lining of the joints and sometimes other internal organs. RA tends to persist for many years, typically affects many different joints throughout the body, and ultimately can cause damage to cartilage, bones, tendons and ligaments. RA is a chronic, inflammatory, connective-tissue disorder affecting more than five million individuals in the U.S., and accounting for considerable disability in terms of missed work, lost wages, and reduced productivity. The disease can occur at any age, but it most commonly begins in the third to fifth decades of life.
The American College of Rheumotology has established criteria of the diagnosis of rheumatoid arthritis which include:
1. Morning stiffness lasting at least one hour;
2. Swelling of three or more joints;
3. Swelling of the wrist, metacarpophalangeal or proximal interphangeal joints;
4. Symmetric joint swelling;
5. Rheumatoid nodules;
6. Positive rheumatoid factor; and
7. Changes on hand radiographs typical of rheumatoid arthritis that must include erosions or unequivocal bony decalcification.
The correct diagnosis of RA is essential for the clinician and involves certain clinical, laboratory and radiological findings. The diagnosis is influenced by the age and sex of the patient, the pattern of joint involvement, the onset and course of the disease and extrarticular manifestations.
In contrast to rheumatoid arthritis, osteoarthritis (hereinafter sometimes referred to as OA), the illness most often contemplated in the differential diagnosis, usually begins after the age of 50 and affects men and women equally. The joints involved in OA are different from those in RA and are not necessarily symmetrically affected. In OA, joint pathology is primarily mechanical, and synovial membrane inflammation is minimal.
As pertaining to the present invention certain other inflammatory arthritis is differentiated from RA as listed in Table I.
TABLE I
Differential Diagnosis of Rheumatoid Arthritis*
Seronegative spondyloarthropathy
(ankylosing spondylitis, reiters syndrome, psoriatic
arthritis, enteropathic arthritis)
Crystal-induced arthropathy
(gout, pseudogout)
Diffuse connective tissue disease
(systemic lupus erythematosus, polymyosiis,
fibromyalgia)
Infectious arthritis
Osteoarthritis
Polymyalgia rheumatica
Reactive arthritis
Hemoglobinopathies
Hemachromatosis
Lyme disease
Malignancy
Thyroid disease
Hemophilic arthropathy
Hypertrophic osteoarthritis
*Adapted from
Textbook of Rheumatology.
Philadelphia, W.B. Saunders Co., 1989, pp 943-981.
With varying clinical significance, RA can at times affect other areas of the body. The most characteristic of these so-called extra-articular manifestations are rheumatoid nodules. They can be found subcutaneously in up to 25% of rheumatoid patients, especially over extensor surfaces and in pressure areas. Common sites include the olecranon regions, fingers, Achilles tendons, the sacrum and the occiput. The presence of subcutaneous nodules is helpful diagnostically, because they are uncommon in the other forms of inflammatory arthritis. Nodules can also occur in visceral organs, including the lungs and the heart.
As discussed above, the primary cause of RA is unknown. It is thought to be triggered by the presence of an as yet unidentified antigen(s) in an immunogenetically susceptible host, and the nature of the antigen responsible for the arthritic reactions in RA has yet to be clearly established.
Heretofore medical management of RA involved three general approaches.
The first is the use of aspirin and other nonsteroidal anti-inflammatory analgesics, and low-dose glucocorticoids to control the symptoms and signs of the local inflammatory process. These agents are rapidly effective at mitigating symptoms and signs, but they appear to exert little effect on the progression of the disease.
A second group of drugs includes a variety of agents that have been classified as the disease-modifying drugs. These agents appear to have the capacity to decrease elevated levels of acute phase reactants in treated patients, and therefore, are thought to modify the destructive capacity of the disease.
The third class of agents includes the immunosuppressive and cytotoxic drugs that have bee shown to ameliorate the disease process in some patients. These last two classes of agents, however, often cause serious side effects including the development of heart and liver diseases, increase in blood pressure, blindness and malignant neoplasms.
The prior art treatment of RA is based on the following two principles: first, RA is a systemic connective-tissue disorder that is not remediable solely through local measures. Second, RA is a progressive disease that can potentially lead to severe cartilage and bone destruction, organ damage, and decreased life expectancy. Current regimens are predicated on controlling the immune system disturbance to reduce joint discomfort and destruction and this to maintain the patient's activities of daily living.
Available drug preparations for the treatment of RA include the following.
(1) NSAIDS
Nonsteroidal Anti-Inflammatory Drugs
Pharmacologic treatment of RA has advanced steadily in the past several decades, but none of the agents used so far can cure RA. Aspirin remains an important part of the treatment program for many people with RA. To be effective, it must be given in doses much higher than commonly used as an over-the-counter remedy for minor aches and pains. Compared to other similar NSAIDS, aspirin is less expensive and its blood level can be precisely measured. However, it can cause stomach problems in many people. Many physicians recommend the use of enteric (coated) forms of aspirin.
NSAIDS are a large group of drugs that have mechanisms of action similar to aspirin. Like aspirin, these medications can relieve some of the pain associated with RA temporarily. The NSAIDS are the most frequently recommended antirheumatic medications, and the first line of therapy in RA. As a result of the capacity of these agents to block the activity of the enzyme cyclooxygenase and therefore the production of prostaglandins, prostacyclin and thromboxames, they have analgesic, anti-inflammatory and antipyretic properties. Table II lists the most commonly prescribed NSAIDS.
TABLE II
Commonly Prescribed NSAIDS Grouped According To Their
Elimination Half-Lives
Short Acting
Intermediate Acting
Long Acting
(6 hours)
(7 to 14 hours)
(15 hours)
Aspirin
Diflunisal
Azapropazone
Diclofenac
Naproxen
Nabumetone
Etodolac
Salsalate
Oxaprozin
Fenoprofen
Sulindac
Piroxicam
Flufenamic acid
Flurbiprofen
Ibuprofen
Indomethacin
Ketoprofen
Meclofenamic acid
Tolmetin
Table III lists the commonly prescribed NSAIDs by classification, half-life and dosage range.
TABLE III
Commonly Prescribed NSAIDS
Classification
Half Life, hr
Dosage Range, mg/day
Proprionic Acid
Ibuprofen
2
1200-3200
Naproxen
13
250-1500
Fenoprofen
2
1200-3200
Ketoprofen
1.5
100-300
Oxaprozin
40
600-1800
Phenylacetic Acid
Diclofenac
1.5
100-150
Indoleacetic Acid
Indomethacin
3-11
50-200
Sulindac
16
300-400
Tolmetin
1-2
600-2000
Fenamate
Meclofenamate
2-3
200-400
Oxicam
Piroxicam
30-86
20
These agents are all associated with a wide spectrum of toxic side effects. A common side effect of these drugs is bleeding from the stomach. Overall dose is limited by such gastrointestinal erosions, as well as azotemia, platelet dysfunction, exacerbation of allergic rhinitis and asthma, liver function abnormalities, some renal and cardiovascular irritation, and CNS toxicity like tinnitus, although patients occasionally differ unpredictably in their response to an individual NSAID.
An individual's response to the various NSAIDS is quite variable. Gastrointestinal ulcerations develop in 0 to 30% of NSAID-treated patients. Du
Balogh Imre
Kulkosky Peter F.
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