Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-09-23
2004-03-02
Page, Thurman K. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S307000, C514S311000, C514S381000, C514S382000, C514S383000, C514S365000, C514S394000, C514S252100, C424S400000
Reexamination Certificate
active
06699894
ABSTRACT:
TECHNICAL FIELD
This invention relates to the treatment of inflammatory bowel disease.
BACKGROUND OF THE INVENTION
Inflammatory bowel disease (“IBD”) refers to two chronic diseases that cause inflammation of the intestines: ulcerative colitis and Crohn's disease. Ulcerative colitis and Crohn's disease are different diseases that manifest similar symptoms. Up to 2,000,000 Americans are estimated to suffer from IBD.
Both diseases are chronic and most frequently have their onset in early adult life. Some patients have alternating periods of remission alternating with periods of relapse or flare. Other patients have continuous symptoms from continued inflammation. The severity of the diseases varies widely between individuals. Some suffer only mild symptoms, but others have severe and disabling symptoms. Medical science has not yet discovered a cause or cure.
The most common symptom of both ulcerative colitis and Crohn's disease is diarrhea, sometimes severe, that may require frequent visits to a toilet—in some cases up to 20 or more times a day. Abdominal cramps often occur, the severity of which may be correlated with the degree of diarrhea present. Blood may also appear in the stools, especially with colitis. Fever, fatigue, and loss of appetite may accompany these symptoms (with consequent weight loss).
At times, some ulcerative colitis and Crohn's disease patients experience constipation during periods of active disease. In Crohn's disease, this can result from a partial obstruction usually of the small intestine. In colitis, constipation is most often a consequence of inflammation of the rectum (also known as proctitis); the colon has a nervous reaction and stasis of stool occurs upstream.
Inflammation can affect gut nerves in such a way as to make the patient feel that there is stool present ready to be evacuated when there actually is none. That results in tenesmus, an uncomfortable urge to defecate but where nothing happens. The feeling of urgency to pass stool also is a frequent consequence of proctitis. Inability to retain stool is an extreme manifestation of urgency.
Pain usually results from intestinal cramping or inflammation causing reflex irritability of the nerves and muscles that control intestinal contractions. Pain may also indicate the presence of severe inflammation or the development of a complication such as an abscess or a perforation of the intestinal wall.
Current IBD drug therapies are inadequate. The two most widely used drug families are steroids and 5-aminosalicylic acid (5-ASA) drugs, both of which reduce inflammation of the affected parts of the intestines. Immunosuppressive drugs such as 6-mercaptopurine are increasingly used for long-term treatment of IBD. They are particularly used for patients dependent on chronic high-dose steroid therapy with its severe and predictable side effects.
Sulfasalazine (Azulfidine, Azulfidine EN-Tabs in the US; SalazopyrinEN-Tabs, SAS in Canada; salazosulfapyridine, salicylazosulfapyridine) is the “staple” drug generally prescribed as the first course of therapy for IBD patients. It is an 5-ASA type drug intended first to reduce inflammation of the intestinal lining and then to maintain remission in mild to moderate cases. Side effects are common and include nausea, heartburn, headache, dizziness, anemia, and skin rashes. It is also known to cause a reduced sperm count in men, but only for the duration of treatment. It may also turn urine a bright orange-yellow color. Hence, there have been considerable efforts to develop alternatives to sulfapyridine (a sulfasalazine metabolite) and other sulfa-based drugs for the treatment of IBD.
Olsalazine is a drug that uses a different mechanism to deliver 5-ASA to the terminal ileum and colon. Whereas sulfasalazine links a 5-ASA molecule with a sulfapyridine molecule, olsalazine links two 5-ASA molecules. This compound passes through the stomach and upper ileum. Intestinal bacteria break the drug in the terminal ileum, making 5-ASA available there and also in the colon. The major side effect is watery diarrhea, seen in many patients. Patients with ulcerative colitis or Crohn's disease affecting the entire colon seem especially susceptible. Increased cramping and audible bowel sounds are also commonly reported.
5-ASA drugs commonly fail. When that happens or when symptoms are more severe, the next therapeutic step usually involves steroids (e.g., prednisone, prednisolone or hydrocortisone) which are very powerful anti-inflammatory drugs. These are available in oral, enema, or suppository forms. The topical forms are useful in treating distal colitis. The oral forms are useful for achieving remission in mild to moderately active ulcerative colitis and Crohn's disease. They are not useful for prolonged use in maintaining a remission. The oral forms can, however, be effective in suppressing active Crohn's disease to the point where it appears to be in remission.
Steroid side effects vary widely between patients, but are generally pretty severe particularly when used at moderate to high doses (e.g., more than 15 mg. prednisone daily). Common side effects include rounding of the face (moon face) and increase in the size of fat pads on the upper back and back of the neck (buffalo hump), acne, increased appetite with consequent weight gain, increased body hair, osteoporosis (especially in women), compression fractures of the vertebrae, diabetes, hypertension, cataracts, increased susceptibility to infections, glaucoma, weakness of arm, leg, shoulder, and pelvic muscles, personality changes including depression (suicidal tendencies are not uncommon), irritability, nervousness, and insomnia. Children's growth may also be affected, even by small doses. An important and serious (but rare) complication of steroid therapy is avascularnecrosis of the hip. This results in death of the bone in the hip joint resulting in arthritis and severe pain.
Long term use of steroids (more than a few days) suppresses the adrenal gland's normal production of steroids and can affect its function for along time (up to a year, or in some cases even two) even after steroid use has stopped. During this period, the body may not be able to produce an adequate supply of steroids during extreme stress, such as surgery or severe infection.
Steroid drugs unfortunately can cause osteoporosis that causes bones to become weak and much more likely to fracture. Without protection within the first six months of steroid therapy, a person can lose 10 percent to 20 percent of bone mass. As many as one in four of these people may eventually suffer a fracture as a result. Unlike osteoporosis associated with aging, steroid-induced osteoporosis can occur at any age, even in children. For many years it was thought that only high (i.e., more than 20 mg. daily) doses of steroids were a problem, more recent studies have shown that chronic use of low oral doses—as little as 7.5 milligrams a day—can cause significant though gradual bone loss.
Immunosuppressives such as 6-mercaptopurine or orazathioprine are increasingly used in treating more severe IBD that does not respond to 5-ASA therapy and short-term steroid therapy. The most frequent use of immunosuppressives is for patients unable to reduce the steroid dosages in steroid-dependent patients without causing a disease flare. The minimum time to respond to immunosuppressives is about three months and can be as long as 12 months. These drugs can be effective in maintaining remission in many patients. An important side effect is pancreatitis. This usually occurs within a few weeks of starting treatment and is manifested by upper abdominal pain that may radiate to the back and be associated with nausea and vomiting. If pancreatitis occurs, then the patient cannot take the drug in the future.
Drug treatments are reportedly ultimately ineffective in about 20% of ulcerative colitis patients. Accordingly, these patients must have their colons removed due to debilitating symptoms. The colon may also removed because of the threat of cancer
Alila Hector W.
Earle Keith A.
Gollamudi Sharmila S
Lee Shu M.
OSI Pharmaceuticals, Inc.
Page Thurman K.
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