Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-26
2002-09-17
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06451813
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for the treatment of gastroparesis in males and females in particular treatment groups, such as diabetics. The methods of the present invention comprise the utilization of pharmaceutical compositions to patients who are free of symptoms of cardiac disease and who have not been treated with drugs which cause hypotensive effects, such as nitrites and nitrates.
BACKGROUND
Gastroparesis, or delayed stomach emptying, is most often a complication of diabetes. Seven million people in the United States may be affected by diabetes, and up to 75% of diabetic patients may experience gastrointestinal dysfunction, including diabetic gastroparesis, a syndrome of delayed gastric emptying, leading to nausea, vomiting, abdominal pain and early satiety.
There is more than one cause of gastroparesis. Although diabetes is the most common known cause, gastroparesis can be the result of physical problems, medications, as well as metabolic, smooth muscle and nervous system disorders. For example, physical problems leading to gastroparesis can include scarring from tumors and ulcers, as well as surgery on the vagus nerve or stomach. Certain medications, including Cardizem and other calcium blockers, which slow contractions in the intestine or weaken the stomach, can contribute to gastroparesis. Hypothyroidism is an example of a metabolic disorder associated with gastroparesis. Smooth muscle disorders such as amyloidosis and scleroderma can cause gastroparesis, as can disorders of the nervous system, such as Parkinson's disease and abdominal migraine, a syndrome characterized by recurrent sterotypic episodes of paroxysmal abdominal pain and nausea and/or vomiting.
In addition to symptoms such as nausea, vomiting, an early feeling of fullness when eating, weight loss, abdominal bloating and discomfort, gastroparesis can lead to several complications. For example, if food lingers too long in the stomach, it can cause problems like bacterial overgrowth from the fermentation of food. Also, the food can harden into solid masses called bezoars, that may cause nausea, vomiting, and obstruction in the stomach. Bezoars can be dangerous if they block the passage of food into the small intestine. In diabetic patients, gastroparesis can make diabetes worse by adding to the difficulty of controlling blood glucose. When food that has been delayed in the stomach finally enters the small intestine and is absorbed, blood glucose levels rise. Since gastroparesis makes stomach emptying unpredictable, a person's blood glucose levels can be erratic and difficult to control. High blood glucose causes chemical changes in nerves and damages the blood vessels that carry oxygen and nutrients to the nerves. This can damage the vagus nerve, potentially leading to symptoms of gastroparesis, if blood glucose levels remain high over a long period of time.
Some of the treatments available to help manage gastroparesis include meal and food changes. A patient may be asked to eat six small meals a day, rather than three large ones. Several liquid meals a day may be recommended until the gastroparesis is corrected. Avoiding fatty and high-fiber foods may also be recommended, as fat naturally slows digestion and some high-fiber foods like oranges and broccoli contain material that cannot be digested. The indigestible part will remain in the stomach too long and possibly form bezoars.
If other approaches do not work, a patient may need surgery to insert a feeding tube. The tube is inserted through the skin on the abdomen into the small intestine. This allows nutrients to be put directly into the small intestine, bypassing the stomach altogether. A feeding tube can be temporary and is used only if necessary when gastroparesis is severe. As an alternative to a feeding tube, parenteral nutrition may be delivered. A catheter is inserted in a chest vein, leaving an opening outside the skin. For feeding, a bag containing liquid nutrients or medication is attached to the catheter, and fluid enters the bloodstream through the vein. This bypasses the digestive system when gastroparesis is severe and not helped by other methods.
In diabetic patients with gastroparesis, food is being absorbed more slowly and at unpredictable times. These patients may need to take insulin more often, take insulin after eating, rather than before, and check blood glucose levels frequently after eating, administering insulin whenever necessary.
These treatments clearly involve inconvenience to the patient, turning eating and mealtimes into challenges. In the cases of feeding tubes or catheters, surgical intervention may be associated with risks and complications that can accompany any surgery. What is needed is an intervention that is effective and less disruptive to the patient while lacking in significant side effects.
SUMMARY OF THE INVENTION
The present invention provides methods for the treatment of gastroparesis in males and females in particular treatment groups, including diabetics. The methods of the present invention comprise the utilization of pharmaceutical compositions to patients who are free of symptoms of cardiac disease and who have not been treated with drugs which cause hypotensive effects, such as nitrites and nitrates. The compositions comprise quinolinones, including derivatives thereof. Quinolinones are also known as quinolones and oxo-quinolines.
It is not intended that the present invention be limited by the nature of the derivative. In one embodiment, the quinolinone derivative is cilostazol (6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone; 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyril; 3,4-Dihydro-6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-2(1H)-quinolinone).
In yet other embodiments, metabolites of cilostazol are contemplated for use in the methods of the presently claimed invention. Metabolites of cilostazol include, but are not limited to monohydroxycilostazol, monohydroxydehydrocilostazol, 3,4-dihydro-6-hydroxy-2(1H)-quinolinone, their conjugates and dehydrocilostazol.
In another embodiment, the present invention contemplates halogenated quinolinones (e.g., fluoroquinolinone). In a preferred embodiment, the quinolinone is a thioquinolinone or a sulphinyl or suphonyl derivatives thereof. In one embodiment, the halogenated quinolinone is flosequinan [(−)-7-fluoro-1-methyl-3-(methyl-sulphinyl)-4(1H)-quinolinone]; [7-Fluoro-1-methyl-3-(methylsulfinyl)-4(1H)-quinolone]. In a preferred embodiment, an enantiomer of flosequinan is used.
In one embodiment, the present invention contemplates a method, comprising: a) providing: i) a male or female with symptoms of gastroparesis, and ii) a composition comprising a quinolinone selected from the group consisting of a racemic mixture of flosequinan and an enantiomer of flosequinan; and b) administering said composition to said male or female (e.g. such that said symptoms are reduced). It is not intended that the present invention be limited to particular symptoms of gastroparesis. A variety of such symptoms are contemplated, including but not limited to, nausea, early satiety, postprandial bloating and fullness, and vomiting. In one embodiment, the present invention contemplates administering said flosequinan to said male or female under conditions such that symptoms of said male or female are improved.
In another embodiment, the present invention contemplates a method, comprising: a) providing: i) a male or female with symptoms of gastroparesis, and ii) cilostazol; and b) administering said cilostazol to said male or female (e.g. such that said symptoms are reduced). It is not intended that the present invention be limited to particular symptoms of gastroparesis. A variety of such symptoms are contemplated, including but not limited to, nausea, early satiety, postprandial bloating and fullness, and vomiting. In one embodiment, the present invention contemplates administering said cilostazol to said male or female under conditions such t
Cutler Neal R.
Sramek John
Cook Rebecca
Medlen & Carroll LLP
R. T. Alamo Ventures I, LLC
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