Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1999-06-17
2001-09-04
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C530S350000
Reexamination Certificate
active
06284260
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a novel use for the pharmaceutical compound Erythropoietin. The invention further relates to methods for controlling bleeding of the gastro-intestinal tract, uterine cavity, nasal cavity (cavitary organs) as well as the prolonged bleeding of incompletely/improperly healed surgical wounds as well as from any organ or body part involved with benign or malignant lesions.
BACKGROUND OF THE INVENTION
Bleeding from benign and malignant lesions in patients being naturally or therapeutically anti-coagulated or having other hemostatic abnormalities is a serious medical problem. Below are some challenging clinical conditions associated with recurrent bleeding with no satisfactory treatment conservative or surgical. It is in these and other conditions that Erythropoetin helps to control the bleeding. Diffuse GI (gastrointestinal) bleeding is a major medical problem following radiation treatments. Angiodysplasia of the intestine is now considered the most frequent cause of major colorectal bleeding being more frequent with diverticular bleeding. Radiation proctosigmoiditis has been studied by Gilinsky et. al. (1983) who found that 35% of patients had moderate GI bleeding and 20% had appreciable bleeding with a significant number of these patients needing operation to remove the affected bowel segment.
Patients suffering from diffuse GI bleeding are currently treated with repeated blood transfusions and surgical resection of the involved segment of the GI tract. A major problem with surgical treatment, however, is that a bowel that has been irradiated does not heal well and the breakdown of a suture line after surgery is a frequent complication, requiring further surgery and the removal of more of the bowel. Also, the dense adhesions that developed following radiation to the pelvis often make it difficult to delineate normal anatomy from pathology, and surgery therefore results in the removal of more bowel than is strictly necessary. Sometimes, it is difficult to establish the exact site of bleeding. Sometimes, the small and large bowel are affected concomitantly and establishing the exact extent of re-section can be very difficult for the surgeon.
Colonoscopic electro-coagulation and laser therapy are the preferred method of treatment for recurrent bleeding. The incidence of re-bleeding and the need for repeating the procedure varies from 0-34%. Surgical resection is often necessary when bleeding recurs. Occasionally re-bleeding occurs post-resection when the site of bleeding is more extensive that originally thought. In both situations presented, there is a need for a conservative treatment which should work on extensive areas of the GI mucosa.
Conservative treatment (steroid retention enemata) by administration of sulphasalazine and 5-aminosalicylic acid (mesalamine—a gastrointestinal anti-inflammatory used in the treatment of ulcerative colitis) has been tried with variable results. In cases of angiodysplasia of the intestine, the use of vasopressin infusions lead to re-bleeding in 21% of cases. Embolisation with Gelfoam has a high risk of re-infarction. These attempts at conservative treatments demonstrate that there has been a long felt need for an alternative to surgical intervention to reduce diffuse GI bleeding.
Erythropoietin (also known as procrit or Epo) is a glycoprotein hormone, thought to be produced primarily in the kidneys and to a lesser extent in the liver, which is a stimulating factor for erythropoiesis, the process by which erythrocytes (red blood cells) are formed. Human erythropoietin has been produced by recombinant technology, and is known as Epoetin.
Erythropoietin is being used successfully in the treatment of anemia of chronic renal failure, anemia of cancer and in HIV patients. It is primarily used to induce production of red blood cells to combat anemia, and not to restrain diffuse bleeding. A recent study pointed towards the usefulness of Erythropoietin in the treatment of GI malignancies but it only pointed its red blood cell stimulating effect leading to improvement of the anemia and did not refer/recognize at all at its hemostatic effect (stopping the GI blood loss). Erythropoietin is known to decrease the bleeding time in uremic (kidney failure) patients. In vitro and in vivo studies have shown an improved platelet endothelial cell interaction, which explains the shortening of the bleeding time. But there has been no recognition prior to the present invention of the significant limitation of GI bleeding that can be achieved by the administration of Erythropoietin.
There are three reported cases of Jehovah's witnesses patients who had acute as opposed to chronic blood loss with critically low Hgb. The patients refused blood transfusions and were successfully treated with recombinant Erythropoietin plus ferrous sulfate, folic acid and vitamin B-12 subcutaneously.
One patient was a 66 year old woman who bled from multiple peptic ulcers. She had melena (passing of black bloody bowel movement) and sycope (passing out) with a Hcrt of 14.5%. Since she refused blood transfusion she was treated with recombinant Erythropoietin 20,000 units for three doses followed by 6,500 units up to two weeks. On the 14th day, her Hcrt was 27.1%. The Erythropoietin was not administered to contain bleeding, but was administered to increase the hematocrit count by boosting the red cell production only after the bleeding had stopped. Furthermore there's nothing in the publication, “Erythropoietin and Anemia of Gastrointestinal Bleeding in a Jehovah's Witness”, Ann. Int. Med. 112, 552 (April 1990), that indicates that erythropoietin would stop diffuse GI bleeding. The thrust of the publication is the use of Erythropoietin as a substitute for blood transfusion for Jehovah's Witnesses.
The second case was a four year old black male Jehovah's witness with hematemesis (vomiting of blood) who was found to have a 2.5 cm fundal ulcer and a Hcrt of 19.1. He was treated with Fe Dextran IV 100 mg/day, Erythropoietin 50 units/kg IV. On the 8th day, his Hcrt was 22.9 and he was discharged home.
The third and last case presented in the literature was a 14 year old black male who had massive hematemesis (vomiting of blood) following esophageal dilatation for an esophageal stricture. Being a Jehovah's witness, blood transfusion was refused. He underwent surgical repair for Gastroesofphageal tear. The post-operative Hcrt was 14.4. Recombinant Erythropoietin 50 units/kg IV was given. Four days after surgery, his Hcrt was 25.9 and was discharged home on the 9th post-operative day tolerating oral feeding and oral iron supplementation.
Erythropoietin beta has been used successfully in the treatment of advanced gastrointstinal cancer, but only to increase haemoglobin/hematocrit (Hgb/Hcrt) by stimulation of red blood cell production. Its effect on stopping gastrointestinal bleeding was not recognized in that context (“Erythropoietin Beta in the treatment of anemia in patients with advanced gastro intestinal cancer”) J. Clin. Oncology 16, No. 2 (February 1998) p. 434-40).
In uremic patients, it is known that erythropoietin corrects the prolonged bleeding time after one week of treatment and increases the hemoglobin/Hcrt after two weeks of treatment. But this information has not been previously considered related to the problem of GI bleeding in uremic or non-uremic patients. An enhanced platelet aggregation in response to ristocetin was noted and, in erythropoietin treated patients, correlated with the rise in platelet serotonin. A decrease in protein C & S and Antithrombin III was noted, leading to shortening of the bleeding time. These results pointed towards an improved platelet vessel wall interaction possibly via a serotoninergic mechanism.
BRIEF DESCRIPTION OF THE INVENTION
In patients with bleeding from benign or malignant lesions from any body part or organ (angiodysplasia of the colon, radiation proctitis, rectal cancer, endometrial cancer, epistaxis (bleeding from the nasal cavity), in a patients naturally or therape
Azpuru Carlos A.
Gottlieb Rackman & Reisman P.C.
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