Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-06-12
2001-11-06
Azpuru, Carlos A. (Department: 2165)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
Reexamination Certificate
active
06312707
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to the use of a naturally occurring sugar-phosphate compound called fructose-1,6-diphosphate, for treating the sporadic crises that arise in people suffering from sickle cell anemia.
The following paragraphs provide background information on sickle cell anemia, under its subheading, and then on fructose-1,6-diphosphate, under a different subheading. However, it must be emphasized that fructose-1,6-diphosphate (abbreviated herein as FDP) apparently has never before been used to treat sickle cell anemia. A search of the National -2O Library of Medicine computerized database, combining “sickle cell anemia” or “sickle hemoglobin” with either “fructose diphosphate” or “fructose phosphates” identified only a single article, which involved a different compound. That article, Colomer et al 1991 (complete citations are provided below) related to the levels of fructose-2,6-bisphosphate in certain types of cells, congenital hemolytic anemias. As described below, 2,6-FDP (which is of no interest whatever in the current invention) has very different biochemical properties than 1,6-FDP, which is the compound used in this invention. The 1,6-FDP isomer (with phosphate groups coupled to the #1 and #6 carbon atoms of the fructose molecule) is the only form of FDP that is of interest herein. It is discussed in more detail below.
Accordingly, sickle cell anemia and 1,6-FDP have both been studied extensively. However, there apparently has never been any prior effort to treat sickle cell anemia, using 1,6FDP.
Background Information on Sickle Cell Anemia Sickle cell anemia is a well-known disease, in which red blood cells (abbreviated as RBC's; also called erythrocytes) contain hemoglobin molecules which have a dangerous tendency to crystallize and become non-functional, due to a genetic mutation. In the most common form of this disease, the beta (or B) chain of the hemoglobin protein has a valine residue, instead of a glutamate residue, at the number 6 position. Other substitutions have also been identified, such as “sickle C” disease (which has a lysine residue at the #6 position) and “sickle D” disease (which has a glutamine residue at the #6 residue).
This genetic mutation is relatively common in Africa, since a person who carries a single copy of the mutated gene has a relatively high resistance to malaria, without suffering from major adverse health effects. Accordingly, it has been estimated that roughly 30% of all people native to Nigeria (as just one example) carry at least one such gene (Barnhart et al 1976). About 8% of African-Americans also carry at least one such gene, although local populations often contain higher levels. The gene which disposes red blood cells to sickling is often referred to as HbS, where “Hb” refers to hemoglobin, and “S” refers to sickling. By contrast, a normal, healthy, adult hemoglobin is usually referred to as HbA.
As briefly noted above, a single copy of the gene does not inflict major adverse health effects on the person carrying that gene. Such people are often referred to as “heterozygotes,” since they carry two different types of genes (i.e., one is the defective HbS gene, and the other is the normal HbA gene). Usually, only about 40% or less of their hemoglobin is of the sickling variety, while the rest (the majority) is normal. Their red cells will sickle, but only if exposed to hypoxia at much more severe levels than will provoke sickling in homozygotes. Heterozygotes (single-gene carriers) usually have few if any clinical problems, and they do not suffer from reduced life expectancies or increased hospitalization rates.
By contrast, “homozygotes” carry two copies of the defective HbS gene, and do not have any normal and healthy HbA hemoglobin (they may sometimes retain variable amounts of a fetal type of hemoglobin, called HbF, which does not occur in healthy adults). Accordingly, they are the ones who suffer from the debilitating, often devastating effects of sickle cell anemia. They usually suffer severe spleen damage by the age of about 6, and for the rest of their lives, they suffer from elevated levels of gradually accumulating damage to their other organs and tissues, including the liver and kidneys. In the United States, despite having advanced medical care, typical life expectancy for men having the disease is 42 years, and 48 years for women (Platt et al 1994).
The abnormal amino acid residue on the beta chain allows hemoglobin to polymerize, when it is subjected to a condition of even relatively mild hypoxia. This polymerization activity can be observed in intact red cells, or in cell-free hemoglobin solutions. Polymers are typically 14 stranded helices, and are up to 20 nm long. The formation of polymerized hemoglobin inside red cells provokes a change in the shapes and structures of red blood cells, causing an increase in rigidity of the cell wall, and deformation of the cell into a dehydrated, flattened curved shape, which is the classic “sickle” shape (named after the old grain-harvesting tool) that gives the disease its name. Hemoglobin polymerization can also lead to other severely deformed cell shapes, in addition to the sickled shape. For a review of this molecular process and its effects on red blood cells, see Dean and Schechter 1978.
In a patient, these changes in red blood cell shapes may be widespread (for example, during surgery that requires anesthesia), or regional (for example, behind a venous tourniquet when drawing a blood sample). They can also be triggered by events such as bacterial or viral infections, which stress the body (or certain parts of the body) in various ways that can generate localized ischemia and/or hypoxia.
For most patients, sickle cell anemia does not cause constant or chronic pain. However, most sickle cell anemia patients suffer from sporadic yet recurrent episodes that are referred to herein as “ischemic crises” (all references herein to a crisis or crises refer to these sporadic, recurrent crises which occur in the normal course of sickle cell disease; such references do not relate to any other type of ischemic crisis, such as a stroke or heart attack). During such crises, a sickle cell (SC) patient will usually experience severe pain, at one or more locations which frequently vary between patients, and between different crises in a specific patient. It is not uncommon for one or more joints to become swollen and sore, and/or for the patient to suffer from either sharp or diffuse pain in the abdomen, which is presumed to be due to ischemic conditions in one or more portions of one or more organs.
Such crises are generally referred to as ischemic crises, since they typically involve blockade of capillaries and prevention of blood flow into a tissue that becomes starved of oxygen and glucose. This blockade of the capillaries is caused by red blood cells that have lost their normal shape and flexibility, and have collapsed or distorted into the rigid or semi-rigid “sickled” shapes that gives the disease its name. This blockade of capillaries shuts off the flow of fresh blood through those portions of the organ or tissue that are normally serviced by the blocked capillaries. This state of events, due to the sickling of the red blood cells due to the polymerization of HbS-type hemoglobin molecules, leads directly to ischemia, which is the medical term for inadequate blood flow to an organ or tissue.
Most sickle cell patients usually suffer several such ischemic crises per year. During these crises, the patient usually must be hospitalized, restricted to bed rest with little or no exertion, and treated with a variety of drugs, including strong painkillers such as morphine, codeine, and meperidine (also known as Demerol™), and by broad-spectrum antibiotics, both to help control any infections that may be contributing to the crises, and to help prevent or reduce additional infections in tissues or organs that are weakened by the ischemic crisis.
The physiological damage and increased morbidity and mortality caused by sickle cell anem
Fox Anthony W.
Marangos Paul J.
Markov Angel K.
Azpuru Carlos A.
Pennie & Edmonds LLP
Questcor Pharmaceuticals, Inc.
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