Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1998-05-29
2001-05-15
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S451000, C424S464000, C514S538000, C514S546000, C514S554000
Reexamination Certificate
active
06231880
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to composition methods for the treatment and prevention of blood disorders such as anemia, neutropenia, thrombocytopenia, thalassemia and sickle cell disease using such compositions. The compositions include C
1
-C
4
substituted and/or phenyl substituted carboxylic acids such as dimethyl substitutions onto carboxylic acids. The methods comprise the administration of compositions that stimulate the expression of a globin protein and, in particular, fetal hemoglobin, or the proliferation or development of hemoglobin expressing, myeloid cells or megakaryocytic cells.
2. Description of the Background
The major function of red blood cells is to transport oxygen to tissues of the body. Minor functions include the transportation of nutrients, intercellular messages and cytokines, and the absorption of cellular metabolites. Anemia, or a loss of red blood cells or red blood cell capacity, can be grossly defined as a reduction in the ability of blood to transport oxygen. Anemia can be measured by determining a patient's red blood cell mass or hematocrit. Hematocrit values are indirect, but fairly accurate measures of the total hemoglobin concentration of a blood sample. Anemia, as measured by a reduced hematocrit, may be chronic or acute. Chronic anemia may be caused by extrinsic red blood cell abnormalities, intrinsic abnormalities or impaired production of red blood cells. Extrinsic or extra-corpuscular abnormalities include antibody-mediated disorders such as transfusion reactions and erythroblastosis, mechanical trauma to red cells such as micro-angiopathic hemolytic anemias, thrombotic thrombocytopenic purpura and disseminated intravascular coagulation. In addition, infections by parasites such as Plasmodium, chemical injuries from, for example, lead poisoning, and sequestration in the mononuclear system such as by hypersplenism can result in red blood cell disorders and deficiencies.
Impaired red blood cell production can occur by disturbing the proliferation and differentiation of the stem cells or committed cells. Some of the more common diseases of red cell production include aplastic anemia, hypoplastic anemia, pure red cell aplasia and anemia associated with renal failure or endocrine disorders. Disturbances of the proliferation and differentiation of erythroblasts include defects in DNA synthesis such as impaired utilization of vitamin B
12
or folic acid and the megaloblastic anemias, defects in heme or globin synthesis, and anemias of unknown origins such as sideroblastic anemia, anemia associated with chronic infections such as malaria, trypanosomiasis, HIV, hepatitis virus or other viruses, and myelophthisic anemias caused by marrow deficiencies.
Intrinsic abnormalities include both hereditary and acquired disorders. Acquired disorders are those which have been induced through, for example, a membrane defect such as paroxysmal nocturnal hemoglobinuria. Hereditary disorders include disorders of membrane cytoskeleton such as spherocytosis and elliptocytosis, disorders of lipid synthesis such as an abnormally increased lecithin content of the cellular membrane, red cell enzyme deficiencies such as deficiencies of pyruvate kinase, hexokinase, glutathione synthetase and glucose-6-phosphate dehydrogenase. Although red blood cell disorders may be caused by certain drugs and immune system disorders, the majority are caused by genetic defects in the expression of hemoglobin. Disorders of hemoglobin synthesis include deficiencies of globin synthesis such as thalassemia syndromes and structural abnormalities of globin such as sickle cell syndromes and syndromes associated with unstable hemoglobins.
Mammalian globin gene expression is highly regulated during development. The basic structure of the &agr; and &bgr; globin genes are similar as are the basic steps in synthesis of &agr; and &bgr; globin. There are at least five human &agr; globin genes located on chromosome 16 including two adult &agr; globin genes of 141 amino acids that encode identical polypeptides which differ only in their 3′-untranslated regions, one embryonic a gene, zeta (&zgr;), and at least two pseudo-alpha genes, psi zeta (&psgr;&bgr;) and omega alpha (&ohgr;&agr;). The human &bgr; globin gene cluster includes one embryonic gene, epsilon (&egr;), two adult beta globin genes, beta (&bgr;) and delta (&dgr;), two fetal beta globin genes G-gamma (G-&ggr;) and A-gamma (A-&ggr;), which differ by only one amino acid, and at least one pseudo-beta gene, psi beta (&psgr;&bgr;). All are expressed from a single 43 kilobase segment of human chromosome 11 (E. F. Fritsch et al., Nature 279:598-603, 1979).
Hemoglobin A comprises four protein chains, two alpha chains and two beta chains (&agr;
2
&bgr;
2
), interwoven together, each with its own molecule of iron and with a combined molecular weight of about 68 kD. The hemoglobin macromolecule is normally glycosylated and upon absorbing oxygen from the lungs transforms into oxyhemoglobin (HbO
2
). There are at least six distinct forms of hemoglobin, each expressed at various times during development. Hemoglobin in the embryo is found in at least three forms, Hb-Gower 1 (&zgr;
2
&bgr;
2
), Hb-Gower 2 (&agr;
2
&ggr;
2
), and Hb-Portand (&zgr;
2
&ggr;
2
). Hemoglobin in the fetus comprises nearly totally HbF (&agr;
2
&ggr;
2
), whereas hemoglobin in the adult contains about 96% HbA (&agr;
2
&bgr;
2
), about 3% HbA
2
(&agr;
2
&dgr;
2
) and about 1% fetal HbF (&agr;
2
&ggr;
2
). The embryonic switch of globin expression from &zgr; to &agr; and from &egr; to &ggr; begins in the yolk sac. However, chains of embryonic &zgr; and &egr; have been found in the fetal liver and complete transition to the fetal form does not occur until late in fetal development. The fetal switch from &ggr; to &bgr; begins later in erythropoeisis with the amount of &ggr; globin produced increasing throughout gestation. At birth, &bgr; globin accounts for about 40% of non-&agr; globin chain synthesis and thereafter continues to rapidly increase. Neither the switch from embryonic to fetal or fetal to adult appears to be controlled through cell surface or known cytokine interactions. Control seems to reside in a developmental clock with the switch occurring at times determined only by the stage of fetal development.
Defects or mutations in globin chain expression are common. Some of these genetic mutations pose no adverse or only minor consequences to the person, however, most mutations prevent the formation of an intact or normal hemoglobin molecule through a functional or structural inability to effectively bind iron, an inability of the chains or chain pairs to effectively or properly interact, an inability of the molecule to absorb or release oxygen, a failure to express sufficient quantities of one or more globin chains or a combination of these malfunctions. For example, substitutions of valine for glutamic acid at the sixth position of the &bgr; chain produces HbS and was found to occur in about 30% of black Americans. In the HbS heterozygote, only about 40% of total hemoglobin is HbS with the remainder being the more normal HbA.
Upon deoxygenation, HbS molecules undergo aggregation and polymerization ultimately leading to a morphological distortion of the red cells which acquire a sickle or holly-leaf shape. Sickling has two major consequences, a chronic hemolytic anemia and an occlusion of small blood vessels that results in ischemic damage to tissues. Further, when exposed to low oxygen tensions, polymerization converts HbS hemoglobin from a free-flowing liquid to a viscous gel. Consequently, the degree of pathology associated with sickle cell anemia can be correlated with the relative amount of HbS in the patient's system.
Individuals with severe sickle cell anemia develop no symptoms until about five to six months after birth. In these infants it was determined that fetal hemoglobin did not interact with HbS and, as long as sufficient quantities were present, could modulate the effects of HbS disease. This m
Azpuru Carlos A.
Nixon & Peabody LLP
Perrine Susan P.
LandOfFree
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