Method of treating sickle cell anemia

A method of treating a person for sickle cell anemia including administering to the patient's blood a therapeutically effective dosage of ethacrynic acid. The dosage may be administered to blood removed from the patient which blood after addition of the compound is restored to the patient or by other means such as orally.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to a method of treating sickle cell anemia and, more 
specifically, it relates to a method of resisting sickling of hemoglobin 
in a sickle cell anemia patient. 
2. Description of the Prior Art 
Sickle cell anemia is a hereditary blood disease which can afflict African, 
Mediterranean and Mideastern peoples. The anemia results from the physical 
aggregation of a mutant hemoglobin protein constituent in red blood cells. 
This aggregation results in a distortion in shape of deoxygenated red 
blood cells and causes impairment of flow of the blood through the 
capillaries (sickle cell "crises"). As the principal function of 
hemoglobin is to transport oxygen from the lungs to body tissues, 
efficient flow of oxygen throughout the body's tissues is impeded by the 
anemia due to a lower number of red blood cells. Sickle cell anemia also 
may have an indirect effect on the heart, lungs, kidneys, spleen, hips and 
brain. Sickle cell anemia crises can be extremely painful, can result in 
infections such as pneumonia, can result in skin ulceration, can 
contribute to strokes and seizures in the one afflicted and can also 
result in the development of chronic bone infections. 
In general, the result of the differences between cells containing 
hemoglobin A, the normal hemoglobin, and hemoglobin S, the sickle cell 
hemoglobin, is that the former cell is generally flexible and bioconcave 
discoid in shape, while the latter is more rigid and crescent shaped and 
typically has pointed ends. This rigidity and distortion in shape causes 
the cells to be lodged in the capillary. Hemoglobin molecules contain two 
beta polypeptide chains and two alpha polypeptide chains. In the sickle 
cell hemoglobin, a mutation is present in the beta chains. More 
specifically, the sixth amino acid of each beta chain is changed from 
glutamic acid to valine. As a result of this mutation, hemoglobin S upon 
deoxygenation polymerizes and causes the cell to assume the elongated, 
sickle-like configuration. As the sickle cells have a much shorter life 
span than normal red cells, the effect on the body is to deplete the total 
volume of blood cells thereby creating an anemic condition. 
Electrophoresis is one of the well established laboratory tests employed in 
diagnosing sickle cell anemia. Electrophoresis tests determine whether an 
individual has sickle cell anemia (homozygous) or merely the sickle cell 
trait (heterozygous). The latter refers to an individual not having the 
disease but having the capability of transmitting the disease to offspring 
if mated to anoter heterozygote. Treatment for the various complications 
which have resulted from sickle cell anemia are known and should be 
distinguished from prophylactic treatment generally (unknown) which would 
eliminate the occurrence of the complications and adverse symptoms. 
Currently, symptomatic treatment is available. For example, one can treat 
the symptoms by using analgesics for pain, and antibiotics for infection, 
but these approaches do not arrest the underlying sickling phenomena. 
There remains, therefore, a very real and substantial need for a treatment 
method which minimizes the adverse consequences of sickle cell anemia by 
directly inhibiting the underlying cause of sickle cell crises. 
SUMMARY OF THE INVENTION 
The present invention has met the above-described need by providing a 
method which preferably involves administering to a person a 
therapeutically effective dosage of ethacrynic acid. This dosage is 
preferably administered by the acid being reacted extracorporeally with 
the patient's own blood or orally. In the former approach the acid is 
preferably administered to stored blood samples taken from patients and 
then readministered. 
It is an object of the present invention to provide a method of treating a 
sickle cell anemia patient's blood so as to reduce undesired sickle cell 
crises. 
It is another object of the present invention to provide an effective means 
for resisting undesired sickling of hemoglobin in sickle cell anemia 
patients. 
These and other objects of the invention will be more fully understood from 
the following description of the invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS 
In the preferred method of the present invention a sickle cell anemia 
patient is administered a therapeutically effective dosage of ethacrynic 
acid. This compound may be represented as follows: 
##STR1## 
As this is a commercially available compound which has been marketed as a 
diuretic agent and for the treatment of certain brain injuries, those 
skilled in the art know how to prepare the compound and disclosure of the 
same is not required herein. See generally Schultz et al., J. Med. Pharm. 
Chem 5, 660 (1962); U.S. Pat. No. 3,255,241 and Belgian Patent 612,755. 
See also Cragoe et, J. of Med. Chem. 1982, 25, 567. 
It is generally preferred to administer to a patient a dosage of less than 
about 100 mg./day with a preferred range being about 50 to 100 mg./day. 
It will generally be preferred to administer the compound in a 
therapeutically effective dosage extracorporeally or orally. As the 
compound has known dieuretic effects it may be desirable to have the 
patient consume fluids administered orally in order to offset any fluid 
loss which may be experienced. 
As the compound has known diuretic effects it is preferred to react it with 
blood removed intravenously from the patient. The reacted blood is washed 
thoroughly to remove the excess or nonpermanently bound drug and then the 
reacted blood is returned to the individual. This extra-corporeal approach 
may be performed by employing quantities of blood on the order of one pint 
per time. 
EXAMPLE 1 
An example of extracorporeal treatment will be considered. 
One pint of homozygous blood cells removed from a patient are washed with a 
1 to 3 mM. solution of the sodium salt of ethacrynic acid. This washing is 
performed until the Hemoglobin S is substantially completed converted to 
the new species having the ethacrynic acid bound to the Hemoglobin. This 
may be accomplished by washing the cells with about 4 to 6 l of 1 to 3 mM 
sodium salt of ethacrynic acid. The reaction is followed by 
electrophoresis which demonstrates the percentage of conversion to the new 
hemoglobin derivative. The reacted cells are then washed thoroughly with 
isotonic saline until substantially all of the excess and lightly bound 
drug is removed from the hemoglobin and the red cell membranes. The 
treated blood may then be reconstituted with plasma or nutrients or given 
as is to the patient. 
In comparative tests which we reported in J. of Med. Chem., 1984, 27, 
103-105, which is incorporated herein by reference, ethacrynic acid was 
compared with active agents (1) [(3,4-dichlorobenzyl)oxy]acetic acid 
(DiClBz.sub.2) and (2) [(p-bromobenzyl)oxy]acetic acid (p-BrBz). The 
solubility assay measures the ability of a compound to increase solubility 
of sickle hemoglobin (HbS). At low concentrations (5 mM.) ethacrynic acid 
exhibited a higher solubility ratio than DiClBz and p-BrBz. The higher the 
ratio the higher the activity of the compound. Chromatographic separation 
confirmed the fact that desired tight covalent binding between the HbS and 
ethacrynic acid had occurred. Tests of transport across erythrocyte 
membranes confirmed the ability of ethacrynic acid to cross the red blood 
cell membrane and react with hemoglobin. 
It is believed that the ethacrynic acid functions by convalently bonding to 
the hemoglobin at two locales and form a new kind of hemoglobin which does 
not sickle. This is not true of clofibric acid or other phenoxy acids. 
In general it is preferred that the process be practiced extracorporeally 
although other means of administering the medication such as orally may be 
employed. The presently preferred dosage is about 50 to 100 mg./day. 
It will be appreciated that the present invention provides a method for 
treatment of sickle cell anemia patients so as to resist undesired sickle 
cell anemia crisis. The method may advantageously be employed as a 
prophylactic. 
Whereas particular embodiments of the invention have been described above 
for purposes of illustration, it will be evident to those skilled in the 
art that numerous variations of the details may be made without departing 
from the invention as defined in the appended claims.