Method of treating sickle cell anemia with danazol

Treatment of sickle cell disease using danazol.

This invention relates to the use of danazol or an equivalent anabolic 
steroid in the treatment of hemolytic anemias, particularly sickle cell 
disease. 
Said earlier applications disclose the use of danazol, a known material, in 
the treatment of various disorders including hemolytic anemias. The 
present disclosure is concerned primarily with the treatment of one such 
form of hemolytic anemia, namely, sickle cell anemia, which has become of 
particular concern in recent years. 
Sickle cell anemia is a common genetic disorder characterized by anemia, 
painful crises involving joints, bones, the abdomen and other viscera. It 
is due to an abnormal hemoglobin that distorts the shape of the affected 
patient's red blood cells impairing their passage through small blood 
vessels, leading to minute occlusions (microinfarcts) which not only cause 
pain and shorten the survival of the red blood cells but also damage vital 
tissues such as the kidney, heart and brain, leading ultimately to organ 
failure. At present the only available treatments are blood transfusions 
and drugs to relieve pain. 
While the molecular basis of sickle cell ("S-S") disease has been 
delineated, the exact pathophysiology of the vasoocclusive crises has 
never been adequately defined. There is little clinical correlation 
between the degree of hemolysis and the incidence or severity of painful 
crises, suggesting that the mechanisms of the two may be at least in part 
independent. It is known that erthrocytes which are homozygous for the S 
hemoglobin gene but are morphologically normal have a tendency to adhere 
abnormally to vascular endothelium. Drugs that can alter the erythrocyte 
cell membrane could conceivably decrease this erythrocyte-endothelial cell 
affinity, thus resulting in decreased vasoocclusion. 
The effects of using conventional androgens given to patients with sickle 
cell disease have previously been studied and reported. See the following: 
(1) Isaacs, W. A. and Hayhoe, F. G. J.: Steroid Hormones in Sickle-Cell 
Disease, Nature 215: 1139-1142, 1967; 
(2) Mentzer, W. C.; August, C. S., and Nathan, D. G.: The Effects of 
Androgen Administration in Sickle Cell Anemia, Pediat. Res. 3: 378, 1969; 
(3) Raper, A. B.; Black, A. J., and Huntsman, R. G.: Sickling and Steroid 
Hormones, Trans. Royal Soc. Trop. Med. Hyg. 64(2): 293-295, 1970; 
(4) Lundh, B., and Gardner, F. H.: The Haematological Response to Androgens 
in Sickle Cell Anemia, Scand. J. Haemat. 7: 389-397, 1970; 
(5) Isaacs, W. A., Effiong, C. E., and Ayeni, O.: Steroid Treatment in the 
Prevention of Painful Episodes in Sickle-Cell Disease, Lancet pp. 570-571, 
Mar. 11, 1972; and 
(6) Adadfvoh, B. K. and Isaacs, W. A.: The Effect of Megestrol Acetate on 
Sickling, AM. J. Med. Sci., 265(5): 367-370, 1973. 
Preparations of hormones, dosages and modes of administration were varied 
in these prior studies. While improvement in hemoglobin levels were seen, 
discordant results were reported with respect to crises, ranging from a 
decrease in incidence (see papers 1, 5 and 6 above), to no apparent 
benefit (see papers 2-4) and in men there was an increase in epsiodes of 
painful priapism (paper 4).

The present invention is based on the finding that danazol can be used with 
significant benefit in the treatment of sickle cell disease. The effects 
obtained with the invention represent a significant improvement over the 
previous reported results using conventional androgens. 
Danazol is known chemically as 
17-pregna-2,4-dien-20yno[2,3-d]-isoxazol-17-ol; 
17a-pregn-4-en-20-yno[2,3-d]-isoxazol-17-ol; 
1-ethynyl-2,3,3a,3b,4,5,10,10a,11,12,12a-dodecahydro-10a-12a-dimethyl-1H-c 
yclopenta-[7,8]-phenanthro[3,2-d]isoxazol-1-ol; or 
17-ethynyl-17-hydroxy-4-androsteno-[2,3-d]-isoxazole. See British Pat. No. 
905,844 (1962 to Sterling Drug), C.A. 58, 689c (1963); and U.S. Pat. No. 
3,135,743 (1964 to Sterling Drug). It is available as "Danocrine" from 
Winthrop Laboratories and is a synthetic hormone derived from ethisterone. 
It was originally approved for use in the treatment of endometriosis. 
Subsequently it has been found to be useful in the treatment of idiopathic 
thrombocytopenic purpura, autoimmune hemolytic anemia, paroxysmal 
nocturnal hemoglobinuria and other disorders as described in the earlier 
applications referred to above and in related papers as follows: 
Ahn, Y. S; Harrington, W. J.; Simon, S. R.; Mylvaganam, R; Pall, L. M., and 
So. A. G.; "Danazol for the Treatment of Idiopathic Thrombocytopenic 
Purpura", NEJM 308: 1396-1399, 1983; 
Ahn, Y. S.; Mylvaganam, R.; Garcia R. O.; Kim, C. I.; Palow, D., and 
Harrington, W. J.: "Low Dose Danazol Therapy in Idiopathic 
Thrombocytopenic Purpura", Ann. Int. Med., 1986 (accepted); 
Ahn, Y. S.; Harrington, W. J.; Ayub, J., Mylvaganam, R., and Pall, L. M.: 
"Danazol Therapy for Autoimmune Hemolytic Anemia", Ann. Int. Med. 102: 
298-301, 1984; 
Harrington, W. J.; Ahn, Y. S.; Cohen, J. J.; Ayub, J., and Pall, L. M.: 
"Treatment of Paroxysmal Nocturnal hemoglobinuria with Danazol", presented 
at the Twentieth Congress of the International Society of Hematology, 
Buenos Aires, Argentina, September 1984 (Abstract); 
Harrington, W. J.; Ahn, Y. S.; Cohen J. J.; Ayub, J., and Pall, L. M.: 
"Treatment of Paroxysmal Nocturnal Hemoglobinuria with Danazol", presented 
at the Annual Meeting of the American Society of Hematology, December 
1984, Blood 64 (5): 253a. 
The amount of danazol administered for present purposes can be varied and 
the optimum to use in any particular situation can be readily determined. 
Typical dosages may be in the order of 10-500 mg administered one or more 
times daily depending on the seriousness of the condition, the health, sex 
and age of the patient, as well as other factors. For most adult patients 
an oral dose of 200 mg two or four times a day may be given as an example 
although it will be recognized that other dosages may be used depending on 
the circumstances. These dosages may be in conventional form suitable for 
oral or injectable administration, e.g., tablets, capsules, syrups, 
sterile solutions, or suspensions and the like. 
The invention and its advantages are illustrated by tests carried out on 
six patients suffering from sickle cell disease (S-S disease). These 
patients had been previously given clinical trials of other agents, with 
no benefit. Each of the patients was experiencing at least one painful 
crisis a month. In addition, one of the patients had had, over a six month 
period, daily episodes of painful priapism lasting two to three hours. 
Danazol was administered in a dosage of 200 mg three times daily. The 
results are summarized in Table 1. 
TABLE 1 
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Response to Danzol Therapy in Six Patients 
Painful/Crisis 
Duration of 
Hemoglobin 
Reticulocyte 
MCHC Haptoglobin 
Average/Month 
Treatment 
(mg/dl) Count (%) 
(g/dl) (mg/dl) 
Pt. 
Before 
After 
Weeks Before 
After 
Before 
After 
Before 
After 
Before 
After 
__________________________________________________________________________ 
1 1 0 24 8.0 8.6 26 15 35 33 &lt;5 &lt;5 
2 2 0 32 8.8 10.7 
20 4 35 31 &lt;5 70 
3 2 0.3 41 9.1 10.6 
24 9 33 34 &lt;5 &lt;5 
4 2 0.5 31 8.1 9.8 18 7 33 32 &lt;5 &lt;5 
5 2 0.4 20 8.1 9.8 21 3 34 33 &lt;5 85 
6 1 0.3 17 7.0 8.7 20 4 33 34 &lt;5 44 
__________________________________________________________________________ 
The results tabulated above show marked symptomatic benefit in the use of 
danazol for the treatment of S-S disease. Particularly significant is the 
decrease of 85% in incidence of painful crises. 
In addition to the indicated amelioration of crises, each patient noted 
improvement in sense of well-being and a substantial decrease in narcotic 
requirement. Especially dramatic was the prompt relief of chronic 
recurrent priapism in patient number five. Some benefit was also apparent 
in hematological parameters. 
The manner in which the danazol functions to benefit patients with sickle 
cell anemia is not fully understood. However, danazol is beneficial in the 
treatment of autoimmune hemolytic anemias and paroxysmal nocturnal 
hemoglobinuria and it appears that a feature common to the pathogenesis of 
these anemias is red cell membrance modification. It is considered that by 
using danazol in the treatment of sickle cell disease the red cell 
membranes can be favorably modified in the direction of decreasing the 
fragility of the red cells while increasing their deformability thereby 
favoring improved red cell survival with the indicated clinical benefit. 
The results obtained appear to be unique to the case where danazol is 
used, apparently because of the special affinity it has for red cell 
membranes so as to make them less fragile and more pliable. The compound 
appears to be better suited than conventional androgens for use in females 
as well as males. It has few side effects when used and appears to offer 
the first practical long term management of sickle cell disease.