Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-03-22
2002-05-07
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C560S041000
Reexamination Certificate
active
06384076
ABSTRACT:
TECHNICAL FIELD OF INVENTION
The present invention relates to the treatment of sickle cell disease with N-L-alpha-aspartyl-L-phenylalanine 1-methyl ester.
BACKGROUND OF THE INVENTION
Under low oxygen tension, sickle cell deoxyhemoglobin (HbS) forms multi-stranded fibers (Rodgers, et al. 1987.
Proc Natl Acad Sci USA
84:6157-6161; Eaton, W. A. and Hofrichter, J. 1990.
Adv Protein Chem
40:63-279) that force a red blood cell (RBC) into a crescent (sickle) shape (Carache, S. and Davies, S. 1991.
Acad Med
66:748-74). In 1949, Pauling et al. demonstrated that HbS was electrophoretically distinct from normal human adult hemoglobin (HbA) and coined the name molecular disease to describe the pathological effects of HbS (Pauling, et al. 1949.
Science
110:543-548). Seven years later, Ingram (Ingram, V. M. 1956.
Nature
178:792-794) reported that HbS differed from HbA by the substitution of valine for glutamic acid in position 6 of the &bgr; chain. This hydrophobic for polar substitution occurs on the surface of the three-dimensional structure of HbS on the first (A) &agr;-helix (Padlan, E. A. and Love, W. E. 1985.
J Biol Chem
260:8280-8291). It creates a sticky site which is covered by a complementary (acceptor) crevice between the E and F helices in the &bgr; chain of an antiparallel Hb molecule in the fibril. Key contact residues in the acceptor site are phenylalanine 85 and leucine 88 from the F helix. Each &bgr; chain thus contains a donor and acceptor site which together interact with two other offset Hb molecules, the key condensation events in producing double stranded helical stacks of indefinite length. As the strands of hemoglobin molecules stack together they, continue to elongate and stretch the normally round, flexible RBC into an inflexible sickle or spiculated shape.
Physiologically, the sickled RBCs impair blood flow, enhance hypoxia and accentuate the production of more sickling (Embury, S. H. 1986.
Ann Rev Med
37:361-376). The HbS gene is present in about 8-9% of African Americans (Schneider, et al. 1976.
Blood
48:629). If homozygous for the gene, a patient shows the severe symptoms of “sickle cell disease” such as anemia, hemolysis, severe muscle pain, thrombotic complications, and even sudden exertional death. A heterozygous individual has “sickle cell trait” with milder symptoms and more infrequent crises. The gene is believed to have been preserved in successive generations because RBCs containing HbS appear to promote survival in endemic malarial regions of Africa, Asia and European countries on the Mediterranean Sea (Allison, A. C. 1956.
Scientific American
195:87-94; Friedman, M. J. and Trager, W. 1981.
Scientific American
244:154-164).
Research for therapeutic agents known to delay the onset of sickle cell gelation without introducing unacceptable side effects has been ongoing for many years. (Murayama, M. 1966.
Science
153:145-149; Dean, J. and Schechter, A. N. 1978.
New Engl J Med
299:804-811; Dean, J. and Schechter, A. N. 1978.
New Engl J Med
299:863-870; Dean, J. and Schechter, A. N. 1978.
New Engl J Med
299:752-763). No significant approach has been advanced for the treatment of sickling phenomena (Ranney, H. M. 1972.
Blood
39:433-439; Aluoch, J. R. 1984.
Trop Geogr Med
36:SI-26; Serjeant, G. R. 1997.
Br J Haematol
97:253-255; Olivieri, N. F. and Vichinsky, E. P. 1998.
J Pediatr Hematol Oncol
20:26-31), although there are many stimulating research approaches and hydroxyurea has some effect. (Dickerson, R. E. and Geis, I. Hemoglobin: Structure, Function, Evolution, and Pathology. Benjamin/Cummings Publishing Co., Menlo Park, 1st Park, ed., 1983). Clinical management of a sickle-cell crisis is usually described as supportive, using fluids for hydration (Scott-Conner, R. E. and Brunson, C. D. 1994.
Am J Surg
168:268-274), oxygen for alleviation of hypoxic sickling and analgesics for pain relief (Pollack, et al. 1991.
J Emerg Med
9:445-452). Though often effective, even exchange transfusion remains controversial as preventive therapy (Selekman, J. 1993.
Pediatr Nurs
19:600-605).
U.S. Pat. No. 5,654,334 discloses APM as a pain reliever which is especially effective in relieving pain associated with osteoarthritis and multiple sclerosis. Further, International Application WO 97/00692 discloses APM as an antipyretic. In a clinical trial, APM was demonstrated to alleviate the pain and inflammation of osteo- and mixed osteo- and rheumatoid arthritis by an unknown mechanism (Edmundson, A. B. and Manion, C. V. 1998.
Clin Pharm Therap
63:580-593). Additionally, International Application WO 98/13062 discloses the efficacy of APM in the treatment of a disease affected by the presence of TNF&agr;, particularly arthritis and rheumatoid arthritis. U.S. Pat. No. 5,629,285 discloses sickle cell anemia as one of numerous diseases in which the overproduction or unregulated production of TNF&agr; has been implicated
It has now been found that APM displays binding behavior with HbS resulting in a modified HbS molecule useful for treatment of the sickle cell family of diseases.
SUMMARY OF THE INVENTION
The present invention relates to the use of the compound
where R is CH
3
or an alkyl which allows transport of the compound across the red blood cell membrane to prepare a pharmaceutical composition useful for effecting a reduction in sickle cells in a mammal. The preferred compound used to prepare the pharmaceutical composition is N-L-alpha-aspartyl-L-phenylalanine 1-methyl ester (R=CH
3
). In one embodiment, these compounds are used to prepare a pharmaceutical composition useful for treating sickle cell disorders.
In another aspect the present invention relates to a pharmaceutical preparation in dosage unit form adapted for administration to obtain an antisickling effect in red blood cells, comprising, per dosage unit, an antisickling effective non-toxic amount of a compound comprising
where R is CH
3
or an alkyl which allows transport of the compound across the red blood cell membrane and a pharmaceutical carrier. Preferably, the compound comprises N-L-alpha-aspartyl-L-phenylalanine 1-methyl ester (R=CH
3
).
In another aspect, the present invention relates to a pharmaceutic dosage form for use as an antisickling agent comprising the compound
where R is CH
3
or an alkyl which allows transport of the compound across the red blood cell membrane, wherein the dosage form comprises preferably from about 1.5 milligrams to about 6 milligrams per kilogram body weight of the compound. More preferably, the dosage form comprises about 6 milligrams per kilogram body weight of the compound, preferably to be administered twice a day. The preferred dosage form comprises N-L-alpha-aspartyl-L-phenylalanine 1-methyl ester (R=CH
3
).
In another aspect, the present invention relates to a pharmaceutical dosage form comprising an active antisickling ingredient, wherein the active antisickling ingredient comprises the compound
where R is CH
3
or an alkyl which allows transport of the compound across the red blood cell membrane. The effective amount of the compound in the active ingredient is preferably from about 1.5 milligrams to about 6 per kilogram body weight. More preferably, the effective amount of the compound in the active ingredient is about 6 milligrams per kilogram body weight, preferably to be administered twice a day. The preferred active ingredient comprises N-L-alpha-aspartyl-L-phenylalanine 1-methyl ester (R=CH
3
).
In another aspect, the present invention relates to the use of the compound
where R is CH
3
or an alkyl which allows transport of the compound across the red blood cell membrane to produce an antisickling effect in red blood cells in vitro. The preferred effective amount of the compound is from about 1 milligrams to about 2 milligrams per milliliter. Preferably, the compound is N-L-alpha-aspartyl-L-phenylalanine 1-methyl ester (R=CH
3
).
In yet another aspect, the present invention relates to a formulation for treatment of red blood cells suspected to contain sickle cells, the formulation c
Edmundson Allen B.
Manion Carl V.
Kifle Bruck
Oklahoma Medical Research Foundation
Sidley Austin Brown & Wood
Uppu Rao
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