Pharmaceutical dipeptide compositions and methods of use thereof: immunostimulants

• US 6,777,195 B2
• Filed: 02/14/2002
• Issued: 08/17/2004
• Est. Priority Date: 12/30/1987
• Status: Expired due to Fees

• Current Assignee: Melmotte Incorporated
• Original Assignee: Cytran, Inc.
• Inventors: Morozov, Vyacheslav G., Sinackevich, Nickolai V., Seryi, Sergey V., Kozhemyakin, Andrei L., Rakhilov, Alexei M., Khavinson, Vladimir Kh.
• Primary Examiner(s): PARK, HANKYEL
• Application Number:
  US10/076,707
• Publication Number:
  US 20020177226A1
• Time in Patent Office: 915 Days
• Field of Search: 435/7.24, 435/325, 435/326
• US Class Current: 435/7.24
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: C07K 5/06104 with the first amino acid being acidic
• CPC Class Codes: C07K 5/1021 with the first amino acid being acidic
• CPC Class Codes: C07K 5/126 Tetrapeptides
• CPC Class Codes: C07K 7/64 Cyclic peptides containing only normal peptide links

Abstract

Methods of treatment of subjects for decreasing cell mediated autoimmunity or humoral autoimmunity by administering an R′-Glu-Trp-R″ pharmaceutical preparation useful in subjects having autoimmune diseases.

Claims

1. A method for treating a subject in need thereof to increase one or more indicia of either cell mediated immunity, humoral immunity, or innate resistance to infection, comprising the step of administering an R′

-Glu-Trp-R″

pharmaceutical preparation to the subject under conditions suitable for inducing said increase in said indicia, wherein said R′

-Glu-Trp-R″

is selected from the group consisting of L-Glu-L-Trp, a cyclic form of L-Glu-L-Trp, a linear or cyclic dimer or trimer of L-Glu-L-Trp and pharmaceutically acceptable salts thereof.

2. The method of claim 1, further comprising administering the R′

-Glu-Trp-R″

to the subject under conditions effective to increase a number, a percentage, a ratio of percentages or an activity of blood cells in a sample of a biological fluid or a tissue from a pre-treatment value to a higher post-treatment value or effective to increase a concentration of a blood protein in a sample of biological fluid from a pre-treatment value to a higher post-treatment value.

3. The method of claim 2, wherein said blood cells are selected from among leukocytes, lymphocytes, monocytes, T-lymphocytes, B-lymphocytes, stem cells, CD2⁺-lymphocytes, CD4⁺-lymphorytes, CD8⁺-lymphocytes, CD19⁺-lymphocytes, plasma cells, neutrophils, stab neutrophils, segmented neutrophils, basophils, eosinophils, platelets, and erythrocytes.

4. The method of claim 2, wherein said blood protein is selected from among an immunoglobulin, a lysozyme, a cytokine, an interferon, a complement protein, a coagulation protein, an fibrinolytic system protein, an enzyme inhibitor, a bradykinin system protein, a hormone, a cytokine, and a receptor protein.

5. The method of claim 1, further comprising administering the R′

-Glu-Trp-R″

to the subject under conditions effective to increase a number or a percentage of blood cells in a sample of biological fluid or increase a concentration of a blood protein in a sample of biological fluid in an immunocompromised subject selected from among;

a patient having a bacterial infection, viral infection, mycoplasma infection, parasitic infection, opportunistic infection, pneumocystis infection, cytomegalovirus infection, herpes virus infection, mycobacterium infection, or human immunodeficiency virus infection,

a patient exposed to radiation or one or more chemotherapeutic antiproliferative drugs,

a patient having a transplant, cancer or autoimmune disease, systemic lupus erythematosus, rheumatoid arthritis, Sjogren'"'"'s syndrome, or at an increased relative risk of developing type 1 insulin-dependent diabetes mellitus,

a patient having a primary or a secondary immune deficiency disease,

a patient having a staphylococcal infection, pyoderma, furunculitis, cellulitis, eczema, acne vulgaris, or psoriasis,

a patient having gingivitis, dental caries, or periapical granulomas,

a patient having a gynecological infection, pelvic inflammatory disease, cervicitis, vaginitis, tubular or ovarian abscess or an adnexal abscess,

a patient having lymphangitis or an infralympatic infection,

a patient having an acute or chronic respiratory disease, upper airways disease, sinusistis or parasinusitis, or rhinovirus or influenza infection,

a patient having otitis media, conjunctivitis, uveitis or keratitis, and

an immunocompromised patient at an increased relative risk of developing an infection.

6. The method of claim 3, wherein the increase in the number of the blood cells in the sample of peripheral blood is selected from among:

an increase in leukocytes of by about 1.1-fold to about 1.6-fold;

an increase in lymphocytes of by about 1.1 -fold to about 2.4-fold;

an increase in CD2⁺-lymphocytes by about 1.1-fold to about 2.6-fold;

an increase in CD4⁺-lymphocytes by about 1.1-fold to about 6.4-fold;

an increase in CD8⁺-lymphocytes by about 1.1-fold to about 2.5-fold;

an increase in CD19⁺-lymphocytes by about 1.1-fold to about 2.3-fold;

an increase in surface immunoglobulin positive B-lymphocytes by about 1.1-fold to about 1.6-fold;

an increase in E-rosette forming T-lymphocytes by about 1.1-fold to about 1.8-fold;

an increase in neutrophils by about 1.1-fold to about 1.4-fold;

an increase in a CD4⁺/CD8⁺ ratio by about 1.1-fold to about 1.8-fold; and

,

an increase in monocytes by about 1.1-fold to about 1.4-fold.

7. The method of claim 4, wherein said immunoglobulin is selected from among an IgG, IgA, IgM, IgD, and an immunoglobulin capable of binding an antigen.

8. The method of claim 2, further comprising administering the R′

-Glu-Trp-R″

to the subject under conditions effective to increase a value in an immune assay from a pre-treatment value to a higher post-treatment value, and wherein the immune assay is selected from among a cytokine assay, a lymphocyte blast transformation assay, an assay for a maturation or an activation state in the blood cells, a phagocytosis assay, a marker enzyme assay for an activation state of a macrophage or a neutrophil, an assay for a synthetic activity of the blood cells, an antibody dependent cellular cytotoxicity assay, a natural killer cell assay, a histological assay, an immunohistochemical assay, a cytofluorimetric assay, and an enzyme-linked immunoassay.

9. The method of claim 8, wherein the value for the assay for the maturation or the activation state markers comprises a percentage of cells bearing a cell surface marker selected from among CD2, CD3, CD4, CD28, B220, surface Ig, Rag 1, Rag 2, and Ia/Mac-1.

10. The method of claim 8, wherein the value for the activation state of the macrophage comprises a measurement of 5′

-nucleotidase enzyme or nonspecific acid esterase activity and the value for the activation state of the neutrophil comprises a measurement of esterase activity or NTB reduction.

11. The method of claim 8, wherein the synthetic activity of the blood cell in the immune assay is selected from the group consisting of an immunoglobulin synthesis value, an interleukin synthesis value, an enzyme synthesis value, an integrin synthesis value, and an adhesin synthesis value.

12. The method of claim 11, wherein the interleukin synthesis value is selected from the group consisting essentially of a value quantifying the amount in the sample of IL-1, IL-2, IL-3, IL4, IL-5, TNF-α

, TGF-β

, IFN-α and

IFN-γ

.

13. The method of claim 8, wherein the increase in the immune assay value is selected from among:

an increase in a blast transformation assay induced by a PHA mitogen or a Concanavalin-A mitogen of by about 1.1-fold to about 1.9-fold;

an increase in a phagocytic index assay of by about 1.1-fold to about 1.8-fold;

an increase in an NK assay of about 1.1-fold to about 1.5-fold; and

,

an increase in a cytokine assay of by about 1.1-fold to about 1.8-fold.

14. The method of claim 1, wherein the preparation is administered at a dose and for a time sufficient to increase a value for a delayed type hypersensitivity skin test assay in the subject so treated from a pre-treatment value to a higher post-treatment value.

15. The method of claim 14, wherein the increase in the delayed type hypersensitivity skin test assay is by about 1.1-fold to about 3.3-fold.

16. The method of claim 1, wherein the preparation is administered at a dose and for a time sufficient to increase a value for an immediate type hypersensitivity skin test assay in the subject so treated from a pre-treatment value to a higher post-treatment value.

17. The method of claim 1, further comprising a second step of administering with said R′

-Glu-Trp-R″

pharmaceutical preparation a pharmaceutical agent selected from among an antibiotic, an anti-inflammatory compound, an interferon, a cytokine, a cytokine inhibitor, an interleukin, an interleukin inhibitor, an immunoglobulin and a chemotherapeutic drug.

18. The method of claim 5, wherein the immunocompromised patients having a bacterial or viral infection are further selected from among patients having an acquired immunodeficiency syndrome, a dermatologic disease, an obstetric or gynecologic disease, a herpes infection, a periodontal disease, a lymphatic infection, an ear-eye-nose-or throat infection, a respiratory infection, a hepatic infection, an opthalmic infection, an influenza infection, a graft versus host disease, an orthopedic fracture or disease, a kidney disease, or an allergic disease.

19. The method of claim 1, further comprising a treatment regimen administering a dose of about 10 μ

g per 1 killogram body weight to about 1 mg per 1 kg body weight daily over a period of 1 day to about 30 days to the subject.

20. The method of claim 19, further comprising administering a single daily intramuscular dose of the R′

-Glu-Trp-R″

pharmaceutical preparation.

21. The method of claim 19, further comprising administering a single daily intranasal dose of the R′

-Glu-Trp-R″

pharmaceutical preparation.

22. The method of claim 19, further comprising administering the R′

-Glu-Trp-R″

in the form of an injectable solution containing 0.001% to 0.01% of R′

-Glu-Trp-R″

.

23. The method of claim 19, further comprising administering the R′

-Glu-Trp-R″

in a unit dose form comprising a tablet, a suppository, a capsule, an eye film, an inhalant, a mucosal spray, a nose drop, an eyedrop, a toothpaste, an ointment, or water soluble based cream.

24. The method of claim 23, wherein said unit dose form consists essentially of 0.01 mg of said R′

-Glu-Trp-R″

.