AP132A - Improved formulation of low-dose interferon alpha. - Google Patents

Abstract

Use of low-dose (1,000 IU/dose) oral IFNa as a mixture of all subspecies in specific proportions in the treatment of Acquired immune-deficiency syndrome (AIDS) caused by human immunodeficiency virus types I and II (HIV-I, HIV-II) in both paediatric and adult cases, asymptomatic individuals who are positive for both HIV-I and HIV-II, viral hepatitis, retroviral and retroviral infections, viral stomatitis, myotrophic lateral scerosis, disseminated sclerosis and other chronic degenerative neurological disorders, opportunistic and other microbial infections.

Description

BACKGROUND TO INVENTION

Interferon alpha (IFNcx.) is a family of leukocyte-derived proteins with immunomodulatory, antiproliferative and antiviral properties. Recombinant and natural IFN have been applied in the treatment of hairy cell leukemia, condyloma acuminatum and Kaposi’s sarcoma.

IFN'oC may be produced:

(a) naturally by cells, (b) through hybridization techniques as a recombinant product (c) by cell lines through stimulation with viruses, a procedure commonly referred to a:- Cantell procedure.

The present invention relates to an improved formulation of interferon alpha in the treatment of viral, opportunistic and other microbial infections. Patients suffering from HIV-1 infection and WITH characteristic features of acquired immunodeficiency syndrom (AIDS) treated with low-dose interferon alpha have responded positively. Signs and symptoms that arc routinely associated with AIDS, together with decreased levels lymphocytes bearing CD4+ markers have been observed to resolve without any other treatments. There has also been scrodcconvcrsion in some cases. In addition, positive response has been observed using low-dose oral interferon alpha in viral stomatitis patients. The improved formulation is also applied in the treatment of other viral infections as well as chronic degenerative neurological disorders.

This invention recognizes and supports other related inventions as contained in US Patent Nos. 4,462,985 (1984); 4,497,795(1985); 4,820,514(1989); and 4,820,515(1989). It further supports International Application Publication No. WO88/0341I (1988) published under the Patent Cooperation Treaty (PCT) of the World Interlcclual Property Organization (WIPO).

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Abstracts of Related Patents Cited

1. US Patent No. 4.462,985 (1984); Cummins JM

Interferon gycoprotcins isolates of heterologous species origin are subjected to treatment in a digestive environmcl and non-spccie-spccific bioogically active fractions thereofare administered, preferably through digestive tract tissue, to the circulatory system of mammals, including humans, to secure antiviral, antiproliferative (e.g neoplastic) and immunomodulatory (e.g immunopotentiating) effects ordinarily associated only with parenteral administration of homologous species interferon.

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2. US-Patent No, 4,497.795 (19S?h Cummins JM

The appetite of a uurm-blooded vertebrate ean be regulated by administering to the vertebrate a biological active fraction of interferon in an amount effective to modulate the vertebrate's food intake or efficiency in utilizing food. The appetite of a cow can be stimulated by the oral or intravenous administration of bovine fibroblast interferon or by interferon secreted nasally by the cow in response to inoculation with a vaccinal virus strain such as that of infectious bovine erhinotraeheitis virus. The appetite of swine can be enhanced by oral administration of bovine fibroblast interferon.

3. US Patent No 4.820.514 (1989): Cummuns JM

A biologically active interferon can be adminstered to an animal in conjunction with the administration of a vaccine to improve the vaccine efficiency and allow the use of a smaller vaccination dose. This procedure will cause a less severe vaccine infection in the animal than if no interferon was administered.

4. US Patent No, 4,820.515 (1989): Cummins JM

Warm-blooded vertebrates can be given very low dosages of interferons, especially huma interferon alpha, to increase efficiency in food utilization. Very low dosages of interferon can also be used to prevent and treat bovine respiratory disease complex. Optimum daily dosages may be as low as 0.10 IU/Ib of body weight and possibly even lower.

5. PCT/WIPO International Publication No. W088Z03411: Cummins JM

Neoplastic disease, hypcrallergenicily, antoimmune disorders characterized by chronic tissue degenerative inflammation an dimmuno-resislanl viral infections are treated by the administration of interferon at a dosage of about 1.0 to about 5 Iu/Ib per day by contacting said interferon with oral/pharyngeal mucosa. Interferon is administered in solution or in a novel solid unitary dosary form adapted to be dissolved in saliva when placed in the mouth.

Other delated Scientific References/Publications.

1. Koech DK, Obel AO, Minowada J, Hutchinson VA and Cummins JM. Low dose oral alpha-interferon therapy for patients seropositive for the human immunodeficiency virus Cypc-1 (HIV-l). Molecular Biothcrapy; 1990; (in press).

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Interferon lor treatment of hairy cell leukemia. Med Lott Drugs Ther 1986; 28:13-19

3. Altman L: FDA approves first drug for an AIDS-related cancer. New York Times, November 22, 1988; p31.

4. Ronel S: Press release, Interferon Sciences, Inc., New Brunswick, New Jersey, October 10, 1989.

5. Bottomly JM, Toy JL: Clinical side effects and toxicities of interferon. In: RK Oldham, NB Finter (cds): Interferon 4, Elsevier, North Holland, 1985; 155-180.

6. Quesada JR, Talpaz M, Rios A, Kurzrock R, Gutlerman JV; Clinical toxicity of interferons in cancer patients: r review. J. Clin Oncol 1986; 4:234-43

7. Dcyton LR, Walker RE, Kovacs JA, ct al: Reversible cardiac dysfunctions associated with interferon alfa therapy in AIDS patients with Kaposi's sarcoma. NEJM 1989; 321:1246-9.

8. Steed VP: Improved survival of four cats infected with feline leukemia virus after oral administration of interferon. Folinc Praciica 1987; 17:24-30.

9. Tompkins MB, Cummins JM; Response of FeLV-induced nonregencrativc ancamia to oral adminstration of a bovine interferon-containing preparation. Feline-induced nonregerative ancamia to oral administration of a bovine interferon-containing preparation. Feline Practice 1982; 12:6.

10. Cummins JM, Tompkins MB, Olsen RG, et al: Oral use of human alpha interferon in cats. J. Biol Res Mod 1988; 7:513-523.

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11. Hutchinson V, Cummins JM: Oral interferon in an AIDS patient. Lancet Dec 26, 1987; ii: 1530-31.

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12. Wright SE. Fagan P, Blackburn C, cl al: Low-dose oral inferferon prophylaxis and therapy of HIV-1 seropositive individuals and contacts. Controlled study in procress in Amarillo, Texas, 198S-1989.

13. Koeeh DK: Subpopulations of T lymphocytes in Kenyan patients with isceral leishmaniasis. Am J Trop Med Hyg 1987; 36:497-500.

14. Yates JW, CHalmcr B, McKegney FP: Evaluation of patients with advanced cancer using Ihe Karnofsky performance status. Cancer 1980; 45;2220-2224.

15. Fukuda S, AN’do S, Sanou 0, et al: Simultaneous production of natural human tumor necrosis faclor-a, -B and inlcrferon-a from BALL-1 cells stimulated by HVJ. Lympokine Res 19S8; 7(2): 175-185.

16. Lane H. Fauci AS: Immunologic abnormalities in the acquired immunodeficiency syndrome. Rev Immunology 1985; 3:477-500.

17. Fauci AS, Masur H, Gelmann EP, ct al: The acquired immunodeficiency Syndrome: an update. Ann Int Med 1985; 102:800-813.

18. Bowen DL, Lane HC, Fauci AS: Immunopathogenesis of the acquired immunodeficiency syndrom. Ann Int Med 1985; 103:704-709.

19. Fauci AS: THe human immunodeficiency virus: infectivity and mechanisms of pathogenesis. Science 1988; 239:617-622.

20. Popovic M, Read-Connole E, Gallo RC: T4 positive human neoplastic cell lines susceptible to and permissible for HTLV III. Lancet 1984; ii: 1473.

21. Klatzmann D, Barre-Sinoussi F, Nugeyre MT, ct al: Selective tropism of lymphadenopathy associated virus (LAV) for helper induced T lymphocytes. Science 19S4; 225-59-92.

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22. Klatzmann D, Champagne E., Chamarei S, et al: T-lymphocylc T4 molecule behaves as the receptor for human retrovirus LAV. Nature 19S4; 312:767-768.

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23. Folks TM, Benn S, Rabson A, et al: Characterization of a continuous T cell line susceptible to the eytopathie effects of the acquired immunodeficiency syndrome (AIDS) associated retrovirus. Proc Nat Acad Sei USA 19S5: 82:4539-4543.

24. McDougal JS, .Mawle A, Cort SP, et al: Cellular tropism of the human retrovirus HTLVIII/LAV 1. Role of T cell aetivtion and expression of the T4 antigen. J. Immun 1985: 135:3151-3162.

25. Hoxie JA Alpers JD, Rackowski JL, et al: Alterations in T4 (CD4) protein and mRN'A synthesis in cells infected with HIV. Science 1986; 234: 1127.

26. Schnittman SM, Psallidopoulos MC, Lane HV, el al: The reservoir for HIV-1 in human peripheral blood is a T cell that maintains expression of CD4. Science 1989; 245-305308.

27. Broder S: Controlled trial methodology and progress in treatment of the acquired immunodeficiency syndrom (AIDS). Ann Int Med 1989; 110:417-418.

28. Abrams D, Gottlieb M, Grieco M, Speer M: AIDS and the immune system. AIDS/HIV Experimental Treatment Directory AmFAR 1989; 2:34-38.

29. Justice AC, Feinstein AR, Wells CK: A new prognostic staging system for the acquired immunodeficiency syndrom. NEJM 1989; 320:1388-1393.

30. Kaslow RA, Phair JP, Friedman HB, et al: Infection with human immunodeficiency virus clinical manifestations and their relationship to immune deficiency. Ann Int Med 1987; 107:474-480.

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Fackelmann KA. AIDS Predictors. Sei News 19S9; 136:298-299.

32. Abrams D, Gottlieb M, Grieco M, Speer M: HIV Stage by State Trial Indiex. AmFar 1989; 2:11-15.

33. DcWit R, Schattcnkcrk JKME, Boucher CAB, ct al; Clinical and virological effects of high dose recombinant interferon-a in disseminated AIDS-relatcd Kaposi's sarcoma. Lancet 1988; 2:1214-7.

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34. Line HC, Kovacs JA, Feinberg J, et al: Anti-relroviral effects of interferon-a in AIDSassociated Kaposi's sarcoma. Lancet I9S8; 2:1218-22.

35. Goldsmith MF: Midwest symposium seeks therapeutic answers to global AIDS problem. JAMA 1990; 263:345-346.

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Claims (7)

1. CLAIM OF INVENTION

   Claim 1

   Use of low-dose (<1,000 IU/dose) oral IFNcx as a mixture of all subspecies in specific proportions as 2oc, 7oc and 8ος subtypes or many other proportions in the treatment of:

   1. Acquired immuno-dcficiency syndrome (AIDS) caused by human immunodeficiency virus types I and II (HIV-I, HIV-II) in both paediatric and adult cases.
2. 2. Asymptomatic individuals who are positive for both HIV-I and HIV-II.
3. 3. Viral hepatitis
4. 4. Rotaviral and retroviral infections
5. 5. Viral stomatitis
6. 6. Myotrophic lateral sclerosis, disseminated sclerosis and other chronic degenerative neurological disorders
7. 7. Opportunistic and other microbial infections

   Claim. 2

   Use of low-dose (<1,000 IU/dose) oral IF NX as a prophylactic in the prevention of microbial infections.

   Claim 3

   Use of low-dose (<1,000 IU/dose) oral LFNx in whatever form in the management of diseases other than those contained in patents cited in this application.

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   Claim 4

   Use of maltose, lactose or starch as innocuous diluents in the formulation of IFNcx. as a drug.

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