Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1994-10-21
2004-04-27
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06727240
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention concerns methods of preventing or treating HIV-1 or HIV-2 infection by administering to a human, especially vaginally administering to a female, a tin or silicon protoporphyrin IX or tin mesoporphyrin IX.
2. Background Information
Human immunodeficiency viruses (“HIV”) have been known as the causative virus for AIDS (Acquired Immunodeficiency Syndrome). The prevalence of AIDS cases is presently increasing at an alarming rate.
Two related retroviruses that can cause AIDS are human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2). The genomes of these two viruses are about 50% homologous at the nucleotide level, contain the same complement of genes, and appear to attack and kill the same human cells by the same mechanism.
HIV-1 was identified in 1983. Virtually all AIDS cases in the United States are associated with HIV-1 infection. HIV-2 was isolated in 1986 from West African AIDS patients.
HIV-1 and HIV-2 are retroviruses, in which the genetic material is RNA, rather than DNA. The HIV-1 and HIV-2 viruses carry with them a polymerase (reverse transcriptase) that catalyzes transcription of viral RNA into double-helical DNA.
The viral DNA can exist as an unintegrated form in the infected cell or be integrated into the genome of the host-cell. As presently understood, the HIV enters the T4 lymphocyte where it loses its outer envelope, releasing viral RNA and reverse transcriptase.
The reverse transcriptase catalyzes synthesis of a complementary DNA strand from the viral RNA template. The DNA helix then inserts into the host genome where it is known as the provirus. The integrated DNA may persist as a latent infection characterized by little or no production of virus or helper/inducer cell death for an indefinite period of time. When the viral DNA is transcribed and translated by the infected lymphocyte, new viral RNA and proteins are produced to form new viruses that bud from the cell membrane and infect other cells.
Attempts to treat AIDS with drugs which inhibit reverse transcriptase such as 3′-azido-3′-deoxythymidene (AZT) have not been met with a desirable degree of success. Moreover, there is a potential for toxicity with the use of anti-viral drugs. Thus there is a need for an effective and safe means to prevent and treat AIDS.
HIV infections are transmitted by means such as contaminated intravenous drug needles and through sexual contact. The transmission of HIV by heterosexual sex poses an especially severe problem for women. By the year 2,000, it is estimated that 90% of HIV infection will be acquired via heterosexual intercourse.
The utilization of condoms provides a substantial degree of protection against transmission of HIV infections during sexual intercourse, but a difficulty arises when condoms are not employed. Moreover, the use of condoms appears to be a culturally and socially unacceptable practice in many countries.
Although men can protect themselves from HIV infection by using condoms, women who are sexually active have no similar means. Women can encourage their male sex partners to use a condom, but may not succeed. The female condom, which is just becoming available, is expensive and there is presently no evidence that it prevents transmission of HIV.
Even maintaining a monogamous sexual relationship is no guarantee of safety, for if a woman's male partner becomes infected, he can pass the virus to her. And as more women are infected, so are more babies.
There is presently frustration in the medical field by the bleak prospect for an effective AIDS vaccine in the near future and the severe limitations of drugs that effectively and safely combat HIV.
There is a need for a safe and effective substance that can be inserted into the vagina to a foam, gel, sponge or other form to kill HIV or prevent it from infecting cells in the body. It is hoped that such substance be used by a woman without her partner's knowledge.
Several recent reports suggested the potential of porphyrins for chemotherapy of HIV-1 infections (Asanaka, M., Kurimura, T., Toya, H., Ogaki, J. & Kato, Y., (1989), “Anti-HIV Activity of Protoporphyrin”,
AIDS
, 3, 403-404; Levere, R. D. Gong, Y.-F., Kappas, A., Bucher, D. J., Wormser, G. P. & Abraham, N. G. (1991), “Heme Inhibits Human Immunodeficiency Virus 1 Replication in Cell Cultures and Enhances the Antiviral Effect of Zidovudine”,
Proc. Natl. Acad. Sci. U.S.A
., 88, 1756-1759; Dixon, D. W. Schinazi, R. & Marzilli, L. G., (1990), “Porphyrin As Agents Against the Human Immunodeficiency Virus.”
Ann N.Y. Acad. Sci
., 616, 511-513; and Dixon, D. W., Kim, M. S., Kumar, V., Obara, G., Marzilli, L. G. & Schinazi, R. F. (1992), “Amino- and Hydroxytetraphenylporphyrins with Activity Against the Human Immunodeficiency Virus.”,
Antiviral Chem. Chemother
., 3, 279-282).
Porphyrin derivatives competitively inhibiting HIV-1 protease have been designed (DeCamp, D. L., Babé, L. M., Salto, R., Lucich, J. L., Koo, M.-S., Kahl, S. B. & Craik, C. S. (1992), “Specific Inhibition of HIV-1 Protease by Boronate Porphyrin”,
J. Med. Chem
., 35, 3426-3428). The effect of these compounds on HIV-1 replication has not been reported. The predominant binding of some porphyrins to the V3 loop of the HIV-1 envelope glycoprotein gp120, and a correlation between the V3 loop binding capacity of some porphyrins and their antiviral activity have been recently demonstrated (Neurath, A. R., Haberfield, P., Joshi, B., Hewlett, I. K., Strick, N. & Jiang, S. (1991), “Rapid Prescreening for Antiviral Agents Against HIV-1 Based on Their Inhibitory Activity in Site-Directed Immunoassays I. The V3 Loop of gp120 as Target,”
Antiviral Chem. Chemother
., 2, 303-312; Neurath, A. R., Strick, N., Haberfield, P. & Jiang, S. (1992), “Rapid Prescreening for Antiviral Agents Against HIV-1 Based on Their Inhibitory Activity in Site-Directed Immunoassays. II. Porphyrin Reacting with the V3 Loop of gp120
”, Antiviral Chem. Chemother
., 3, 55-63; and Neurath, A. R. (1993), “B Cell Antigenic Site Mapping of HIV-1 Glycoproteins. In: Immunochemistry of AIDS”,
Chemical Immunology
, Vol. 56, E. Norrby ed.), pp. 34-60, Karger, Basel; Neurath, A. R., Strick, N. & Jiang, S. (1993), “Rapid Prescreening for Antiviral Agents Against HIV-1 Based on Their Inhibitory Activity in Site-Directed Immunoassays. Approaches Applicable to Epidemic HIV-1 Strains”,
Antiviral Chem. Chemother
., 4, 207-214; and U.S. Pat. No. 5,230,998, the entire contents of U.S. Pat. No. 5,230,998 being incorporated by reference herein).
Levere , R. D., Gong, Y-F., Kappas, A., Bucher, D. J., Wormser, G. P. and Abraham, N. G., (1991), “Heme Inhibits Human Immunodeficiency Virus 1 Replication In Cell Cultures and Enhances the Antiviral Effect of Zidovodine”,
PNAS
, 88, 1756-1759 concern the study of heme alone and heme together with AZT, on HIV replication in human peripheral blood lymphocytes and in the H9 cell line. The following is noted with respect of Levere et al:
(1) The Levere et al results did not achieve substantial suppression of viral infection using only a metalloporphyrin;
(2) Levere et al report only relatively low activity using heme;
(3) The thrust of Levere et al is to use heme in conjunction with AZT.
WO 89/11277 and U.S. Pat. No. 5,109,016 to Dixon, Schinazi and Marzilli concern a method for inhibiting infection or replication of human immunodeficiency virus comprising administering an effective amount of a porphyrin, porphyrin-like compound or a derivative thereof to inhibit HIV infection in cells.
U.S. Pat. No. 5,109,016 describes the following metals which can be inserted into the tetrapyrrole ring of porphyrin: Fe, Co, Zn, Mo, Ti, Mn, Cr, Ni, Mg, Cu, Tl, In, Ru, V and Au, however, Sn is not described in U.S. Pat. No. 5,109,106.
U.S. Pat. No. 5,109,016 indicates that their results demonstrate that non-metalloporphyrins are generally more active than the metalloporphyrins.
EP 337,598 describes the use of porphyrin and metalloporphyrins to treat diseases caused by HIV.
EP 337,598 describes the following metal
Debnath Asim Kumar
Jiang Shibo
Neurath Alexander R.
New York Blood Center Inc.
Travers Russell
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