Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-19
2003-04-08
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S312000, C544S314000
Reexamination Certificate
active
06545007
ABSTRACT:
FIELD OF THE INVENTION
The present invention is compounds, methods, compositions, and devices for preventing infection by sexually transmitted HIV.
BACKGROUND OF THE INVENTION
The retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. Since it emerged as a public health threat in the early 1980's, efforts to control or eradicate the disease have focused principally on options for treating the disease after an individual has already become infected.
The use of condoms provides a substantial degree of protection against transmission of HIV infections during sexual intercourse. However, the use of condoms is not 100% effective against the transmission of HIV. Moreover, couples often do not use condoms. A topical composition that could be inserted into the vagina or rectum by a foam, gel, sponge or other form, or which could be topically applied to the male genitalia, would in many cases be preferred over condoms. Moreover, the prophylactic effectiveness of condoms could be improved by including a suitable microbicide in the lubricant coated on the exterior of the condom. However, to date little progress has been made to develop an effective topical composition against the transmission of HIV.
Most work to develop topical HIV prophylactic compositions has focused on the use of surfactants and buffers, such as the over-the-counter product nonoxynol-9. Surfactants and detergents disrupt microbial and sperm membranes by lysis and emulsification. Surfactant-containing creams and gels have the advantage of being very broad in their killing ability, and thus can kill the HIV virus and viruses associated with other sexually transmitted diseases. The use of surfactants and buffers is, however, substantially limited by the damage they can cause to cell membranes. In the vagina, nonoxynol-9 has been shown to thin vaginal walls. In the rectum, nonoxynol-9 can cause rectum walls to slough off.
Other virusidal compositions being investigated for use as HIV virusides include carageenan and other large sulfated polysaccharides that stick to viral envelopes and possibly shield cell membranes. Philips D M, “Of Mice and Men—Assaying Vaginal Virusides,” Virusides 2000, Mar. 13-16, 2000, Alexandria Va., page 12, abstract A20. Monoclonal antibodies have also been proposed as HIV prophylactics, and some antibodies have shown a promising degree of protection. (Mascola J et al., “Role of IgG Antibody in Protection against Vaginal Transmission of an HIV-1/SIV Chimeric Virus,” Virusides 2000, Mar. 13-16, 2000, Alexandria Va., page 7, abstract A10; Watanabe, M., Boyson, J. E., Lord, C. I. and Letvin, N. L. “Chimpanzees Immunized with Recombinant Soluble CD4 Develop Anti-self CD4 Antibody Responses with Anti-human Immunodeficiency Virus Activity”, Proc. Natl. Acad. Sci. U.S.A., 89, 5103-5107 (1992); and Perno, C. -F., Baseler, M. W., Broder, S. and Yarchoan, R., “Infection of Monocytes by Human Immunodeficiency Virus Type 1 Blocked by Inhibitors of CD4-gp120 Binding, Even in the Presence of Enhancing Antibodies”, J. Exp. Med., 171, 1043-1056 (1990)).
International application published as WO 00/03998 to P. LaColla and M. Artico disclosed substituted 6-benzyl-4-oxopyrimidines useful in the treatment of HIV.
Elise A. Sudbeck, Chen Mao, Rakesh Vig, T. K. Venkatachalam, Lisa Tuel-Ahlgren, and Fatih M. Uckun disclose various dihydroalkoxybenzyloxopyrimidine derivatives shown to be effective against HIV, which were designed based on structure analysis of potent nonnucleoside inhibitors of the human immunodeficiency virus reverse transcriptase.
Scientists have recently reported several biological discoveries that improve our understanding of how HIV enters an organism following sexual contact, which could lead to prophylactic substances that interfere with HIV's interaction with its target cells. These discoveries revolve generally around T lymphocytes, monocytes/macrophages and dendritic cells, suggesting that CD4 cell receptors are engaged in the process of virus transmission (Parr, M. B. and Parr, E. L., “Langerhans Cells and T lymphocyte Subsets in the Murine Vagina and Cervix”, Biology of Reproduction, 44, 491-498 (1991); Pope, M. et al., “Conjugates of Dendritic Cells and Memory T Lymphocytes from Skin Facilitate Productive Infection With HIV-1”, Cell, 78, 389-398 (1994); and Wira, C. R. and Rossoll, R. M., “Antigen-presenting Cells in the Female Reproductive Tract: Influence of Sex Hormones on Antigen Presentation in the Vagina”, Immunology, 84, 505-508 (1995)). Geijtenbeek TBH et al., for example, recently reported that HIV tightly binds the DC—SIGN molecule on the surface of dendritic cells, through the gp120 HIV envelope protein. When the dendritic cells present microbial antigens to CD4+ T helper cells to stimulate an immune response, the dendritic cell inadvertently transfers the HIV to the CD4+ T cells, thereby advancing the progression of the infection.
Some have postulated, based upon these discoveries, that prophylactics can be designed that block the interaction between DC—SIGN and gp120. Similarly, DC4 and chemokine receptor blockers could be designed and administered to prevent the transfer of HIV from the dendritic cells to the CD4+ T cells. However, methods that rely on the specific interaction of HIV and human cells are limited, because the infection pathway has not been fully defined and may be diverse. (Miller, C. J. et al., “Genital Mucosal Transmission of Simian Immunodeficiency Virus: Animal Model for Heterosexual Transmission of Human Immunodeficiency Virus”, J. Virol., 63, 4277-4284 (1989); Phillips, D. M. and Bourinbaiar, A. S., “Mechanism of HIV Spread from Lymphocytes to Epithelia”, Virology, 186, 261-273 (1992); Phillips, D. M., Tan, X., Pearce-Pratt, R. and Zacharopoulos, V. R., “An Assay for HIV Infection of Cultured Human Cervix-derived Cells”, J. Virol. Methods, 52, 1-13 (1995); Ho, J. L. et al., “Neutrophils from Human Immunodeficiency Virus (HIV)-SeronegatiVe Donors Induce HIV Replication from HIV-infected Patients Mononuclear Cells and Cell lines”: An In Vitro Model of HIV Transmission Facilitated by Chlamydia Trachomatis., “J. Exp. Med., 181, 1493-1505 (1995); and Braathen, L. R. & Mork, C. in “HIV infection of Skin Langerhans Cells”, In: Skin Langerhans (dendritic) cells in virus infections and AIDS (ed. Becker, Y.) 131-139 (Kluwer Academic Publishers, Boston, (1991)).
Efforts by researchers to develop an HIV vaccine have also not yet been successful. Siegel et al. reported that vaccination with inactivated SIV did not protect African Green monkeys against infection with the homologous virus notwithstanding a strong immune response to SIV. (Siegel, F., Kurth, R., and Norley, S., (1995), “Neither Whole Inactivated Virus Immunogen nor Passive Immunoglobulin Transfer Protects Against SIV Infection in the African Green Monkey Natural Host”, J. AIDS, 8, 217-226).
Therefore, there remains a need for an effective topical prophylactic against the sexual transmission of HIV. It is an object of the invention, therefore, to provide topical prophylactic compositions against the sexual transmission of HIV, methods for using such compositions, and devices that deliver such compositions.
It is another object of the invention to provide compounds that have extended activity against the HIV virus.
It is another object of this invention to provide a topical composition that can be applied to the areas of skin and mucus epithelia at highest risk for exchanging HIV pathogens. Formulations of such compositions can be based upon existing topical compositions used as lubricants and contraceptives, which are often present as lotions or gels, or coated to the exterior of condoms.
It is another object of this invention to create new, long-term prophylactic methods for women based upon existing contraceptive devices, including sustained release devices to be ins
Artico Marino
Bryant Martin L.
La Colla Paolo
Sommadossi Jean-Pierre
Idenix (Cayman) Limited
King & Spalding LLP
Knowles, Esq. Sherry M.
Reamer James H.
Sullivan, Esq. Clark G.
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