Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-12
2003-11-18
Padmanabhan, Sreeni (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S230500, C514S228800, C514S229500, C514S453000, C514S463000
Reexamination Certificate
active
06649644
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a method of treating human immunodeficiency virus (HIV) infection in a mammal comprising administering to the mammal a therapeutically effective amount of a combination of: (i) at least one cytotoxic agent and (ii) at least one non-nucleoside reverse transcriptase HIV inhibitor (NNRTI). This invention also relates to a method of treating chronic viral infections comprising administering to the mammal a therapeutically effective amount of a combination of: (i) at least one cytotoxic agent and (ii) at least one antiviral agent.
BACKGROUND OF THE INVENTION
HIV infections are at the present time routinely treated with combinations of antiviral drugs (Carpenter, C. et al. Antiretroviral therapy for HIV infection in 1997. JAMA 277, 1962, 1997). The results are beneficial for many patients, with a pronounced drop in viral load, increase in lymphocyte populations, reduction in opportunistic infections and a doubling of time of progression to serious illness and/or death. However, the treatments are done chronically, and can lose effectiveness over time, in part because few if any individuals are cured. Usually HIV persists in cells in the immune system as well as in nervous tissue, and the residual virus may, after months or years of persistence and low-level replication, develop resistance to the drugs and reemerge. At that time, a new set of antivirals is substituted for the initial therapy, and the virus may again be suppressed, although frequently less effectively. The decline in circulating, functional lymphocytes is not only characteristic of HIV infection, it is believed to play a central role in the loss of immunity in the patients (Meyaard, L. et al. Programmed death of T-cells in HIV-1 infection. Science 257, 217, 1992; Ameisen, J. et al. Relevance of apoptosis to AIDS pathogenesis. Trends Cell Biol. 5, 27, 1995). For example, CD4
+
lymphocytes, in which the HIV preferentially replicates, may decline by 90-99% in the final stage of the HIV infection. The current measure of success of conventional HIV antiviral therapy is to protect these cells and restore their numbers and functions. HIV-infected cells are known to be more susceptible to the toxic effects of cytocidal drugs, certain cytokine proteins, radiation and other damaging agents, compared to their uninfected counterparts (Wong, G. et al. TNF alpha selectively sensitizes HIV-infected cells to heat and radiation. PNAS 88, 4372, 1991; Sandstrom, P. et al. HIV gene expression enhances T-cell susceptibility to H
2
O
2
-induced apoptosis. AIDS Res. and Human Retro. 9, 1107, 1993; Katsikis, P. et al. Fas antigen stimulation induces marked apoptosis of T-lymphocytes in HIV-infected individuals. J. Exp. Med. 181, 2029, 1995; Wu X. et al. Apoptosis of HIV-infected cells following treatment with Sho-saiko To and its components. Jpn. J. Med. Sci. Biol. 48, 79, 1995; Gougeon, M. et al. Programmed cell death in peripheral lymphocytes from HIV-infected persons. J. Immunol. 156, 3509, 1996; Hashimoto, K. et al. Stavudine selectively induces apoptosis in HIV type 1-infected cells. AIDS Res. and Human Retro. 13, 193, 1997; Prati, E. et al. Study of spontaneous apoptosis in HIV and patients: Correlation with clinical progression and T-cell loss. AIDS Res. and Human Retro. 13, 1501, 1997). The explanation of the events leading to enhanced death of HIV-infected cells is controversial, but it is clear that the infected cells become depleted of certain broadly acting anti-death proteins normally present in the cells, including the well-known bcl-2 family of proteins (Reed, J. Bcl-2 and the regulation of programmed cell death. J. Cell Biol. 124, 1, 1994). A decrease of bcl-2 typically leads to onset of programmed cell death, or apoptosis, a phenomenon widely observed in HIV-infected cells in vivo and in vitro, both spontaneously and following various external stresses (Liles, W. C. Apoptosis-role in infection and inflammation. Curr. Opin. Inf. Dis. 10, 165, 1997).
The tendency of HIV-infected cells to die or be selectively killed by toxic treatments is known. However, prior to this invention this knowledge has not been exploited for therapeutic purposes. The reason for this is that virtually all cytotoxic treatments cause rapid activation of HIV transcription, leading to a large burst of new progeny virus which proceeds to infect surrounding healthy cells and spread the infection. There has been speculation that the unusually high level of cell killing (for a retrovirus) is part of the biology of HIV, leading to greater spread of the infection (Matsuyama, T. et al. Cytocidal effect of TNF on cells chronically infected with HIV: Enhancement of HIV replication. J. Virol. 63, 2504, 1989; Woloschak, G. et al. HIV expression in dying cells. Bioch. Bphys. Acta 1351, 105, 1997; Zhang, Y. et al. Induction of apoptosis by primary HIV-1 isolates correlates with productive infection in peripheral blood mononuclear cells. AIDS 11, 1219, 1997). Standard antiviral drugs, such as azidothymidine, are not powerful enough to keep HIV in check if infected cells are exposed to a potent cytotoxic drug. This has severely complicated efforts to use chemotherapy to control cancers in HIV-infected individuals (Levine, A. et al. Low-dose chemotherapy with CNS prophylaxis and Zidovudine maintenance in AIDS-related lymphoma. JAMA 266, 84, 1991; Zanussi, S. et al. Effects of anti-neoplastic chemotherapy on HIV disease. AIDS Res. and Human Retro. 12, 1703, 1996).
A number of new antiviral agents have been developed, such as efavirenz, which potently inhibit the reverse transcriptase of the virus. We have discovered in studies in cell culture that such a potent reverse transcriptase inhibitor, combined with a standard cytotoxic drug such as etoposide, can inhibit HIV replication, while infected cells are selectively killed. Surprisingly, a different class of anti-HIV agents, namely protease inhibitors, failed to permit eradication of infected cells.
SUMMARY OF THE INVENTION
One object of the present invention is to provide a novel method of treating human immunodeficiency virus (HIV) infection in a mammal comprising administering to the mammal a therapeutically effective amount of a combination of: (i) at least one cytotoxic agent, and (ii) at least one non-nucleoside reverse transcriptase HIV inhibitor (NNRTI).
Another object of the present invention is to provide a novel method of treating chronic viral infections including, but not limited to, those caused by herpesvirus, cytomegalovirus, hepatitis B virus, hepatitis C virus, and varicella-zoster by selectively eradicating the virally infected cells, comprising administering to the mammal a therapeutically effective amount of: (i) at least one cytotoxic agent, and (ii) and at least one antiviral agent selective for the chronic virus.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventor's discovery that the administration of a cytotoxic agent, component (i) in combination with a NNRTI, component (ii) results in an unexpected, selective eradication of HIV infected cells.
DETAILED DESCRIPTION OF THE INVENTION
Preferred embodiments of the invention have been chosen for purposes of illustration and description, but are not intended in any way to restrict the scope of the invention.
In a first embodiment, the present invention provides a method of treating human immunodeficiency virus (HIV) infection in a mammal comprising administering in combination to the mammal a therapeutically effective amount of: (i) a cytotoxic agent and (ii) at least one non-nucleoside reverse transcriptase HIV inhibitor (NNRTI).
In a preferred embodiment, the NNRTI is efavirenz.
In another preferred embodiment, the cytotoxic agent is losoxantrone.
In a more preferred embodiment, cytotoxic agent is losoxantrone, and the NNRTI is efavirenz.
In another embodiment, the present invention provides a method of treating chronic viral infections including, but not limited to, those caused by herpesvirus types I and II, cy
Bristol--Myers Squibb Company
DuBoff Samuel J.
Goddard Christine
Jiang S.
Padmanabhan Sreeni
LandOfFree
Method of treating HIV infection by combined use of a... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method of treating HIV infection by combined use of a..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method of treating HIV infection by combined use of a... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3134603