Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1995-06-07
2003-02-04
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S198000, C514S369000, C514S374000, C514S378000, C514S561000, C514S563000
Reexamination Certificate
active
06514955
ABSTRACT:
BACKGROUND OF THE INVENTION
Acquired Immunodeficiency Syndrome (AIDS) is one of the most significant infections to appear in the last decade. This epidemic is not confined to a single segment of the population nor is its spread blocked by natural barriers or international boundaries. Millions have died in Africa and many more individuals are infected worldwide. In the United States more than 100,000 people have died and at least 1 million more are presently infected with the virus. This pandemic shows no signs of abating.
AIDS was first diagnosed in male homosexuals who exhibited a variety of infections of fungal (
Candida albicans
), protozoal (
Pneumocystis carinii
), and viral (
Herpes zoster
) origin. Many of these individuals also had an increased incidence of kaposi sarcoma and lymphoma. They had a depressed T helper/T suppressor lymphocyte cell ratio and an absence of delayed hypersensitivity responses. Collectively, these observations suggested a deficiency in cell-mediated immunity.
It is strongly suspected that the causative agent in AIDS is an RNA retrovirus called the human immunodeficiency virus (HIV-1 or HIV-2). HIV possesses an envelope glycoprotein (gp120) that has a high affinity for the CD
4
receptor on T helper cells and other target cells. These other target cells include bone marrow stem cells, macrophages, endothelial cells, glial cells, lymph node, dendritic cells, bowel enterochromaffin cells, cervical eptithlium and possibly Langerhans cells. However, it is the effects of HIV on T-helper cells that are the best known. The infectious process begins when the virus penetrates the body and enters the blood stream. Binding of HIV to CD
4
target cells involves interaction of the external envelope glycoprotein molecule gp120 with the CD
4
molecule, although other cell receptors may be involved. The virus next enters the target cell, or is internalized, through fusion of the viral envelope with the target cell membrane. Through this fusion, the virus loses its coat, and releases its RNA core and reverse transcriptase enzyme into the host cell cytoplasm.
The HIV reverse transcriptase enzyme copies the RNA message producing first a single-stranded, and then a double-stranded, DNA (circular complementary DNA). This newly formed double-stranded DNA becomes incorporated into the host chromosomal DNA once it enters the host cell nucleus. This incorporated viral DNA may remain dormant or, upon activation, will produce viral messenger RNA (mRNA). The viral mRNA codes for proteins that are important in viral replication. Glycoprotein will then envelop the RNA genome resulting in the production of infectious viral particles; completed viral particles are then released to infect other cells.
Greenspan, D. et al., “Aids and the Mouth,” Chap. 4, pp. 50-51, Munksgaard Press, distributed by Mosby Year Book, Inc., Chicago, Ill., (1990), report that because the HIV DNA is integrated into the chromosomal DNA of the host target cell, the HIV DNA survives for the life of the infected cell. Thus, there may be a form of persistent infection where a few new HIV particles are produced with little, if any, killing of host cells. Greenspan et al. also report that the cells killed or inactivated are predominately CD
4
helper T cells with consequent loss in T-helper cell numbers, decrease in T4 helper/T8 suppressor cell ratios and reduction or loss of ability to mount a normal immune reaction, particularly in response to T cell dependent antigens such as those borne by viruses, fungi and encapsulated bacteria. Greenspan et al. also note that while other cells such as monocytes and macrophages are also infected, these cells are generally not killed and any functional defects which they incur from HIV infections are as yet not fully understood.
Schreck et al.,
EMBO J.,
10 (8):2247-2258, 1991, and Duh et al.,
Proc. Nat'l. Acad. Sci.
(
USA
), 86:5974-5978, 1989, report that when using HIV infected Jurkat T lymphocyte cells, there is a factor inside the infected cells which controls transcription of certain nuclear genes of the host cell. This factor is formed of three proteins that bind together, namely, p50, p65 and I kappa B. Schreck et al. further report that normally the three proteins are formed in the target cell cytoplasm in this triad (three proteins bound together) in an inactive state. Under conditions such as oxidative stress, however, the viral reproducing mechanism is activated. The iKB factor is removed from the protein triad and the remaining p50, p65 complex becomes known as NF-kappa B (NFKB).
Schreck et al. have recognized that NFKB is a gene transcription factor that migrates into the nucleus of the HIV infected cell and switches on the production of the HIV virus of a virally infected cell. Schreck et al. also report that hydrogen peroxide and oxygen radicals are agents commonly produced during the inflammatory process and that micromolar concentrations of hydrogen peroxide can induce the expression of HIV-1 in a human T cell line. They further report that the expression of HIV is mediated by NFKB transcription factor which is potently and rapidly activated by a hydrogen peroxide treatment of cells from its inactive cytoplasmic form. They additionally report that N-acetyl cysteine and other thiol compounds block the activation of NFKB. They concluded that these diverse agents thought to activate NFKB by distinct intracellular pathways might act through a common mechanism involving the synthesis of reactive oxygen intermediates. They did not suggest any possible candidates for that reactive oxygen intermediate.
Sherman et al.,
Biochem. Biophys. Res. Comm.,
191 (3):1301-1308, 1993, report that pyrrolidine dithiocarbamate (PDTC) is an inhibitor of NFKB activation. They further report that this compound is an inhibitor of nitric oxide synthase (NO synthase). They further report that oxidative stress in HIV infection is manifested by decreased cysteine and glutathione levels in plasma and leukocytes. They suggest that the redox regulation of macrophages may be crucial to the activation of nitric oxide synthase and that PDTC may act as a scavenger of reactive oxygen species which prevents them from participation in the activation of NFKB.
Current approaches to HIV treatment generally involve immunotherapy (e.g., vaccines against whole killed HIV and a variety of HIV surface glycoproteins) directed at the HIV as well as pharmacological intervention in the fHIV infectious process. In theory, any of the steps of viral replication or release could be points of pharmacological attack against the virus. The major chemotherapeutic attack by available drugs has been at the level of inhibition of viral reverse transcriptase. The first drug licensed for use in HIV treatment became available in 1987; it was azidothymidine (AZT). In the early 1990's, dideoxyinosine (DDI) and dideoxycytidine (DDC) were approved by the FDA. AZT and DDI were approved for monotherapy while DDC is used in combination with one of the other drugs.
A basic problem of HIV research is that experiments aimed at killing the virus in vitro and in vivo appear to give opposite results. For example, AZT is very effective in vitro in killing the HIV virus. Valencia, E. et al.,
Ann. Med. International,
9, (11):531-537, 1992 and Baumgarten, R.,
Dermatol
-
Monatsschr.,
175, (8):469-473, 1989 report, however, that AZT does not prolong the lives of HIV infected victims to any great extent. Other drugs and biological therapies, such as antioxidant therapy, which have produced encouraging in vitro results, also have not proven effective in vivo as reported in the literature. [See, e.g., Cathcart,
Medical Hypothesis,
14:423-433, 1984; Kappus and Diplock,
Free Radical Biol. and Med.,
12:55-74, 1992; Muller,
Free Radical Biol. and Med.,
13:651-657, 1992; Fuchs,
Medical Hypotheses,
36:60-64, 1991; Roederer,
AIDS Res. and Human Retrovirus,
8:209-217, 1992; Harakeh et al.,
Proc. Nat'l. Acad. Sci.,
87:7245-7249, 1990; Hersh et al.,
JAMA,
265:1538-1544, 1991; Staal, et al.,
AIDS Research a
HIV Diagnostics, Inc.
Kishore Gollamudi S.
Price Heneveld Cooper DeWitt & Litton
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