Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1993-10-22
2003-11-25
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S012200
Reexamination Certificate
active
06653293
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to treating body fluid-related diseases, where pathogenic microorganisms and cells infected by the microorganisms are mainly contained in the body fluid, particularly such retrovirus diseases such as AIDS.
2. Behavior of HIV
AIDS is the acronym for Acquired Immunodeficiency Syndrome, caused by Human Immunodeficiency Virus (HIV). The behavior of HIV must be reviewed as the basis of this invention.
HIVs and HIV-infected cells in human blood, seminal fluid, vaginal mucous, etc., are spread from exchange of HIV-infected blood or lymphatic fluid or from contact with infected mucous membrane, thereby establishing a new infection of AIDS.
Glycoprotein, gp120 developed on the HIV envelope in a large quantity, adheres to CD4 protein, developed on the cell membrane of certain leucocyte cells as T-4 helper lymphocytes, macrophage and dendritic cells. These cells are known as CD4 (positive) cells. Fusion of the HIV envelope with the CD4 cell membrane is carried out by gp41 on the HIV envelope. The HIV RNA and reverse transcriptase of the HIV are brought into the CD4 cell. The HIV RNA is reverse transcribed as a complement DNA (pro virus) by the reverse transcriptase, and the provirus-DNA is combined into the host CD4 cell DNA.
The host cell then replicates the HIV RNA from the provirus-DNA as if the provirus were part of its own DNA. It further generates corresponding protein, cuts the protein into HIV components with the protease and assembles the HIV components into a new HIV. New HIVs thus bud out from the host cell membrane, mature and isolate themselves as free HIVs from the host cell. This proliferation process is repeated. HIV cannot proliferate by itself without the host cell. After proliferation is repeated, the host cell dies, reportedly because the host cell membrane has broken. However, more probably, the host cell (infected cell) dies as a result of apoptosis or the programmed death, caused by such substances as TNF or anti-Fas antibody.
When HIVs or infected cells enter human body fluid, CD4 cells are infected and the infected cells replicate free HIVs in such body fluid as blood. Within 6 to 8 weeks, the immune mechanism of human body function forms antibody to HIV, and the HIVs in the blood almost disappear. This antibody is used to verify HIV infection. However, the number of CD4 cells in blood remains nearly equal to and a little less than that of a-healthy person, around 800~1,200/mm
3
.
The newly infected HIV carrier then enters an asymptomatic latent period, which lasts about 5 to 10 years. During the latent, period, the number of HIVs and CD4 cells in the patient's blood will not increase substantially. The number of infected CD4 cells remains around 0.2~1.0% of the total CD4 cells in the blood.
The activity of HIV/infected cells has been thought to be low during the latent period. But it was discovered in March 1993 that most of the HIV-infected CD4 cells remain in lymphonodes throughout the latent period and that new infection progresses during that time. Anthony S. Fauci et al., “HIV infection is active and progressive in lymphoid tissue during the clinically latent stages of disease.”
Nature
, Vol. 362, No. 6418 (Mar. 25, 1993); 355-358. The mechanism for this progressive pathology is not clear but assumed to be as follows. Healthy CD4 cells also present in a lymphonode may be infected from direct cell-to-cell contact with an infected cell. Gp120 developed on the infected cell adheres to CD4 of the healthy cell and cell fusion occurs to form a giant multinucleic cell. Healthy CD4 cells may also be infected with free HIVs generated from neighboring infected cells. As a result of cell-to-cell infection and death of the infected cell (from apoptosis or the like), the number of CD4 cells decreases at the rate of 50/mm
3
every year.
When the number of CD4 cells in the blood approaches 400~300/mm
3
, HIV proliferation of the infected cells is activated by certain factors, and the number of HIVs and infected cells in the blood begins to increase. This stage of infection is described as AIDS Related Complex (ARC). The decrease in CD4 cells allows diseases that have been suppressed by the immune system until then an invasive opportunity. Such diseases include infections such as pneumocystis carinii, cytomegalovirus, candidosis, etc., and neoplasms such as Kaposi's sarcoma, non-Hodgkin's lymphoma, etc.
Almost 10% of AIDS patients also suffer from neuropathy. It has been reported but not definitively shown that macrophage, one of the CD4 cells existing in the brain, becomes infected and causes degeneration of the central nervous system, although the degeneration mechanism is not yet clear. Thus, HIVs and infected cells may exist in cerebrospinal fluid. It is also reported that dendritic cells are infected and exist in Langerhans cells under skin or tissue surfaces. Regardless, both infections may be introduced through the blood stream.
Once the number of CD4 cells in blood decreases below 200/mm
3
, the ARC period has evolved into AIDS. Patients may die in about one year as a result of the dominant ARC enhanced by extreme decrease of CD4 cells in blood.
It is not clear what factor causes the transition from the asymptomatic, latent period to the symptomatic (ARC,AIDS) period. Recently, it was reported(*a) that such transition occurs two months after the spontaneous mutation of 12th base in V3 region of gp120. However, it is not probable that all infected cells are activated by the same mutation. So it is natural to assume a certain substance that the inventors of the present invention call Trigger Factor initiates and stimulates the activation of infected cells and induces the asymptomatic-to-symptomatic transition. The activated infected cells may again generate the Trigger Factor and accelerate the disease. The Trigger Factor may stimulate the proliferation control region of provirus-DNA, accelerate HIV replication and finally bring the host cells to death through the cell membrane breakage or apoptosis.
It is found in vitro that TNF, namely tumor necrosis factor (and/or anti-Fas antibody, etc.) causes coagulation of DNA of the infected T-4 lymphocytes about 3 hours after administration and further subjects the infected cells to death(*b), and that HIV replication is highly stimulated during the process. TNF is not found in blood during the asymptomatic, latent period, but found during the symptomatic (ARC,AIDS) period. TNF could be one of the Trigger Factors defined by the inventors of the present invention. It is assumed(*c) that the infected cells may die following the program incorporated by human body defense system,—apoptosis. TNF (or anti-Fas antibody, etc.) is now the subject of research in this line.
3. Chemical Treatment—Prior Art
Development of vaccine has been unsuccessful, because the identifying target of the vaccine, gp120, is subject to very rapid mutation, more specifically in V3 region, resulting in too much variety of HIV stocks (quasi-HIV species).
Various medicines are under development, inhibiting various stages of HIV infection and proliferation such as adhesion to CD4, fusion into the host cell, reverse transcription, insertion into DNA, RNA replication, protein generation, dividing the protein into components, assembling the components, budding, maturing, etc. Ten or more medicines are reported successful in vitro, but none of them has been successful in vivo. Either they have not worked or have exhibited strong toxicity as a side effect to medication. Exceptions are AZT, ddI, ddC as reverse transcription inhibitors, but they are effective only in extending the amount of time before death and also show toxicity in long-term administration, and drug-resistant HIV stocks to them are found.
4. Extracorporeal Blood Processing—Prior Art
Incurability of AIDS by chemical treatment has led to development of various means of extracorporeal removal, inhibition or destruction of the blood borne HIVs and infected cells. Such means originate from the technology used
Kino Masato
Miwa Hirohide
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Travers Russell
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