Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-20
2002-09-24
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S311000, C514S365000, C546S134000, C546S152000, C546S347000, C548S146000
Reexamination Certificate
active
06455555
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a medicament useful for treating and preventing HIV infection diseases, and a method for treating or preventing HIV infection diseases. More particularly, the present invention relates to an agent for anti-HIV infection, comprising a photosensitizing dye as an active ingredient. The present invention also relates to a method for treating or preventing HIV infection diseases, which comprises administering the photosensitizing dye.
BACKGROUND ART
Acquired immunodeficiency syndrome (abbreviated as AIDS hereinafter) is now epidemic worldwide. AIDS is caused by infection with human immunodeficiency virus (abbreviated as HIV hereinafter), and therefore, it is rather correct to call it an HIV infection disease. Mere infection with HIV does not cause AIDS, and HIV has an asymptomatic period of several months to several years. After the asymptomatic period, HIV starts to rapidly collapse immune system and causes symptoms such as lymph node enlargement, anorexia, diarrhea, weight loss, fever and languor, which are called AIDS-related complex (abbreviated as ARC hereinafter). With the weakened immune system, microorganisms such as bacteria, viruses, fungi and protozoa, which are harmless in ordinary circumstances, start to affect the body seriously and induce opportunistic infection and the like. These infection diseases are called AIDS, which develop as the immune system weakens. AIDS refers to the condition in a terminal stage of HIV infection diseases, where the immunity is lowered to such a level as to allow development of acquired immunodeficiency syndrome. All the symptoms associated with HIV infection including AIDS are called HIV infection diseases.
Inherently, humans have an immune system as a mechanism for recognizing and eliminating xenobiotics including pathogens. CD4-Positive lymphocytes are well known as the cells that activate immune system. After invading a body, HIV binds to CD4 proteins of CD4-positive lymphocytes and gets into a cell. Since HIV has a reverse transcriptase, it can transcribe its own RNA to DNA and insert the transcribed DNA into the cell's nucleus DNA. Thus, CD4-positive lymphocytes infected with HIV gradually die while producing the virus, thus resulting in a decrease in the cells that control the immune system and destruction of the immune system. Making the situation more difficult in the case of HIV infection diseases, the more the body tries to defend the virus with the immune system, the more actively the virus is produced in the infected cells, which in turn produces an opposite effect of decreased CD4-positive lymphocytes.
With regard to HIV infection diseases, many powerful studies have been carried out to develop clinically effective antiviral agents and vaccines. Examples of medicaments currently under clinical use or clinical trail are a reverse transcriptase inhibitor, absorption inhibitor, dekaryotheca inhibitor, Tat inhibitor, translation inhibitor, protease inhibitor as virus particle synthesis inhibitor, provirus activation inhibitor, HIV protease inhibitor and the like.
Of these medicaments, one of the drugs most frequently used is azidothimidine (abbreviated as AZT hereinafter). AZT was approved as an anti-HIV agent, because its administration significantly lowers mortality. However, AZT has side effects including decrease in neutrophiles, anemia, sleeplessness, nausea and headache, and it only delays the onset of AIDS. While other therapeutic agents have been also tried, they have not proved to be basic therapeutic agents.
Considering the immune system, activation of macrophages is extremely important. For example, when bacteria enter a body, macrophages phagocytize them and become antigen presenting cells while being activated. The information from antigen is transmitted from macrophages to CD4-positive lymphocytes, and further to B-lymphocytes, and the B-lymphocytes produce antibodies. Bacteria bound with antibodies, or immunocomplexes, are phagocytically digested and specifically eliminated speedily by macrophages. At this time, Fc receptors to capture immunocomplexes appear on activated macrophages, and the macrophages show marked increase of phagocytic activity, increased capability of active oxygen production to decompose xenobiotics taken in, reinforced antigen presentation function, and secretion of various cytokines. Ultimately, activated macrophages destroy cancer cells and virus-infected cells in cooperation with NK cell and the like. It is well known that immunity is reinforced by activated macrophages in this way.
DISCLOSURE OF THE INVENTION
As described above, CD4-positive lymphocytes control whole human immune system, such as humoral immunity relating to allergy and bacterial infection, cell-mediated immunity relating to cancer and virus diseases, and activation of macrophage. The onset of AIDS can be explained by the decrease of CD4-positive lymphocytes that command the human immune system. The real cause, nevertheless, is that macrophages are not activated, and therefore, cell-mediated immunity cannot be activated. In lower animals without an immune system, phagocyte cells such as macrophages eliminate xenobiotics. It is considered, therefore, that if macrophages can be activated, the functions of cell-mediated immunity can be improved and virus can be eradicated, even if CD4-positive lymphocytes have decreased.
It is well known that macrophages are activated by macrophage activators, such as interferon-gamma, produced by the above-mentioned CD4-positive lymphocytes. When CD4-positive lymphocytes decrease, however, the macrophage activators also decrease. Thus, an activator that fulfills the decrease should be supplemented. Studies have been done from these viewpoints, which resulted in the completion of the present invention.
It is therefore an object of the present invention to provide a novel medicament useful for treating or preventing HIV infection diseases.
Another object of the present invention is to define the dose of a medicament useful for treating or preventing HIV infection diseases.
A further object of the present invention is to provide a method for treating or preventing HIV infection diseases.
In an attempt to solve the above problems, the present inventors conducted intensive studies and found that, when at least one photosensitizinq dye, selected from the group consisting of the compounds represented by formulae (I) and (II), is administered to an HIV-infected subject, the subject shows improvement or cure of the symptoms of ARC and increase in CD4-positive lymphocytes, thus affording an effective treatment of HIV infection diseases:
wherein R
1
, R
2
and R
3
may be the same or different and each represents alkyl group having 1 to 4 carbon atoms, and X
−
represents a physiologically acceptable monovalent anion, preferably a halogen anion, and more preferably an iodide anion,
wherein R
4
, R
5
and R
6
may be the same or different and each represents alkyl group having 5 to 10 carbon atoms, preferably linear alkyl group having 7 carbon atoms, and X
−
represents a physiologically acceptable monovalent anion, preferably a halogen anion, and more preferably an iodide anion.
Accordingly, the present invention relates to the following.
(1) An anti-HIV infection agent comprising, as an active ingredient, at least one photosensitizing dye selected from the group consisting of the compounds represented by the formula (I) and formula (II) (hereinafter to be also referred to as compound (I) and compound (II), respectively):
wherein R
1
, R
2
and R
3
may be the same or different and each represents alkyl group having 1 to 4 carbon atoms, and X
−
represents a physiologically acceptable monovalent anion, preferably a halogen anion, and more preferably an iodide anion,
wherein R
4
, R
5
and R
6
may be the same or different and each represents alkyl group having 5 to 10 carbon atoms, preferably linear alkyl group having 7 carbon atoms, and X
−
represents a physiologically acceptable monovalent anion, preferably a halogen
Nakagawa Yoshinori
Niiyama Takehiro
Tsuboi Satoshi
Desai Rita
Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo
Leydig , Voit & Mayer, Ltd.
Rotman Alan L.
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