Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1999-03-23
2001-11-20
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S474000, C514S052000
Reexamination Certificate
active
06319951
ABSTRACT:
The invention relates to use of 3-amino-4-hydroxybenzoic acid or a derivative thereof in the preparation of a medicament for treating viral infections and pharmaceutical compositions containing 3-amino-4-hydroxybenzoic acid or a derivative thereof. More specifically the invention relates to use of 3-amino-4-hydroxybenzoic acid or a derivative thereof in the preparation of a medicament for the treatment of retroviral infections, specifically but not exclusively HIV infection.
Acquired Immune Deficiency Syndrome (AIDS) is a disease complex caused by the Human Immunodeficiency Virus (HIV) which was identified for the first time in medical history in 1981. The causative virus was identified in 1983. It belongs to a group of RNA viruses called retroviruses.
Retroviruses were discovered in 1940. Later, Jarret discovered a retrovirus that causes Leukemia and immune deficiency in domestic cats. In 1970 Temin and Baltimore independently discovered the enzyme reverse transcriptase which allows transcription of RNA to DNA. From there the search for human retroviruses started leading to the discovery of HTLV-I (1979), HTLV-II (1982) and HTLV-III, the taxonomic equivalent of HIV (Dr Robert Gallo). HTLV-I immortalizes human cells leading to T-cell leukemia and a myelopathy called Tropical Spastic Paraparesis. HTLV-II does not cause any known disease. HTLV-III (HIV) exists as, HIV-1 and HIV-2 both of which cause human immunodeficiency. Simian Immuno deficiency Virus (SIV) also exists which causes a similar immune deficiency in monkeys.
The HIV enters the body in three main ways:
(a) mother/child—vertical transmission occurs before birth through breaches of the placenta or an infected gametocyte (sperm or ovum), at birth (connatal transmission), through breast feeding if there are cracks in the infant's buccal mucosa (postnatal transmission);
(b) through transfusion of infected blood or blood products; and
(c) through sexual contact, especially if there are venereal ulcers on the genitals. Apart from vertical transmission, all the other modes are referred to as horizontal transmission.
Once in the blood the HIV invades the following CD
4
+ve cells by attachment, adsorption, adhesion and penetration:
(i) CD
4
lymphocytes
(ii) Monocytes
(iii) Macrophages
(iv) Follicular cells of lymph nodes
(v) Dendritic cells of the gastrointestinal tract, (GIT) and genito-urinary tract (GUT)
(vi) Langerhan cells of the skin
(vii) Microglial cells of the CNS
(viii) Multinucleated giant cells of the CNS
Other cells which support HIV replication and which have no CD
4
markers comprise: Neurons, glial cells, B-lymphocytes, colo-rectal epithelial cells and myeloid precursor cells of the bone marrow. Affection of these cells seems to suggest the existence of other than CD
4
surface markers.
1. After entering the host cell the HIV single RNA chain replicates to form others. At some point it doubles to form DNA which attaches to the host DNA to form provirus which makes the viral infection “permanent” as long as that host cell lives.
The relationship established by a virus with its host may be:
(1) Symbiotic—as for provirus and herpes viruses
(2) Cytopathic—killing the host cell
(3) Hypertrophic—lytic, forms rashes which then burst after reaching a critical size and being secondarily infected by bacteria.
(4) Oncogenic—cancerous, as in leukemia
Treatment of the viral infection depends on which of the above relationships the treatment is directed at.
The HIV exploits the host biochemistry to make viral RNA and DNA and paralyses the host biochemistry by secreting translational inhibitory protein (TPI). A cell so affected is incapable of enzyme, hormone and ATP formation. Lack of ATP energy leads to failure to maintain active transport for glucose, amino acids, other metabolites and wastes. Maintenance of the Gibbs-Donnan equilibrium to regulate electrolytes also fails. All these failures plus the lytic effect of viral enzymes on the host cellular membrane cause cell death.
These cytopathic effects are greatest on CD
4
lymphocytes because they have the surface markers for the HIV attachment and entry and they actively hunt for HIV, so enhancing contact. These lymphocytes are the principal controllers of both the cell-mediated and humoral types of immunity. When they are decimated the body immunity declines and the body succumbs to opportunistic infections (O.Is) from viruses, fungi, bacteria and protozoa. Opportunistic infections are so called because the healthy body can live within a symbiotic equilibrium with the causative organisms. The organisms take advantage of the low immunity to become pathogenic which they normally are not.
Attack by opportunistic infections is the hallmark of HIV/AIDS. The natural progression of CD
4
s is used to assess prognosis and the progression of HIV/AIDS. The lower the count the more advanced the disease and the worse the prognosis.
FIG. 1
shows a graph of the natural decrease of CD
4
s in HIV/AIDS. The CD
4
count goes down by 30-50/mm
3
year. The point on the graph of a patient's CD count can be used to roughly indicate how long he has had the virus and indicate his prognosis.
Treatment according to the present invention raises the CD
4
count and reverses the progression of the curve to the left.
The infection can be confirmed by testing antibodies to HIV by ELISA or Western blot tests which will be positive at 2-4 weeks after infection. Children may harbour passive maternal antibodies which means that they may not have the HIV for up to 18 months after birth, although they will test positive.
Treatment of HIV/AIDS should be given at any stage after the presence of the HIV has been identified. It is advantageous that any HIV is killed early, before any opportunistic infection sets in. Accordingly, early screening is recommended.
Synthesis of RNA and DNA by the virus using the host biochemistry consumes a lot of vitamin B
12
, folic acid and vitamin C. Depletion of B
12
has been found to be a uniform finding in all AIDS cases.
Medicaments for the prevention and/or treatment of HIV/AIDS, to date, are limited. HIV infection inverts the CD
4
:CD
8
ratio. This inversion is permanent. There is no drug known to revert it back to normal, except the drug of this invention.
To qualify as an anti-HIV drug, a substance must fulfil one, two or all of the following:
(i) Be able to boost the patient's immunity.
(ii) Be able to halt the multiplication of the HIV in the body
(iii) Be able to eliminate the HIV from the patient's body
The compound 3-amino-4-hydroxybenzoic acid has the chemical formula C
7
H
7
NO
3
and the structural formula:
It is a white powder, not readily soluble in water.
The compound has previously been used orally as a Maillard reaction inhibitor as disclosed in European Patent 0474874 for treatment of diabetes mellitus. It has also been used as an active ingredient in vaginal contraceptive formulations where it was erroneously thought to be spermicidal when in actuality it inactivates an achrosomal proteolytic enzyme hyaluronidase essential for sperms to penetrate to the ovum. For the last 25 years 3-amino-4-hydroxybenzoic acid has also been in use along with other compounds such as tartaric acid, citric acid, sodium bicarbonate and sodium carbonate as a spermicidal foaming tablet. The foam from the tablet blocks the entrance to the cervix for the sperms, making fertilization difficult. The bubbles create surface tension forces which immobilize sperms so that they do not reach the ovum for fertilization. The soluble sodium carbonate reacts with calcium ions in semen to form the insoluble calcium carbonate (chalk) which arrests sperm (as though they were swimming in mud) and also blocks the entrance to the uterus so that the sperms cannot reach the ovum for fertilization. Should sperms find their way to the ovum they fail to penetrate the coating of the ovum called zona pellucida because, the 3-amino-4-hydroxybenzoic acid inactivates the proteolytic enzyme necessary for digesting the way through the zona pellucida.
The present invention provi
Morgan & Lewis & Bockius, LLP
Travers Russell
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