HRP920891A2 - Quinone preparation - Google Patents

Description

Field of invention

The present invention relates to a pharmaceutical preparation, specifically to a preparation containing at least one quinone, as well as to its use in the treatment of diseases, especially cancer and viral infections.

State of the art

Traditional cancer treatment generally includes surgery, radiotherapy, chemotherapy or a combination of these methods. Although this treatment is often effective in prolonging the patient's life or, sometimes, in completely removing the tumor, its serious side effects are known. Recently, alternative attempts to treat cancer have been developed. One such technique, called "immunotherapy", is aimed at strengthening the ability of the patient's own immune system to fight cancer.

Although diagnostic and treatment techniques have developed significantly in recent decades, very little progress has been achieved in terms of the overall increase in the number of surviving patients, especially patients with solid tumors who were treated with orthodox methods. In addition, although alternative techniques such as "immunotherapy" show promise, the treatments developed so far can only help a limited number of patients. Also, these treatments still have toxic side effects and/or are still complicated and expensive to perform.

In my pending International Patent Application No. PCT/GB91/00517, which was published on October 17, 1991 as WO 91/15200 and which, inter alia, claims the priority of British Patent Application No. 91 03075.9 of February 13, 1991, a preparation containing:

(a) one or more compounds of the general formula:

X-P

where P is trinitrophenyl and X is selected from the group consisting of OH, NH2, halogen, sulfo, carboxyl, OCH3 or a substituted or unsubstituted hydrazyl group of the formula:

[image]

where A is hydrogen or an unpaired electron of a nitrogen atom, Y is hydrogen or an organic group, and Z is an organic group, or Y and Z, together with a nitrogen atom, form a nitrogen-containing hetero-ring; provided that, when X is a substituted or unsubstituted hydrazyl group as defined, one of the NO 2 groups may be replaced by a sulfo group; and

(b) quinone, if necessary anthraquinone with a glycosidic group, preferably carminic acid.

In the aforementioned application, protection is also requested for:

(A) A formulation containing anthraquinone glucoside, optionally carminic acid, dissolved in an aqueous medium at a concentration of 10-3 to 10-15 moles per liter, for use in the therapy of viral infections in humans and animals; and

(B) The use of anthraquinone glycosides, if necessary carminic acid, in the formulation of drugs for the prophylaxis and treatment of viral infections.

And the present application refers to the priority of British Patent Application No. 91 03075.9 filed on February 13, 1991, and is directed to that approach to the problem of treating cancer which involves the use of low concentrations of readily available quinone compounds such as carminic acid (alone or in combination). The material that is described and for which protection is requested in the current application is part of the material from application No. 9103075.9, for which protection will not be sought in patents that will be recognized in certain countries on the basis of the aforementioned International application.

Description of the solution

The invention which is the subject of the present application is therefore based on the surprising new discovery that quinone compounds are effective by themselves, inter alia, as anti-cancer agents and anti-viral agents when administered in low concentrations, essentially regardless of the body's the weight of the patient. Therefore, the problems of toxicity and high cost that accompanied the solutions from previous science were avoided.

Accordingly, the invention in one aspect provides a pharmaceutical preparation consisting of at least one quinone dissolved or dispersed in a liquid diluent or carrier, at a concentration of about 10-3 moles per liter or less.

According to the present invention, the effect of administering low concentrations of about 10-3 moles per liter or even lower concentrations of at least one quinone is used in the fight against diseases, for example against tumors. Although the mechanism or mechanisms of this action are still not fully understood, I believe that one or more of the following factors may play a role:

(a) free radicals that can act within the cellular structure of the organism, whereby this action can, for example, represent a direct cytotoxic action of free radicals and their products;

(b) modulation of the immune system including, for example, induction of cytokines; and

(c) impact on blood supply, for example on tumor blood supply.

In the preparation from the invention, one or more quinones can be in oxidized or reduced form and preferably represent:

Anthraquinone glycoside, preferably carminic acid.

Compound formula:

[image]

in which R1 represents hydrogen, a sugar such as -C6H11O5, hydroxy,

[image]

or - CH2NH2; R2 is methyl or -CO2H; R3 is hydrogen, -NH2 or -SO3X where X is hydrogen, Na or K; and R 4 is hydrogen or hydroxy.

Quinhydron formulas:

[image]

Tetrahydroxyquinone formulas:

[image]

The preferred compounds covered by formula (I) can be isolated from insects of the family Coccoidea (flour bugs) and are summarized as follows:

Lacainic acid D, formulas:

[image]

Other lakainic acids of the formula:

[image]

Kermesic acid formula:

[image]

Carminic acid formula:

[image]

Ceroalbolic acid formula:

[image]

Erythrolacin formulas:

[image]

Deoxyerythrolacin formulas:

[image]

The invention, therefore, in principle uses polyhydroxylated quinones capable of an oxidation-reduction cycle, and perhaps capable, in defined concentrations, of playing a role in one or more of the mechanisms mentioned in the earlier text, for example in the initiation and propagation of a chain reaction of free radicals in the body.

The preparation from the present invention is based on one or more quinones as the only active ingredients, preferably on at least two quinones. It is also desirable that active compounds, i.e. quinones, are represented in at least approximately equal amounts.

A preparation containing carminic acid, quinhydrone and/or tetrahydroxyquinone is particularly preferred. More closely, this preparation will contain approximately equal amounts of carminic acid, quinhydrone and tetrahydroxyquinone.

In the preparation from the invention, the active quinone compound, or each of the compounds, should be present in small concentrations, in which free radical reactions are more common than alkylation reactions. Alkylation reactions take place up to concentrations of 10-2 moles per liter, so the preparation from the invention will contain at least one quinone in a concentration of about 10-3 moles per liter or even lower. In these concentrations, the active quinone(s) can cause an endogenous reaction of free radicals in the host organism. These reactions selectively kill cells that are cancerous or otherwise diseased, eg due to attacks by viruses, other microbes, and even chemicals such as antioxidants.

The concentration of each of the quinones preferably ranges from about 10-3 to about 10-18 moles per liter, more preferably from about 10-3 to about 10-15 moles per liter, and most preferably from about 10-6 to about 10-15 moles per liter.

In the preparations of the invention, the carrier or diluent may be any pharmaceutically acceptable liquid diluent or carrier. The diluent or carrier, therefore, may be water, polyethylene glycol, an oil such as peanut oil, or liquid paraffin.

Preferably, the diluent or carrier is double or triple distilled deionized water or, when a slower release is required, polyethylene glycol. Although double or triple distilled deionized water is the preferred dissolving or suspending liquid, other diluents/carriers such as dimethylsulfoxide/water solution, peanut oil, olive oil, vegetable oil, or corn germ oil may be used.

The invention also includes a preparation consisting of at least one quinone dissolved or dispersed in a pharmaceutically acceptable liquid medium in a concentration of about 10-3 to about 10-18 moles per liter, for use in the therapy or prophylaxis of diseases in humans and animals.

This preparation has the composition as defined in the previous text, and can be administered orally or parenterally, for example subcutaneously or intramuscularly. The compounds can typically be used in a dosage regimen of about 10-3 moles per kg of body weight to about 10-18 moles per kg of body weight although, as stated earlier, their action is largely independent of body weight. Preferably, the preparation for oral administration has a concentration of each of the quinones of about 10-3 to about 10-6 moles per liter. Alternatively, when administered parenterally, the concentration of each of the quinones will preferably be lower, typically from about 10-9 to about 10-15 moles per liter.

The preparations of the invention are particularly useful in the treatment of cancer and viral infections such as AIDS. It is possible, however; can also be used to treat bacterial and fungal infections, as well as to treat metabolic diseases and degenerative diseases. In fact, wherever cell dysfunction occurs caused by an imbalance of antioxidants within the cell, the preparation from the invention can help correct this balance. Therefore, the macro manifestations of diseases caused by micro imbalance can be brought under control and finally eliminated by restoring the balance between antioxidant and oxidizing functions at the cellular level.

The preparation of the invention can be a pharmaceutical or veterinary formulation and can be used in the preparation of medicines for the treatment of humans and animals.

Significantly, according to the invention, carminic acid exhibits anticancer activity when used by itself in low molar concentrations. An important aspect of the invention, therefore, is the use of carminic acid and its derivatives in obtaining drugs for the prophylaxis and therapy of cancer or viral infections. Such derivatives have the following general formula:

[image]

where R represents COOH (carminic acid) or some other organic or inorganic functional group such as NH2, SO3 �K, H, Na], while the C-glycoside can be any sugar. Anthraquinone can also, if necessary, be benzoquinone (single ring) or naphthaquinone (double ring).

Without being tied to any precise mechanism, the compounds are believed to act by initiating and propagating a free radical mechanism, thereby producing active chemical species that selectively attack abnormal cellular structures. In Cancer Research 36 (1978), p. 1745 to 1750, Bachur et al describe possible free radical mechanisms in connection with the known biological action of quinone-containing anticancer drugs. It has been hypothesized that these drugs may generate oxygen-dependent free radicals, such as peroxide or hydroxyl radicals. In the present invention, the mentioned compounds possibly serve as catalysts for the oxidation-reduction cycle mechanism, which continuously builds free radicals such as peroxides. Free radicals, or their by-products, can selectively act in the destruction of cancer cells, viruses and the like. Alternatively, some other of the mentioned mechanisms may be relevant or dominant.

Carminic acid is usually used in the laboratory to stain nucleic acids. It is interesting that, among other things, free radical scavengers inhibit its action on DNA (Lown et al., Bioorganic Chem. 8 (1979), pp. 17-24).

A typical unit dose of the preparation of the invention in solution or suspension is preferably about 2 ml. However, a volume of about 2.0 to about 5.0 ml can be used, which is particularly useful when the preparation is given by injection. On the other hand, when the preparation is administered orally, an orally acceptable diluent such as water may be used to achieve a drinkable volume, say 100 ml. These doses can, it seems, be essentially independent of the host's body weight, and administration, for example by injection, is done about three times a week. In the case of a tumor, this administration is carried out until its disappearance. After that, the dose required for maintenance will be taken, for example orally, a maximum of four times a day.

According to a further aspect of the invention, the effectiveness of the putative free radical chain reaction mechanism can be increased by providing iron or any other transition metal, especially copper. Another useful catalyst for the free radical mechanism is (in low concentrations) a polyunsaturated fatty acid, a long-chain free carboxylic acid typically found in lipids.

It seems that carminic acid and the other described compounds, in the therapeutically effective concentrations mentioned in the previous text, stimulate the immune system. [moreover, carminic acid and other quinones can be usefully used in the specified concentrations together with the compounds from International Patent Application No. PCT/GB91/00517, i.e. with one or more compounds of the general formula:

X-P

where P represents trinitrophenyl and X is selected from OH, NH2, halogen, sulfo group, carboxyl group, OCH3 or a substituted or unsubstituted hydrazyl group of the formula:

[image]

wherein A represents hydrogen or an unpaired electron of a nitrogen atom, Y is hydrogen or an organic group and Z is an organic group, or Y and Z, together with a nitrogen atom, form a nitrogen-containing hetero-ring; provided that when X is a substituted or unsubstituted hydrazyl group as defined above, one of the NO 2 groups may be replaced by a sulfo group. Each of the compounds used will be present at a concentration of about 10-3 moles per liter or less.

Preparations according to the invention and their use will be described in the following text in Examples, which are given only as an illustration.

Example 1

The preparation for use in the treatment of AIDS is prepared according to the following formulation: Carminic acid

Double distilled, deionized water, up to a concentration of 10-6 moles per liter.

Example 2

In one pilot study, a 37-year-old man underwent a standard ELISA test and was found to be HIV-positive. When he was examined for the first time in November 1990, the patient had oral thrush (aphthosis), very severe herpes zoster of the left facial nerve with involvement of the left orbital region, both neck lymph nodes were hard, as well as an enlarged liver and spleen. The patient was then treated with carminic acid formulated as described in Example 1, in the form of subcutaneous injections. During five days, the patient received one injection of 1.0 ml per day. After a six-day break, a similar five-day regimen was repeated. After the fourth round (20 injections) the patient was in good general condition, he was no longer anemic, and the oral thrush, neck lymph nodes and herpes zoster had resolved. The spleen and liver were normal, and the patient had gained weight. A significant observation is that the number of white blood cells (WBC) increased from 2000 to 12400 cells per mm3, with a corresponding increase in hemoglobin (Hb) from 11.8 to 14.7 g/dl.

Example 3

The preparation for use in the treatment of cancer is prepared according to the following formulation:

Carminic acid

Triple distilled, deionized water, up to a concentration of 10-15 moles per liter.

Example 4

Mouse lymphoma P388 cells were grown on BDFI mice. It was given a single injection of 5 ml of the formulation from Example 3 subcutaneously. After 6 months, the mouse was still alive.

Example 5

AB, a 36-year-old housewife, was well until August 1991, when she noticed an enlarged lymph node in her neck associated with an intra-abdominal mass. The clinical examination that was performed at the time confirmed the general enlargement of the lymph nodes, as well as an enlarged spleen and liver. The spleen and liver were 8 cm and 4 cm below the edge of the ribs, respectively. Histological examinations and computed tomography confirmed the diagnosis of mild lymphoma involving the lymph nodes, spleen, liver and bone marrow. The patient refused palliative chemotherapy.

After that, she was treated with a combination of carminic acid, quinhydrone and tetrahydroxyquinone. In the formulation, all three substances were mixed in equal proportions in sterile distilled deionized water, in concentrations of 10-6 M each. She received subcutaneous injections of 2 ml each of this formulation on days 1, 3, 5 and 7, and then continued oral therapy, using the same formulation, for the next three months. During oral therapy, she took 100 ml of the mentioned formulation four times a day, on an empty stomach. The reaction occurred immediately, and at the end of the third month of treatment, the patient was in complete clinical remission. At the time of writing (February 1992), she is still in good health.

Example 6

GJ, aged 65, suffering from progressive metastatic malignant melanoma involving the right maxillary and ethmoidal sinus, as well as multiple skin lesions, was included in the protocol described in Example 5 on December 22, 1991, because she did not respond to radiotherapy , nor to chemotherapy. At the time of writing this text, i.e. six weeks after the start of the treatment, the patient shows visible reactions to the treatment. All peripheral multiple lesions on the skin have completely disappeared (the largest was 4.5 x 4.5 cm), and the sinus disease is in the phase of neurosis and healing. The swelling and redness are completely gone. There is still steady progress.

Example 7

RB, aged 46, with a metastatic stage 4 cervical tumor involving the entire pelvis including the left kidney and secondary deposits on the lumbar spine. She underwent the same protocol as in Example 5 on December 22, 1991. When she returned for examination six weeks after the start of treatment, she had no pain and the tumor on the cervix had shrunk to half its original size. The patient continues her recovery without any new problems.

Example 8

VW, at the age of 27, was diagnosed with AIDS in 1989 using a standard ELISA test. On October 10, 1991, she presented with persistent fever, chronic diarrhea, productive cough, severe oral thrush, and marked weight loss. Clinical examination indicated a very sick person, with severe anemia and general enlargement of the lymph nodes. She was exhausted, and the oral lotion caused bloody sores all over her mouth. Blood analysis confirmed anemia, Hb 6.5 g/dl (normal range is 14.5 to 17.5 g/dl), as well as a low white blood cell (WBC) count of only 2900 (normal range 4500 to 5800 cells per mm3). The patient underwent the treatment of Example 5 on October 12, 1991. When she returned for follow-up six weeks later, all symptoms had disappeared and she had regained some of her weight. She was mildly anemic, but had no enlarged lymph nodes or oral thrush. Blood analysis showed 13.2 g Hb/dl and 4800 WBC/mm3. VW continues its steady recovery. Although the invention is shown in part through various preferred embodiments, it will be clear to those skilled in the art that various modifications, substitutions, omissions or changes can be made without departing from the spirit and scope of the invention, defined in the appended patent claims.

Claims (17)

1. Quinone preparation, characterized by the fact that it contains one or more quinones, dissolved or dispersed in a liquid diluent or carrier in a concentration of about 10-3 moles per liter or lower. 2. The preparation according to claim 1, characterized in that anthraquinone glycoside is used as quinone, or as one of the quinones. 3. The preparation according to claim 1 or 2, characterized in that the quinone, or one of the quinones, is a compound of the formula: [image] wherein R1 is hydrogen, a sugar such as -C6H11O5, hydroxy, [image] -CH(NH2)CO2H or -CH2NH2; R2 is methyl or -CO2H; R3 is hydrogen, -CO2H, -NH2 or -SO3X where X is hydrogen, Na or K; and R 4 is hydrogen or hydroxy. 4. The preparation according to claim 2 or 3, characterized in that the quinone, or one of the quinones, is carminic acid. 5. The preparation according to claim 3, characterized in that the quinone, or one of the quinones, is lakainic acid A, B, C, D or E, kermesic acid, ceroalbolic acid, erythrolacin or deoxyerythrolacin. 6. The preparation according to any of the preceding claims, characterized in that the quinone. or one of the quinones, represents a quinhydron of the formula: [image] 7. The preparation according to any of the preceding claims, characterized in that the quinone, or one of the quinones, is a tetrahydroquinone of the formula: [image] 8. The preparation according to any of the preceding claims, characterized in that it contains at least two quinones. 9. The preparation according to claim 8, characterized in that the quinones are present in at least approximately equal amounts. 10. Preparation according to claim 8 or 9, characterized in that it contains carminic acid, quinhydrone and/or tetrahydroxyquinone. 11. The preparation according to claim 10, characterized in that it contains approximately equal amounts of carminic acid, quinhydrone and tetrahydroxyquinone. 12. The preparation according to any of the preceding claims, characterized in that the concentration of each of the quinones is from about 10-3 to about 10-18 moles per liter. 13. The preparation according to claim 12, characterized in that the concentration of each of the quinones is from about 10-6 to about 10-15 moles per liter. 14. The preparation according to any of the preceding claims, characterized in that the diluent or carrier is water, polyethylene glycol, oil such as peanut oil, or liquid paraffin. 15. The preparation according to claim 14, characterized in that the diluent or carrier is double or triple distilled deionized water. 16. The preparation according to any of the preceding claims, characterized in that it is in the form of individual doses containing from about 2 to about 5 ml of the preparation, preferably about 2 ml, and which are further diluted for oral administration if necessary. 17. The preparation according to any of the preceding claims characterized by the fact that it contains one or more compounds of the general formula: X-P where P is trinitrophenyl and X is selected from OH, NH2, halogen, sulfo group, carboxyl group, OCH3 or a substituted or unsubstituted hydrazyl group of the formula: [image] where A is hydrogen or an unpaired electron of a nitrogen atom, Y is hydrogen or an organic group and Z is an organic group, or Y and Z together with the nitrogen atom form a nitrogen-containing hetero-ring; provided that when X is a substituted or unsubstituted hydrazyl group as defined above, one of the NO2 groups may be replaced by a sulfo group, wherein the concentration of each compound is about 10-3 moles per liter or less.