WO1984000006A1

WO1984000006A1 - Anti-tumour pharmaceutical preparation

Info

Publication number: WO1984000006A1
Application number: PCT/RO1982/000004
Authority: WO
Inventors: Ion Mihai Leontopol; Nicolae Andronescu
Original assignee: Bucuresti Medicamente
Priority date: 1982-06-18
Filing date: 1982-06-18
Publication date: 1984-01-05
Also published as: EP0112329A1

Abstract

Drug for the treatment of cancer or some other forms of tumours. The drug is composed of 10...350 mg of hydroquinone, 30...200 mg of metol, 10...100 mg of amidol; these three active ingredients may be or not associated with 10...100 mg of paraminosalicylic acid; the quantities are expressed per unidose and the association ratio (by weight) between hydroquinone and metol is comprised between 1:3...7:4. The drug is toxicity-free in the dosage limits stipulated in the present invention.

Description

AM) I - TUM0UR PaABMAC-BϋlJPAL BRBPABA-CIOM Technical ffieXd

The present invention will refer to a pharmaceutical to be used for the treatment of cancer, as well as other forms of tumors.

Beckground Art

A number of anti-cancer drugs are already known, the most important being the so-called cytostatics: Endoxan, Saroolizine, Tio-tepa, Vincristin, Methotrexate, IOB 82, etc. (Vademecum terapeutic, Ed.med., 1973, Bucuresti). Ail such prenarations have some common disadvantages: they do not produce the complete regression of tumors or metastases, but only a temporary remission; they are highly toxic for the human body and, shortly after the treatment, they induce the so-called cytostatic disease with destructive effects upon the hematoυoietic System (leukopenia, tromocytopenia, haemorrhagipar syndrome, erythropenia, agranulocitosis), upon the digeetive apparatus (hypo or anachlorhydria, transient atrophy of the intestinal lymphatic System, melena, diarrhea), upon the nervous System (asthenia, cephalgia, insomnia, hallucinations, etc) upon the endocrine System (oligomenorrhea, atrophy of the uterus or of the tests, etc.), upon the mezenchyme (increase of capilaries permeability, intraparenchycje hemorrhages, etc.).

Moreover, the treatment with cytostatic agents has general consequences upon the organisai such as loss of weight, hypotension, modification of humoral pH and ef oxygen consumption in the t issues, decrease of resistance to infections, etc.

Disclosure of Invention

The pharmaceutical preparation as per the present invention increases the range of products for the treatment of cancer tumors; it is composed of 10 ... 350 mg hydroquinone, 30 ... 200 mg metol, 10 ... 100 mg amidol; the above-said three active ingredients may or not be associated with 10 ... 100 mg paraaminosalicylic acid; the quantities are expressed per unidose and the association, ratio (by weight) between hydroquinone and metol is between 1: 3 ... 7: 4.

The advantages of the pharmaceutical preparation as per this invention are the foilowing:

- the drug is toxicity-free, in the doses recommended in the present invention;

- the drug is well tolerated during treatment;

- the association, if required, of classical methods of oncological treatment is not excluded (surgery, irradiation, associated medication);

- the preparation limits the evolution of the tumoral process and sometimes covered inoperable cases to operable ones;

- if administered post-surgery, it is indicated for consolidating the treatment and preventing the ocurrance of relapses or metastases;

- it improves and increases the survival duration of cases which are beyond all hope of recovery;

- it improves the general objective and subjective state of the patients, through a biological and functional reballancing: good appetite, weight gain good general condition. Brief Description of Drawings

Figures 1-3 illustrate the anti-tumor effect as well as s ome other aspects in c onnection the experime nta carried out on this preparation.

- Figure 1 - Inhibiting activity for 1 micromole of product administered to the animal;

- Figure 2 - DNA biosynthesis in Ge lls of Erlich ascitis grafted on mice WHT / HI;

- Figure 3 - The average tumoural surface in rats treated per os with the drug as per the prese nt inve ntion, starting from the 7th day from the graft.

Best Mode of Carrying out the Inve ntion

Example l

The composition, f or 1 dose, of the pharmaceutical preparation as per the prese nt invention is the following: Hydroquinone 23.5 mg

Metol 70 mg

Amidol 93 mg

Para aminosalicylic acid 47 mg

The above-described composition is f ormulated as hard or s oft gelatine caps ules, for internal administration, using common adjuvants and the usual galenic technique.

This drug can also be f ormulated as vaginal ovules and suppose itories, according to the type and localization of the disease. The composition may also be lyophilized in view of administration as injection or infusion.

This drug is to be administered in one or several doses, according to the clinical c ondition of the patie nt, 15 to 30 minutes after a meal c ontaining proteins. The drug is to be added in tea or in stewed fruit at room temperature. After the intake of the medicine, the patie nt should not eat or drink anythiog for 1 hour, and a rest is to be recomme nded.

During treatment, a specify diet shall be recommended to each patie nt, according to his clinical condition and the stage of the disease.

Example 2

The composition, for 1 dose, of the pharmaceutical preparation as per the inve ntion is the following:

Hydroquinone 10 mg

Metol 30 mg Amidol 10 mg

Para aminosalicylic acid 10 mg

The drug is prepared and administered as described an Example 1.

Example 3

The composition of the pharmaceutical product as per the invention is the following:

Hydroquinone 10 mg

Metol 30 mg

Amidol 10 mg

The drug is prepared and administered as described under Example 1.

Example 4

The composition of the pharmaceutical preparation as per the invention is the f ollowing:

Hydroquinone 300 mg

Metol 225 mg

Amidol 40 mg

The drug is prepared and administered as described under Example 1.

Example 5

The compos ition of the pharmaceutical preparation as per the invention is the following:

Hydroquinone 300 mg

Metol 200 mg

Amidol 50 mg

Para aminosalicylio acid 100 mg

The drug is prepared and administered as described under Example 1.

The experimental pharmacology and pharmacodynamics researches carried out on the pharmaceutical preparation as per the invention, whose composition has been described in 5 possible variants, have led to the following conclusions.

- Wistar rats have been chronically treated, for 6 months, with an oral daily dose of 5 mg / kg of bodyweight or 10 mg / kg of bodyweight; the treatment was well tolerated, no signs of general intolerance were recorded and the animals did not show particular aspects as compared to the control lot.

- the humor and haematological parameters analyzed at the end of the chronic treatment were within the same limits as those of the healthy control animals (protein count, transaminases, cholesterol, total fluids, lipoproteins, glycemia).

- organotropic researches have pointed out that there are no essential modifications between the two lots of animal (treated and control ones).

- the researches of molecular pharmacodynamics have indicated that the pharmaceutical preparation as per the present invention inhibits DNA synthesis in tumor cells (the results are illustrated in Fig. 1 and Fig. 2).

- the specifie anti-tumor effect of the drug has been studied on Wistar rats on which a H 18 R tumor (dorsal sub-cutaneous) had been grafted (the results are illustrated in Fig. 3). From the careful analysis of the results, it could be concluded that, for the lots treated w ith doses of 5 and 10 mg / kg of bodyweight, the size of the tumor was significantly smaller as compared to the controls.

Figure 1 shows the inhibiting effect of one micromole of the preparation as per the invention and of one micromole of each active ingredient, as compared to guanazole as c ontrol. The graph in Fig. 1 illustrates the results obtained on laboratory animals with the substances marked by means of indicative izotopes. It can be noticed that each of the active ingredients has a specific inhibiting effect on 1210 leukemic ascitis and each of them is more active than the refere nce substances (guanazole); amidol low an activity of 32%, metol of 15% and hydroquinone of 13%.

Moreover, the graph indicates that the inhibiting effect of the mixture of ingredients is of 86.5%, which justifies their association through the mutual potentiation of their activities.

Amidol both pote ntiates the effect of the other active ingredients and creates a biological bugfer medium, favorable to the activity of the drug.

The treatment with the pharmaceutical preparation as per the invention, described under Examples 1 ... 5, may be associated with some other pharmaceutioals, such as: analgetios, general tonic agents, vitamins (with the exception of Vitamin B ₁₂ in a quantity over 20 g / day). Mention must be made of the fact that the ass ociated pr oducts should be preferably administered 1/2 - 1 h after the administration of the preparation as per the present invention.

Similarly, since the drug as per the invention has a radios ensitizing action, it may be associated with radiotherapy thus increasing the effect of iradiation. The administration, during treatment, of infusion s olutions c ontaining amino-acids is not recomme nded. The above-mentioned examples for the composition of the drug as per the invention are not exclusive; within certain limits of dosage, several versions of the established composition may be used, depending upon the stage and 10-calization of the disease, the biological equilibrium of the organism and the tolerance of the organism.

Claims

CLAIM

Anti-tumor pharmaceutical preparation composed of 10 ... 350 mg of hydroquinone, 300..200 mg of metol, 10 ... 100 mg of amidol; these three active ingredients may be or not associated with 10 ... 100 mg of para aminosalicylic acid; the αuantities are expressed per unidose and the association ratio (by weight) between hydroquinone and metol is between 1: 3 ... 7: 4.