EP1086090A1

EP1086090A1 - Composition for the treatment of cancer and colitis ulcerosa as well as the use of a titanium complex and a zinc salt for the preparation of the composition

Info

Publication number: EP1086090A1
Application number: EP99911640A
Authority: EP
Inventors: Even Marstrand
Original assignee: Individual
Current assignee: Individual
Priority date: 1998-04-07
Filing date: 1999-03-30
Publication date: 2001-03-28
Also published as: AU3025599A; DK173459B1; WO1999051585A1

Abstract

Composition comprising a complex of 36 moles of ascorbic acid, 1 mole of Ti3+ and 6 moles of Cu2+ combined with one or more zinc salts in a amount of 12 to 200 mg of zinc salt, calculated as zinc, per 600 mg of complex. The composition has a prophylactic and curative effect on a disease or condition showing an abnormal blood concentration of titanium, zinc and/or manganese including leukaemia and colitis ulcerosa.

Description

1

Title: Composition for the treatment of cancer and colitis ulcerosa as well as the use of a titanium complex and a zinc salt for the preparation of the composition-

Technical Field

The present invention relates to a composition comprising a mixture of a complex of ascorbic acid, Ti³⁺ and Cu²⁺ with a Zn salt and optionally also with an Mn salt with a prophylactic, palliative or curative effect on diseases in human beings and animals, said diseases manifesting themselves as abnormal blood pictures in the persons or animals suffering therefrom, where the abnormal blood pictures reveal a reduced content of zinc, titanium and manganese. Examples of such diseases are for instance cancer including leukaemia and colitis ulcerosa. The invention relates furthermore to the use of said mixture for the preparation of a composition with a prophylactic, palliative or curative effect on such diseases.

Background Art

Previously, cancer including leukaemia has been treated with cytostatica, which are chemical compounds effective on the cell division and with a drastic toxic effect. The treatment is prolonged and because of the toxicity attended with very serious side effects.

The lack of minerals in human and animal blood is assumed to play a decisive part for the existence of cancer. Numerous scientific research reports support this assump- tion.

It is known from Nature 284, 626 (1980) that vitamin C alone or in combination with copper is selectively toxic against melanotic cancer cells.

The US-PS No. 4,211,712 of the Applicant discloses a compound for treating dis- eases manifesting themselves as an abnormal blood picture, viz. a complex of ascorbic acid, trivalent titanium and divalent copper, where the molar ratio of the ingredients is ascorbic acid:Ti³⁺:Cu²⁺ = 36: 1 :6. Below this complex is referred to as the "titanium complex" . However, it turned out that cases exist where the known tita- nium complex does not have an effect or only to an insufficient degree. Thus it turned out that when used alone the titanium complex is unable to prolong the life of A.K.R. mice genetically tending to suffer from malignant cancer diseases and which accordingly never live more than 14 months.

Now it has been ascertained that it is possible to obtain an effect in cases where the titanium complex alone is ineffective by mixing the titanium complex of ascorbic acid, trivalent titanium and divalent copper in the above molar ratios with a zinc salt and optionally also with a manganese salt.

Brief Description of the Invention

The present invention relates to a composition of the above type which comprises a complex of 36 moles of ascorbic acid, 1 mole of Ti³⁺ and 6 moles of Cu²⁺, and which is characterised by further comprising one or more zinc salts in an amount of 12 to 200 mg of zinc salt, preferably 30 to 100 mg, especially 45 to 70 mg, calculated as zinc per 600 mg of the complex.

Although the use of the above titanium complex alone has provided good results for the treatment of diseases which are characterised by causing abnormal blood pictures in man and animals, it has now also been ascertained that it is possible to obtain an effect in many of the cases where the complex alone is insufficient by combining the titanium complex with a zinc salt and optionally also with a manganese salt.

It turned out surprisingly that it was possible to prolong the life of A.K.R. mice by treating them with the composition according to the invention, said A.K.R. mice being mice spontaneously developing malignant diseases in form of leukaemia or tumours. No previous reports exist on A.K.R. mice which have been able to live for more than 14 months whichever treatment was tried. Both the use of zinc alone and the use of the combination according to the invention of both the titanium complex and zinc, respectively, have resulted in an unprecedented survival. A treatment of A.K.R. mice being 10 to 11 months old at the beginning of the test revealed thus 20% and 31.4% , respectively, live mice 206 days after the beginning of the test, i.e. the mice were then approximately 17 months.

The extent of applicability of the invention appears from the following detailed description. It should, however, be understood that the detailed description and the specific examples are merely included to illustrate the preferred embodiments, and that various alterations and modifications within the scope of protection will be obvious to persons skilled in the art on the basis of the detailed description.

Detailed description of the invention.

The composition according to the invention turned out to be efficient in the treatment of cancer. The composition according to the invention is, however, potentially applicable for the prophylaxis, alleviation or treatment of any type of disease causing an abnormal blood picture.

Examples of diseases treatable with the composition according to the invention are cancer including leukaemia as well as colitis ulcerosa.

In support of the understanding of the effect of the composition according to the invention an illustration is provided below of the concentration of selected metals in the blood of a group of arbitrarily selected leukaemia patients compared with the concentration of the same metals in the blood of healthy (normal) persons. The numbers are average numbers for each group. 4

Blood picture (mg metal per 100 ml blood)

Normal (28 persons) Leukaemia (12 persons)

Na 1944 2181

K 1716 1401

Ca 61 68

Mg 33.4 28.6

Cu 1.23 1.32

Fe 438 315

Al 1.96 1.91

Zn 7.60 5.96

Ba 0.67 0.75

Si 4.05 4.53

Ti 0.023 0.017

Sn 0.34 0.28

Pb 0.23 0.21

As 0.43 0.41

Cr 0.024 0.020

Mn 0.33 0.24

Co 0.00032 0.00023

Ni 0.42 0.387

It appears that the leukaemia patients reveal a substantially lower content in the blood of the metals zinc, titanium as well as manganese compared to healthy (normal) persons.

Example 1 The following example shows that a complex of ascorbic acid, trivalent titanium and divalent copper as described in US-PS No. 4,211,712 has no effect in A.K.R. mice.

The examples includes two test groups, viz. a test group and a control group. The test employed 140 days old A.K.R. mice.

The test group included 50 A.K.R. mice which were administered 25 mg of titanium complex per kg of body weight in the daily portion of drinking water.

The control group included 50 A.K.R. mice which received no composition.

The test results are shown in the following table 1 :

TABLE 1

% death-rate

Number of days Ti-complex Control group

0 0 0

7 0 0

14 2 0

21 2 0

28 2 2

35 2 2

42 2 2

49 2 2

56 2 2

63 4 2 77 10 4

84 10 6

91 12 6

98 14 12

105 18 18

112 18 18

119 22 22

126 26 26

133 32 30

140 34 32

147 38 34

154 54 42

161 58 48

168 60 56

175 64 58

182 66 58

189 66 60 196 70 60

The results show that the known titanium complex cannot prolong the life of the A.K.R. mice.

Example 2

The test employed 70 inbred female mice of the strain A.K.R./ABomf from Gl. Bomholtgard, DK-8680 Ry. At the beginning of the test the mice were 10 to 11 months old.

For a week prior to the beginning of the test and during the test the animals lived in Makrolon trays (type III) with litter. The number of animals in the trays varied from 2 to 7. The animals were fed ad libitum with Boserups Rostock mixture. HC1 was added to the drinking water to pH = 2.5 until the dosing of the test composition was begun. The drinking water was fed ad libitum. Fresh lettuce was given daily.

The room temperature was 21 °C ± 1 °C. The relative atmospheric humidity was 50 + 5 % . The air renewal was 14 times per hour, and the animals had light from 7.00 a.m. till 7.00 p.m.

The 70 mice were divided by a random selection into two groups with 35 in each group. During the first 74 days all the animals of the test group were daily fed by gavage with 25 mg of titanium complex as well as 6 mg of zinc sulfate per kg of body weight. From day No. 75 till day No. 107 the test group was fed by gavage 5 days a week. Over the weekend the test group was fed with the composition, viz. the titanium complex and the zinc sulfate, through the drinking water. From day No. 108 till the end of the test period, i.e. till day No. 206, the test group was exclusively fed with the compositions through the drinking water.

The control group was treated in the same manner, but only with ZnSO₄.

The dosing was as follows:

Test group: 5 g of titanium complex + 1.2 g of ZnSO₄ were dissolved in 2000 ml of water.

Control group: Solution of 1.2 g ZnSO₄ in 2000 ml of water.

Dosing through gavage feeding: 10 ml/day /kg body weight

Dosing in the drinking water: 60 ml solution to 940 ml of water. The following tables 2A, 2B and 2C illustrate the test results.

TABLE 2A

Titanium complex -1- ZnSO₄ Control group

Number of % death-rate % death-rate days

7 2.9 5.7

14 11.4 11.4

21 17.1 14.3

28 20.0 25.7

35 31.4 28.6

42 40.0 34.3

49 42.9 42.9

56 45.7 45.7

63 48.6 48.6

70 54.3 51.4

77 54.3 54.3

84 54.3 54.3

91 57.1 62.9

98 60.0 65.7

105 60.0 65.7

112 60.0 68.6

119 60.0 68.6

126 60.0 68.6

133 60.0 68.6

140 60.0 68.6 147 65.7 71.4 154 65.7 71.4

161 65.7 74.3

168 65.7 74.3

175 65.7 77.1

182 65.7 80.0

189 68.6 80.0

196 68.6 80.0

203 68.6 80.0

206 68.6 80.0

The table shows the death rate of A.K.R. mice administered a composition comprising a complex of ascorbic acid, trivalent titanium and divalent copper with ZnSO₄, where the molar ratio of ascorbic acid:Ti³⁺:Cu²⁺:Zn²⁺ = 36: 1 :6: 10. The control group is administered ZnSO₄.

Table 2A shows also the death rate of A.K.R. mice administered a composition comprising a Ti-complex combined with ZnSO₄ compared with the death rate of A.K.R. mice administered ZnSO₄ alone (the control group). It appears from the table that at the end of the test, viz. on the 206th day after the beginning of the test, the death rate of the test group and the control group, respectively, was 68.6% and 80.0% , respectively. In other words, the titanium complex combined with ZnSO₄ has a stronger effect than ZnSO₄ alone as far as the chance of survival is concerned. At the end of the test, viz. on the 206th day after the begmning of the test, the test group included 11 live animals and the control group included 7 live animals. These animals were approximately 17 months old (10 to 11 months + 206 days/30 days/month). It should be underlined that previously no A.K.R. mice became more than 14 months old. Thus the present test demonstrates that it has been possible to prolong the life of several of the A.K.R. mice by more than 3 months compared to previously. The latter applies both to the test group which as administered the tita- 10 nium complex + ZnSO₄ and to the control group which was administered ZnSO₄ alone.

During the entire test period, every single dead mouse was subjected to an autopsy.

On the 206th day the remaining 18 live mice were killed and subjected to an autopsy. The following table 2B shows the autopsy findings of all mice, whereas table 2C shows the autopsy findings of the 18 mice which were still alive on the 206th day.

11 TABLE 2B

Autopsy findings Titanium complex Control + ZnSO₄

Enlarged spleen 5 15

Enlarged mesenteric lymph glands 4 8

Development of tumours 4 7

Abces in lung/lungs 1 _

Running lung/lungs 5 _

Enlarged kidneys 4 6

Enlarged liver 4 7

Enlarged thymus 8 13

Pneumoni 2 2

Fibrinous pericarditis 1 _

Pleuritis 1 _

Otitis media 1 _

Infiltration in liver _ 1

Enlarged submandibular glands _ 1

Consolidated lung/lungs 1 1

Abces below front legs _ 1

Enlarged lung/lungs _ -

Reddishly discoloured lung/lungs 6 4

Pale spots in the liver - 1

Table 2B shows the number of various symptoms of disease for the mice in the test group as well as for the mice in the control group. Here the difference between the test group and the control group concerning the number of cases of an enlarged spleen should be particularly noticed. The test group included 5 cases of an enlarged 12 spleen whereas the control group included 15 cases of an enlarged spleen. As it is known that leukaemia patients (viz. both human and animal patients) develop an enlarged spleen, it is accordingly reasonable to assume that the titanium complex in combination with ZnSO₄ has a curative or prophylactic effect on leukaemia in A.K.R. mice, and that it is therefore also potentially applicable for a curative or prophylactic treatment of leukaemia in man.

TABLE 2C

Autopsy on mice alive on the 206th day.

The test group

11 mice (31.4%) were alive until the 206th day. After destruction the autopsy revealed:

9 mice (25.7%): Nothing abnormal macroscopically.

2 mice: The spleen perhaps slightly enlarged; otherwise nothing abnormal.

The control group

7 mice (20%) were alive until the 206th day. The autopsy revealed:

2 mice (5.7%): Nothing abnormal macroscopically .

2 mice: The spleen and thymus enlarged; otherwise nothing abnormal.

The remaining 3 mice revealed the following: 13 1 mouse: Small tumour in the spleen; otherwise nothing abnormal.

1 mouse: The spleen enlarged with a tumourous tissue, thymus enlarged.

1 mouse: Liver and spleen tumourously changed; mesenteric glands and kidneys enlarged.

It appears that the animals of the test group still alive on day No. 206 showed none or only weak symptoms of disease whereas distinct symptoms of disease were seen in a predominant number of animals in the control group still alive on day No. 206.

Example 3

Tests were performed on 70 6 months old A.K.R. mice, viz. 35 mice in the test group and 35 mice in the control group. The daily feed of the test group was admixed 5 ml of 1 % ascorbic acid + 2 drops of 15% Ti₂(SO₄)₃ + 5 drops of approximately 30% CuSO₄ and 5 drops of approximately 30% ZnSO₄. The control group received no composition. The results concerrning survival appear from table 3.

Table 3

% death-rate

Number of days Titanium complex + Control ZnSO₄

0 0 0

3.5 0 0

7 0 0

10.5 0 0 14 0 2.9 14

17.5 0 5.7

21 0 8.6

24.5 0 14.3

28 2.9 14.3

31.5 2.9 14.3

35 2.9 17.1

38.5 5.7 20.0

42 5.7 22.9

45.5 5.7 31.4

49 5.7 34.3

52.5 8.6 37.1

56 11.4 40.0

59.5 14.3 40.0

63 14.3 40.0

66.5 17.1 40.0

70 17.1 42.9

73.5 20.0 45.7

77 20.0 48.6

80.5 22.9 48.6

84 25.7 48.6

87.5 28.6 51.4

91 28.6 51.4

94.5 28.6 51.4

98 31.4 51.4

101.5 31.4 54.3

105 31.4 57.1

Clinical test 1 15

In the autumn of 1995 a 45-year-old man had suffered from pronounced tiredness and headache. He was diagnosed to suffer from chronic lymphatic leukaemia. The patient was treated with chemotherapy (leuceral).

In September 1997 the patient still suffered from headache and pronounced tiredness. A daily treatment was begun with 1200 mg of titanium complex, 132 mg of zinc (in form of zinc sulfate) + 20 mg of manganese (in form of manganese sulfate), where the indicated weight quantities refer to the weight of Zn and Mn, respectively.

After 3 weeks, the patient experienced no headache, and the tiredness no longer applied. In addition, a normal blood picture was seen.

The chemotherapy was stopped in February 1998, whereas the treatment with titanium complex, zinc and manganese was continued, and the blood picture remained normal. After having been reported unfit for work for more than two years, the patient was reported fit for work and was able to start working again on 1 March 1998.

Clinical test 2

In June 1997 a 4-year-old girl was diagnosed as having acute lymphatic leukaemia, where immature lymphocytes were found in the spinal fluid. The patient was treated with chemotherapy and X-ray therapy. In early December 1997, the case was consid- ered hopeless, and the patient was expected to die within 2 months. Therefore all medical treatment was interrupted.

On 20 December 1997 the condition of the patient was such that it was necessary to feed her by gavage. The patient lost weight and vomited 10 to 15 times daily; her haemoglobin number was 4.8 compared to the normal 7 to 9; and the number of thrombocytes was 120,000 compared to the normal 250,000 to 400,000. On this day, 16 a treatment was begun with titanium complex-zinc-manganese. The daily dosage was 400 mg of titanium complex, zinc sulfate in an amount corresponding to 44 mg of zinc and manganese sulfate in an amount corresponding to 10 mg of manganese.

A control on 27 December 1997 revealed a recovery so well that a scheduled blood transfusion was found unnecessary. In early January 1998, an examination revealed that it was no longer possible to detect immature lymphocytes in the spinal fluid. In late January and February 1998, an examination revealed a normal blood picture.

On 24 March 1998 the patient was still fed by gavage, but she was able to start eating a few mouthfuls in a normal way. No vomiting was experienced, and the patient started to gain weight. The haemoglobin number and the thrombocyte number were both normal, viz. 7.8 and 295,000, which signal a normally functioning bone marrow.

On 4 August 1998, the patient was pronounced as cured.

Clinical test 3

An 82-year-old male patient has suffered from colitis ulcerosa for the last 5 to 6 years, and he has daily been treated with 600 mg of titanium complex 45 mg of zinc and 8 mg og manganese. Apart from a few cases of small amounts of blood and mucus in the faeces and stomach aches, the patient has been symptomless. In 1996 the patient tried 4 times to omit the titanium complex, and twice he tried to omit zinc and manganese. All six times a strong aggravation occurred which disappeared again when the complete treatment was resumed. During the last 6 months the patient has been administered an increased amount of manganese, viz. a dosis of 25 mg, and since then he has been completely symptomless.

A corresponding effect has been demonstrated in more than 200 patients. 17 Clinical test 4

In October 1994 a 45-year-old woman had been diagnosed with kidney adenocar- cinom with numerous metastases in both lungs. The disease was refractory to all treatments. A treatment was started with prednisolon. During 3 months, the patient lost 15 kg in weight. Pleural effusion was performed several times.

In February 1995 an X-ray picture was taken after pleural effusion, said X-ray picture showing numerous metastases. A few days after the X-ray picture was taken, a daily treatment with administration of 1200 mg of titanium complex and 132 mg of zinc was started. The patient started to eat again, and the loss of weight ceased.

On 30 March 1995 a new X-ray picture showed a distinct regression of metastases and of pleural effusion. In the middle of May 1995, the patient died as a consequence of heart failure.

Further clinical observations

Patients suffering from rheumatic arthritis and a number of cancer patients have revealed an abnormal blood picture with a low content of titanium, zinc and manganese and a high content of copper. It can be assumed that the treatment of these diseases with the composition according to the invention will reveal favourable results.

A regeneration of cartilage after treatment with the composition according to the invention has been demonstrated in 2 patients from a group of 7 patients suffering from arthrosis and revealing a reduced content of titanium in the blood.

A number of patients suffering from psoriasis, including psoriasis arthritis and psoriasis pustulosa, were surprisingly found symptomless after treatment with the compo- 18 sition according to the invention.

An observation for 7 years of a group of 490 approximately 58-year-old and older women revealed that a treatment of arthrosis with the composition according to the invention for at least 5 months resulted in a halving of the statistic death rate caused by ischaemic heart diseases and cancer.

Based on these observations, the composition according to the invention must be considered suited for prophylaxis and treatment of diseases such as cancer, arthrose, rheumatic arthritis, psoriasis, psoriasis arthritis, psoriasis pustulosa, artherosclerose and ischaemic heart diseases.

The composition according to the invention is usually administered orally in form of a powder or in form of tablets, but any other form of administration of the composition is potentially possible, such as for instance rectally.

For a grown-up patient, the normal daily dosis of the composition according to the invention is 175 mg to 1.5 g of titanium complex, preferably 675 to 900 mg of titanium complex in combination with 1 to 4 parts by weight of ZnSO₄ per 8 parts by weight of titanium complex.

Examples of preferred embodiments according to the invention are indicated below.

Composition 1

Tablets are produced in a conventional manner, each tablet comprising a homogenous mixture of the following ingredients:

200 mg of the previously defined titanium complex comprising ascorbic acid, trivalent titanium and divalent copper, 19

25 mg of ZnSO₄, 7 H₂O,

90 mg of potato starch,

3 mg of silicium dioxide,

6 mg of magnesium silicate,

27 mg of crystalline cellulose,

4 mg of alkyl cellulose

Composition 2

200 mg of titanium complex,

100 mg of ZnSO₄, 7 H₂O,

90 mg of potato starch,

3 mg of silicium dioxide,

6 mg of magnesium silicate,

27 mg of crystalline cellulose,

4 mg of alkyl cellulose

Composition 3

200 mg of titanium complex,

66 mg of ZnSO₄, 7 H₂O,

15 mg of MnSO₄, 4 H₂O

90 mg of potato starch, 3 mg of silicium dioxide, 20

6 mg of magnesium silicate, 27 mg of crystalline cellulose, 4 mg of alkyl cellulose

The above description of the invention reveals that it is obvious that it can be varied in many ways. Such variations are not to be considered a deviation from the scope of the invention, and all such modifications which are obvious to persons skilled in the art are also to be considered comprised by the scope of the succeeding claims.

Claims

21 Claims.

1. Composition comprising a complex of 36 moles of ascorbic acid, 1 mole of Ti³⁺ and 6 moles of Cu²⁺, characterised by further comprising one or more zinc salts in an amount of 12 to 200 mg of zinc salt, calculated as zinc, per 600 mg of the complex.

2. Composition as claimed in claim 1, characterised by further comprising one or more manganese salts in an mount of 5 to 40 mg, calculated as manganese, per 600 mg of the complex.

3. Composition as claimed in claim lor2, characterised by being formu- lated for use by the treatment of or prophylaxis against a disease or condition showing an abnormal blood concentration of titanium, zinc and/or manganese.

4. Composition as claimed in claim lor2, characterised by being formulated for use by the treatment of or prophylaxis against cancer.

5. Composition as claimed in claim lor2, characterised by being formu- lated for use by the treatment of or prophylaxis against colitis ulcerosa.

6. The use of a complex of 36 moles of ascorbic acid, 1 mole of Ti³⁺ and 6 moles of Cu²⁺ combined with one or more zinc salts for the preparation of a composition for the prophylaxis against and/or alleviation of a disease or condition showing an abnormal blood concentration of titanium, zinc and/or manganese.

7. The use of a complex of 36 moles of ascorbic acid, 1 mole of Ti³⁺ and 6 moles of Cu²⁺ combined with one or more zinc salts for the preparation of a composition for the prophylaxis against and/or alleviation of cancer or colitis ulcerosa. 22

8. The use as claimed in claim 7 for the preparation of a composition for the treatment of or prophylaxis against leukaemia.