WO1994005271A1

WO1994005271A1 - Gastrointestinal cancer therapy composition containing dimethylsulphone and dimethylsulphoxide

Info

Publication number: WO1994005271A1
Application number: PCT/GB1993/001869
Authority: WO
Inventors: Aws Shakir Mustafa Salim
Original assignee: Aws Shakir Mustafa Salim
Priority date: 1992-09-04
Filing date: 1993-09-03
Publication date: 1994-03-17
Also published as: GB9218712D0; AU4974093A; CN1108525A

Abstract

The present invention relates to synergistic compositions comprising methylsulphonylmethane and dimethylsulphoxide and their use in formulations and methods of treatment for gastrointestinal cancer.

Description

GASTROINTESTINAL CANCERTHERAPY COMPOSITION CONTAINING DIMETHYLSULPHONE AND DIMETHYLSULPHOXIDE

The present invention relates to the treatment of gastrointestinal cancer and to synergistic compositions for use therein.

Gastrointestinal cancer is currently a common invasive tumour in man, making its diagnosis and management a formidable public health problem. The frequency of this cancer among the population has been increasing gradually over the past five decades, thus emphasizing the need for improving its management. Surgery for gastrointestinal cancer is followed by an unacceptable high recurrence rate even when a curative resection has been carried out, therefore efforts have concentrated on the development of a more effective application of chemotherapy and radiotherapy. These modalities, however, have made only a small impression on the natural history of the disease. Moreover, currently available adjuvant therapies have limitations pertaining to patient selection or treatment application. The present invention aims at minimizing one or more of these disadvantages.

This invention provides a synergistic composition for use in the treatment of gastrointestinal cancer, which composition comprises methylsulphonylmethane with dimethylsulphoxide, and which has been found in a very surprising and unexpected manner to protect against malignant transformation and cancer development in the gastrointestinal tract in addition to having utility in the treatment of this cancer. The treatment benefits have been realized in relation to a significant reduction in the recurrence rate coupled with prolongation of the disease free interval and the overall survival rate. These therapeutic gains are particularly noticeable when the present invention is used as an adjuvant to surgery regardless of whether this surgery has been radical or palliative. The components of this invention exhibit a greater or lesser degree of synergism in that the sum of the individual acitivity of these ingredients is less than that of their combination together.

Advantageously, the composition of the present invention includes a vasodilator such as for example menthol in order to further increase the effectiveness of the composition of the invention in the mucosa. Advantageously also there may be included an anti-ischaemic substance and in particular papaverine, and/or an anti-cholinergic and/or vagal nerve blocking substance, especially one or more compounds selected from procaine, propoxycaine and amethocaine.

In a further aspect, this invention provides a pharmaceutical composition comprising a combination of the invention in intimate admixture with a physiologically acceptable carrier or vehicle for use in the treatment of gastrointestinal cancer. The carrier or vehicle should be acceptable in terms of exerting no deleterious action on the gastrointestinal tract and being compatible with all the .other ingredients of the invention. Suitable vehicles are well known in the art, being noted for example in such standard works as the British Pharmacopoeia and the British National Formulary.

While not restricting the scope of the present invention, it is believed that the mechanism of action behind the beneficial effects afforded by the invention is scavenging oxygen-derived free radicals besides combating the tendency for their formation via the inhibition of xanthine oxidase. The compositions of the present invention (optionally with other active ingredients and/or a suitable vehicle) can be administered orally, or parenterally, in particular by intravenous injection, or per rectum.

For oral administration, the compositions of the invention and any accompanying material may be presented as a draught in water or in a syrup, in capsules, sachets, boluses or tablets, as an aqueous or oleaginous solution or suspension or in suspension in a syrup, such suspensions optionally including suspending agents or as an oil-in-water or water-in-oil emulsion. The compositions of this invention may also be taken orally in an alcoholic drink be that a spirit, wine or beer. The non-alcoholic forms of these drinks may also serve as vehicles for the oral consumption of the invention. Moreover, the present invention can be added for oral administration to any fruit juices, mineral waters be they carbonated or not, and to all forms of soft drinks. Where desirable or necessary, flavouring, sweetening, preserving, thickening or emulsifying agents may be included in the formulation. Tablets may contain the compositions of the invention and any accompanying material as a powder or granules optionally mixed with binders, lubricants, inert diluents or surface-active or dispersing agents.

For parenteral administration, the compositions of the invention and any accompanying material may be presented in sterile solutions or suspensions in aqueous or oleaginous vehicles, which may also contain preservatives and material for rendering the solution or suspension isotonic with the blood of the intended recipient. Such formulations may conveniently be presented in unit-dose or multi-dose sealed containers. For administration orally in liquid form or parenterally, the active ingredients of the invention are preferably presented in solution, suspension, or emulsion at a concentration of from 0.5 to 15% w/v more preferably 1 to 10% w/v e.g. 2% w/v in unit multidose form. When presented in unit dose form each unit dose preferably contains from 200 to 1000 mg of each of the ingredients.

The compositions of the invention can also be directly delivered to the lung via smoke and in this respect, can be added as a powder or solution to tobacco leaves or to the tobacco of cigarettes, cigars and pipes. The compositions of the invention may also be included as a solution or powder in the cigarette's filter or small delivery compartments included in the cigarette. These compartments may also contain the invention in the form of granules which evaporate upon contact with smoke, thus delivering their substances to be carried by the smoke.

In general, for the purposes of treating gastrointestinal cancer, dimethylsulphoxide and methylsulphonyl methane are administered at a dosage in the range of from 10 to 400 mg/kg body weight per day, preferably from 20 to 60 mg/kg body weight per day. The dosage may be administered in one or more doses per day and is preferably administered at intervals of from 2 to 8 hours, most preferably every 6 hours.

Advantageously, the ingredients of the compositions of this invention are administered in a slow release or sustained release vehicle, various suitable vehicles of this type being known in the art.

When papaverine is included, this is generally used at a dosage of lmg/kg body weight per day. Addition of procaine is most preferably at a dosage in the range from 30 to 50mg/kg body weight per day. Menthol on the other hand is usually added in a dosage range of from 20 to 40mg/kg body weight.

Further preferred features and advantages of the invention will appear from the following detailed examples given by way of illustration only:

Example 1 - Preparation of aqueous compositions

A. methylsulphonylmethane lOg dimethylsulphoxide lOg double distilled water add to 100 ml

B. methylsulphonylmethane lOg dimethylsulphoxide lOg menthol crystals lg double distilled water add to 100 ml

The formulation is prepared at a temperature of about 25°C. The appropriate volume of the dimethylsulphoxide stock solution is measured then 10 grams of methylsulphonylmethane are added to it alone or if indicated with one gram of finely ground menthol crystals. The solution is stirred for a few seconds. The volume is then made up to 100 ml with double distilled water and the whole mixture is stirred for a few seconds before being placed in airtight dark coloured glass bottles and stored at a temperature not exceeding 26°C. This preparation should not be used for at least 12 hours, should not be left exposed to the air for long periods and should not be directly exposed to sunlight. Example 2 - Preparation of capsules

A. methylsulphonylmethane 500mg dimethylsulphoxide 500mg

B. methylsulphonylmethane 500gm dimethylsulphoxide 500mg menthol crystals 250mg

Capsules were prepared at room temperature of about 26°C. When making capsules which contain menthol, the crystals of this agent were first finely ground. The appropriate weight of powder of each ingredient is added and the whole preparation is thoroughly mixed then filled into gelatinous capsules. These capsules were stored in opaque or dark coloured glass containers away from direct light and at room temperatures not exceeding 26°C.

Example 3 - Treatment of gastrointestinal cancer

When the solutions listed under Example 1 were being used, 5 ml were administered orally every six hours. The capsules listed under Example 2 were taken one every six hours. When the treatment is offered as an adjuvant to surgery, administration generally commences on the fifth post-operative day, which is usually the time for the return to solid food intake by mouth. If administration per rectum is indicated, 5 ml of the solutions listed under Example 1 can be given every 6 hours. When this is being carried out post-operatively, treatment can start 2 days after surgery. As a rule, treatment should be continued indefinitely, however, it may be possible after eighteen months to reduce therapy to three times daily. Example 4 - Protection against carcinogenesis

Male Sprague-Dawley rats, bred and maintained in a closed conventional rat colony and weighing 40 to 55 grams at weaning, were allocated at random to groups of twenty (n = 20) , then housed in stainless steel suspended wire mesh cages (to minimise coprophagy) under controlled environmental conditions. At 10 weeks of age, rats were randomized to drink tap water, dimethylsulphoxide (0.5, 1, 5, 10 or 15%), methylsulphonylmethane (0.5, 1, 5, 10 or 15%), or the latter two agents together. At this time period, rats were also injected subcutaneously with 10 mg per kg body weight of 1, 2 - dimethylhydrazine (DMH) or with 1 ml per kg body weight of saline every week for 28 weeks. When the injections were completed, rats were killed by ether overdose and full necropsies were performed. Tissues were fixed with 10% formalin prior to detailed macroscopic examination, then sectioned, stained and studied microscopically.

Administration of DMH for 28 weeks produced colonic tumours in all of the rats (100%) . Macroscopically, these tumours were confined to the colon and distributed evenly over all of its parts. They were polypoidal or annular. Microscopically, both adenomatous polyps and invasive adenocarcinomas were seen in every animal which had developed colonic tumours. The level of invasion varied from submucosal to extraserosal. The latter cases always demonstrated lymphatic metastases in the epicolic and paracolic lymph nodes but not beyond or in the liver.

Each of dimethylsulphoxide and methylsulphonylmethane used alone afforded some protection against carcinogenesis, an action which was intensified in a synergistic manner by their combination together. There were no treatment related adverse effects and there was no difference in the activity or food and water consumption (calorie intake) between control and treatment groups. This study also suggested that the dosage used in Example 1 is an optimal one.

The following table details the results obtained:

Experimental number developing group cancer

0% 100%

90% 85% 75% 70% 70%

90% 80% 75% 70% 70%

40%

10%

5%

0%

0%

DMSO: dimethylsulphoxide MSM: methylsulphonylmethane DMH: 1,2 - dimethylhydrazine Example 5 - Protection against metastases

Male Sprague-Dawley rats, bred and maintained in a closed conventional rat colony and weighing 50 to 60 grams at weaning, were allocated at random to groups of twenty (n = 20) then housed in stainless steel suspended wire mesh cages (to minimise coprophagy) under controlled environmental conditions. At 10 weeks of age, rats were randomized to receive DMH or saline as described above. After these injections had been completed, an ileostomy was fashioned under ether anaesthesia to divert the gastrointestinal contents in case of a colonic obstruction later on, then animals were randomized to drink tap water, methylsulphonylmethane (0.5, 1, 5, 10 or 15%), dimethylsulphoxide (0.5, 1, 5, 10 or 15%), or the combination of the latter two agents. Three months later, all the animals were killed by ether overdose and examined for the incidence of hepatic metastases as detailed above. The rats that' died within ten days of their ileostomy operation were excluded from analysis. DMH alone produced multiple hepatic metastases involving both lobes of the liver. The protection against cancer spread to the liver afforded to some degree by each of the agents employed was synergiεtically enhanced by their administration in combination together as shown in the following Table:

animals developing

Experimental animals surviving hepatic group the ileostomy, n matastases, n

Saline + tap water 18 0%

DMH + tap water 19 19 100%

DMH + 0.5% DMSO 18 DMH + 1% DMSO 18 DMH + 5% DMSO 19 DMH + 10% DMSO 17 DMH + 15% DMSO 18

DMH + 0.5% MSM 19 DMH + 1% MSM 19 DMH + 5% MSM 18 DMH + 10% MSM 17 DMH + 15% MSM 18

DMH + 0.5% DMSO + 0.5% MSM 17

DMH + 1% DMSO + 1% MSM 17

DMH + 5% DMSO + 5% MSM 18

DMH + 10% DMSO + 10% MSM 17

DMH + 15% DMSO + 15% MSM 19

DMH: 1, 2 - dimethylhydrazine

DMSO: dimethylsulphoxide

MSM: methylsulphonylmethane

On the basis of the results obtained, the dosage used in

Example 1 appears to be optimal. The following clinical trials were carried out on prospective randomized double blind controlled basis. Controls were given saline. Randomization was effected by drawing sealed envelopes.

Example 6 - Survival studies in patients with gastric cancer

The influence of the formulation of Example l.A on survival in gastric cancer (adenocarcinoma) with serosal invasion and metastases to the lymph nodes surrounding the stomach was assessed in a two year study conducted on consecutive patients making an uneventful recovery from a potentially curative distal two thirds partial gastrectomy for carcinoma of the distal third of the stomach. Patients were considered to be suitable for the study if their carcinoma had invaded the serosa, but not any contiguous structures, and had only metastasised to the lymph nodes surrounding the stomach and not to any of the nodes along the main arteries. The lymphatic metastases had to be confined to the lymph nodes without any extension to the perinodal fatty tissues. In addition, the gastrectomy specimen had to show tumour free proximal resection lines for at least 2 cm. and complete excision of all the stomach's regional lymph nodes. The patients recruited into the study were randomized on the fifth post-operative day to receive five ml of saline or of the formulation by mouth four times a day until the end of the study 2 years later. There were 20 fully evaluable controls (8 women and 12 men, age range 43 to 76 years, mean 56) and 21 fully evaluable treatment cases (9 women and 12 men, age range 43 to 78 years, mean 55) who were analysed by the Kaplan-Meier's product limit method and the Mantel-Cox statistics. Administration of the formulation incurred a significant (p<0.01) survival advantage relative to control values at the end of each of the first (patients alive: 17 (81%) vs 11 (55%)) and second (patients alive: 13 (62%) vs 7 (35%)) years of treatment. It was, thus, construed that oxygen-derived free radicals mediate the aggressiveness of gastric cancer by producing the tissue damage which allows it to spread. Consequently, these radicals are implicated in the mechanism of gastric cancer and removing them provides patients with a survival advantage.

Example 7 - Survival studies in patients with colonic cancer

The influence of the formulation of Example l.B on survival in colonic cancer (adenocarcinoma of the sigmoid colon) at Dukes' stage C with secondary tumour deposits in the lymph nodes at the origin of the inferior mesenteric artery was assessed in a two year study conducted on consecutive patients making an uneventful recovery from curative resection of the sigmoid colon with primary anastomoses. Resection was considered to be curative when there was no evidence of metastases to distant organs or of residual local tumour at the end of the operation or no microscopical tumour deposits at the lines of resection. The patients recruited into the study were randomized on the fifth post-operative day to receive 5ml of saline or the formulation by mouth four times a day until the end of the study two years later. The fully evaluable patients (20 controls: 5 women and 15 men, age range 41 to 78 years - mean 62; and 21 treatment cases: 6 women and 15 men, age range 42 to 79 years - mean 61) were analysed by the Kaplan-Meier's product limit method and the Mantel-Cox statistics. Administration of the formulation was found at the end of the study to have significantly (p<0.01) increased the disease free interval and the overall survival of patients (number alive after two years: 14 (67%) vs 7 (35%)) besides significantly (p<0.01) reducing the local recurrence rate of the disease. It was therefore, concluded that the role of oxygen-derived free radicals in colonic cancer is the name as that in gastric cancer and that free radical scavengers increase the disease free interval and reduce the local recurrence rate in addition to. prolonging the overall survival rate of patients bearing colonic carcinoma. Consequently, application of radical scavengers in the management of this form of cancer provides an adjuvant to other therapeutic modalities.

Example 8 - Survival studies in patients with advanced colonic cancer

The effect of the formulation of Example l.B on the survival of consecutive patients who had undergone palliative resection of the sigmoid colon with primary anastomoses for adenocarcinoma at Dukes' stage D (defined for the purposes of this study as colonic carcinoma with matastases confined to the liver) in addition to electrocoagulation of multiple liver metastases during the same operation. Patients were only studied if they had 5 or more hepatic lesions. All these lesions were biopsied during surgery and were packed with a haemostatic sponge after they had been destroyed by electrocoagulation. The patients who made an uneventful recovery from surgery were randomized on the fifth post-operative day to receive 5ml of saline or the formulation by mouth four times a day for eighteen months (end point) . The fully evaluable patients (21 controls: 6 women and 15 men, age range 39 to 79 years - mean 64 and 22 treatment cases: 10 women and 12 men, age range 40 to 78 years - mean 61) were analysed as in the previous example.

Administration of the formulation significantly (p<0.01) reduced the incidence of local and hepatic recurrences and significantly (p<0.01) prolonged the survival of patients (number alive at the end of the study: 11 (50%) treatment cases and 5 (24%) controls) . The implications of this study are consistent with those previously made on the direct involvement of free radicals in the mechanism of gastrointestinal cancer and the benefits derived from employing radical scavengers as adjuvant agents for its managment.

Example 9 - Toxicity studies

Solutions of dimethylsulphoxide (DMSO) or methylsulphonylmethane (MSM) in double distilled water were employed to prepare the following compositions:

1. 1% DMSO + 1% MSM

2. 2% DMSO + 2% MSM

3. 5% DMSO + 5% MSM

4. 10% DMSO + 10% MSM

5. 15% DMSO + 15% MSM

Groups of ten Sprague-Dawley rats of either sex weighing 210 to 280 grams were fasted for 24 hours then given one ml of one of the above mentioned preparations by intraperitoneal injection into the left iliac fossa, intramuscular injection or orogastric instillation under light ether anaesthesia. Animals were observed for 24 hours then allowed access to food and drink and observed for another six days. They were then killed by ether overdose and subjected to a full necropsy. The same study was also carried out in the Syrian golden Hamster weighing 150 to 200 grams and in nude mice weighing 40 to 50 grams. In the latter species the fast before and after drug administration was reduced to 12 hours and only 0.25 ml of each preparation was administered.

No deaths occured a oung the groups and discomfort, distress, excitation, drowsiness, withdrawal, depression, vomiting or diarrhoea was not encountered in any case. The necropsy studies showed no changes caused by the medication.

It is, therefore, concluded that the preparations used do not exhibit over a wide dosage range any adverse effects or acute toxicity, thereby making the elected therapeutic range stated in the present invention safe to administer.

In groups of ten healthy male volunteers of an age range between 18 to 30 years, the safety of 5 ml by mouth, four times daily for 10 days, of each of the following preparations (solutions made as detailed above) was examined:

1. 1% DMSO + 1% MSM

2. 2% DMSO + 2% MSM

3. 5% DMSO + 5% MSM

4. 10% DMSO + 10% MSM

5. 15% DMSO + 15% MSM

Physical examination was carried out twice daily and standard hae atology and biochemistry tests (including liver and urinary function tests, blood glucose, serum amalyse, and blood gases) with urine examination were made every day. An electrocardiogram with cardiac enzymes' level estimation were performed every other day.

No toxicity or any significant adverse events were noted in any case, thus, reflecting the safety of these preparations. Moreover, it was also observed that all the doses used were very well tolerated. The clinical safety of the elected therapeutic doses is, thus, established.

It will be appreciated that although the methylsulphonylmethane and dimethylsulphoxide are advantageously used in equal amounts, by weight, in the synergistic compositions of the invention, other ratios may also be used. Generally there is used a ratio of from 10:1 to 1:10, preferably from 5:1 to 1:5, most preferably about 1:1, by weight.

Claims

1. A composition comprising methylsulphonylmethane and dimethylsulphoxide for use in the preparation of a formulation for the treatment of gastrointestinal cancer.

2. A composition according to claim 1 wherein said methylsulphonyl methane and dimethylsulphoxide are present in a ratio of from 1:5 to 5:1 by weight.

3. A composition as claimed in claim 1 or claim 2 which includes a vasodilator.

4. A composition as claimed in any one of claims 1 to 3 which includes at least one of an anti-ischaemic anti-cholinergic and vagal nerve blocking agent.

5. A formulation comprising a composition according to any one of claims 1 to 4 in intimate admixture with a physiologically acceptable carrier therefor, for use in the treatment of gastro-intestinal cancer.

6. A liquid formulation according to claim 5 which contains at least 0.5% w/w of each of methylsulphonyl methane and dimethylsulphoxide.

7. A formulation according to claim 6 which contains from 1 to 10% w/w of each of methylsulphonyl methane and dimethylsulphoxide.

8. An oral formulation according to claim 6 or claim 7 which is in unit dosage form, each unit dose containing from 200 to 1000 mg of each of methylsulphonylmethane and dimethylsulphoxide.

9. A method of treatment of gastro intestinal cancer which method comprises administering an effective dosage of a formulation according to claim 5.

10. A method according to claim 9 wherein said formulation is administered at- least 3 times per day.

11. A method according to claim 9 or claim 10 wherein said dimethylsulphoxide and methylsulphonyl methane are each administered at a dosage rate of from 10 to 400 mg/kg body weight per day.

12. A synergistic composition, which composition comprises methylsulphonylmethane and dimethylsulphoxide, and which composition is substantially free of urea.