WO1994005273A1

WO1994005273A1 - Gastrointestinal compositions containing dimethylsulfone and dimethylsulfoxide

Info

Publication number: WO1994005273A1
Application number: PCT/GB1993/001879
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: AU4975093A

Abstract

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

Description

GASTROINTESTINAL COMPOSITIONS CONTAINING DIMETHYLSULFONE AND DIMETHYLSULFOXIDE

The present invention relates to a synergistic composition for use in the treatment and improving the condition of the gastrointestinal tract, and in particular its mucosa.

The aetiopathological processes involved in the causation and development of gastrointestinal diseases are usually diverse and very complicated, thereby rendering therapeutic approaches to these diseases a considerable challege. Consequently, the treatment of such diseases has been based on their individual characteristics rather than on the provision of unified therapeutic formulations which address the broad scope of the pathological processes, thus, minimizing the specifc therapeutic requirements of each individual case. Such an approach would obviously reduce the momentum of the race for newer pharmaceutical agents, with the benefit that human bodies would be less exposed to an ever increasing number of newer chemicals and medicines with their built in adverse potential. This therapeutic approach is very much feasible because it is now recognized that the final common pathway in the mechanism of various gastrointestinal diseases is mediated by specific agents and that sustaining the integrity of the gastrointestinal mucosa opposes the potential for disease development. The present invention offers a unique approach in the management of gastrointestinal diseases by offering synergistic pharmaceutical compositions which remove the mediators of gastrointestinal disease while sustaining the integrity of the mucosa against these diseases and stimulating the repair of any damage already sustained. Therefore, this invention provides protection against and treatment for a large spectrum of gastrointestinal diseases.

The present invention presents a synergistic pharmaceutical composition comprising methylsulphonylmethane with dimethylsulphoxide.

Administration of the compositions of this invention has been surprisingly found to protect the mucosa of the oesophagus, stomach, duodenum and intestines against injury and damage besides enhancing the healing of its acute and chronic injury, inflammation and the various types of ulceration including the stress-induced variety. In addition, this invention sustains the integrity of the oesphageal and gastrointestinal mucosa and protects against the recurrence of their non-mechanical injuries such as those caused by acid-peptic digestion, drugs, inflammatory processes be they specific or non-specific or ulceration whether stress-induced or otherwise.

The compositions of this invention exhibit a synergistic action in that the sum total of the actions of the individual active ingredients is lesε than that achieved by their combination together. In addition, the compositions of the invention exert the beneficial property of adhesion to the mucosa thereby affording prolonged contact with the treatment zone and an enhanced therapeutic delivery.

Advantageously, 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 composition of the invention in intimate admixture with a physiologically acceptable carrier or vehicle for use in the treatment of the oesophagus and gastrointestinal tract.

The carrier or vehicle should be acceptable in terms of exerting no deleterious actions 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:

a. scavenging oxygen-derived free radicals which are the cytotoxic agents involved in tissue damage and injury besides impairing the process of healing and repair.

b. cytoprotection which refers to sustaining the physio-chemical properties of living tissues, thus increasing their resistance to noxious stimuli.

c. biosynthesis and donation of methyl groups and sulphur which effect enhanced repair and healing. 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. Other suitable vehicles are well known in the art and are presented in all its standard publications.

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.

This 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 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 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 the oesophagus and the gastrointestinal tract, dimethylsulphoxide and methylsulphonylmethane are administered at a dosage 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 given 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 per day.

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 solution compositions

For the treatment of the oesophagus and gastrointestinal tract, aqueous solutions were prepared with the following compositions:

A. methylsulphonylmethane dimethy1sulphoxide double distilled water

B. methylsulphonylmethane dimethylsulphoxide menthol crystals double distilled water

The compositions are 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 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 100ml 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 composition 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

Capsules for use in treating the oesophagus and gastrointestinal tract were prepared with the following compositions:

A. methylsulphonylmethane 500mg dimethylsulphoxide 500mg

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

Capsules were prepared at a room temperature of 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 opague or dark coloured glass containers away from direct light and at room temperatures not exceeding 26°c.

Example 3 - Treatment regimens

When the solutions listed under Example 1 were being used, 5ml doses were administered orally every six hours. The capsules listed under Example 2 were taken one every six hours. When the treatment is offered following surgery, administration generally commences on the fifth post-operative day, which is usually the timing of the return to solid food intake by mouth. If administration per rectum is indicated, 5ml of the solutions listed under Example 1 can be given every 6 hours. When this is being done post-operatively, treatment can start 2 days after surgery.

In general treatment is carried out for as long as is thought necessary. For therapeutic purposes it is recommended that stress-induced acute gastric mucosal injury should be treated for 5 days; erosive gastritis should be treated for a similar length of time; reflux oesophagitis is treated for 4 weeks and sometimes 8 weeks; peptic ulceration is treated for 8 to 12 weeks; and ulcerative colitis is treated for about 6 weeks. For symptomatic relief only, e.g. non-ulcer dyspepsia, treatment may be implemented for as short as one to two days, but most preferably for one week. Maintenance therapy on the other hand may be extended for a year or longer.

These therapeutic programmes are also recommended in cases where the formulations of the present invention are being used as adjuvant treatments.

Example 4 - Detailed evaluation of the Compositions

A. In groups of twenty Sprague-Dawley rats of either sex allocated at random and weighing 200 to 270g, the influence of methylsulphonylmethane and dimethylsulphoxide on acute gastric mucosal injury was investigated. Solutions of methylsulphonylmethane(MSM) and/or dimethylsulphoxide(DMSO) were prepared using double distilled water. Solutions were administered into the stomach by gavage under light ether anaesthesia using a 6FG feeding tube. Animals were fasted for 24 hours then 1ml of MSM and/or DMSO or double distilled water was instilled into the stomach. One hour later gavage with 1ml of 40% ethanol or double distilled water was carried out. Animals were killed two hours later, their gastric acid secrection was collected, then analysed for the H⁺output by titration to pH 7.0 with 0.1 M NaOH and their stomachs were pinned out and examined for the extent of alcohol-induced acute gastric mucosal injury (mm² surface area expressed as the mean + the standard error of the mean, SEM, for each group) . The following observations were made:

Treatment % incidence Injury area of animals mm' showing injury (mean + SEM)

distilled water + distilled water 0% distilled water + ethanol 100% 41.6 + 0.9

0.5% MSM + ethanol 90% 32.1 + 1.1 1% MSM + ethanol 80% 24.2 + 0.8 5% MSM + ethanol 60% 17.4 + 0.6 10% MSM + ethanol 60% 15.7 + 0.5 20% MSM + ethanol 60% 15.2 + 0.4

0.5% DMSO + ethanol 80% 30.2 + 0.8 1% DMSO + ethanol 70% 25.7 + 1.1 5% DMSO + ethanol 50% 16.1 + 0.9 10% DMSO + ethanol 50% 15.5 + 0.4 20% DMSO + ethanol 50% 15.2 + 0.3

0.5% MSM + 0.5% DMSO + ethanol 50% 10.1 + 0.9

1% MSM + 1% DMSO + ethanol 20% 4.7 + 0.6 5% MSM + 5% DMSO + ethanol 0% 0 10% MSM + 10% DMSO + ethanol 0% 0 20% MSM + 20% DMSO + ethanol 0% 0 Ethanol disrupts the gastric mucosal barrier causing hydrogen ion back diffusion and coagulative necrosis. The alcohol-induced acute gastric mucosal injury has been shown to be mediated by oxygen-derived free radicals. Dose dependent protection against this injury was afforded by each of DMSO and MSM. Moreover, the combination of these two agents exhibited a synergistic influence on the protection against tissue damage. No influence on the gastric acid secretion was associated with any of these actions.

It is, thus, construed that each of MSM and DMSO exhibit cytoprotection against tissue injury and interact with each other in this respect synergistically. The mechanism of this action is believed to be scavenging oxygen-derived free radicals which mediate tissue damage.

B. The ability of methylsulphonylmethane and/or dimethylsulphoxide to influence the healing rate of the alcohol -induced acute gastric mucosal injury was then investigated. Groups of 20 Sprague-Dawley rats of either sex allocated at random and weighing 200 to 290g were fasted for 24 hours, and then 1ml of 40% ethanol or double distilled water was gavaged into the stomach by orogastric instillation under light ether anaesthesia using a 6 FG feeding tube. One hour, 24 hours, and 48 hours later, animals were similarly gavaged with 1ml of double distilled water or solutions of methylsulphonyl methane (MSM) and/or dimethylsulphoxide (DMSO) prepared in double distilled water. Ten animals from each group were killed by ether overdose six hours after each of the second and third instillations, their gastric acid secretion collected and analysed for the H⁺ output as stated above and their stomachs pinned out and examined to assess the integrity of the mucosa and to determine the presence or absence of injury. The following observations were made ;

Treatment % incidence of animals showing injury (n=20) after the second after the third dose dose

distilled water + distilled water 0% 0%

80% 60% 60% 50% 50% 50%

70% 60% 60% 60% 60%

20%

10%

0%

0% Administration of methylsulphonylmethane and/or dimethylsulphoxide did not influence gastric acid secretion in a significant manner. Thus the actions of these agents is independent of and not mediated via acid secretion. The results show that each of methylsulphonylmethane and dimethylsulphoxide stimulates the healing of acute mucosal damage and that they interact synergistically with each other towards this objective. The enhanced healing being independent of acid secretion suggests mechanisms operating at cellular levels such as biosynthesis, transmethylation, sulphur donation and scavenging the oxygen-dervied free radicals which impair healing by a direct deleterious effect upon tissues.

On the basis of these two sets of experiments it is inferred that methylsulphonylmethane and dimethylsulphoxide protect tissues in vivo against injury (cytoprotection) and enhance the healing of the damage they have incurred, and that these beneficial actions are synergistically enhanced by the administration of DMSO and MSM together. Moreover, it appears that the dosage of each of these two agents as illustrated in Example 1 is optimal.

Example 5 - Clinical trials

Clinical investigations were then carried out on a prospective randomized double blind controlled basis to examine the efficacy of the formulations presented in this investigation against a wide range of digestive disorders and diseases. Controls were given saline unless stated otherwise, and all the medications were administered orally. Randomization was effected by drawing sealed envelopes. The treatment code for each trial was only broken after completion of the study. All the statistical analyses were carried our using the Chi-squared test with Yates' correction.

After excluding the patients who were not fully evaluable, the following observations were made:

A. Patients who had symptomatic endoscopy proven grade I or II reflux oesophagitis with or without hiatus herniation were randomized to receive

(1) saline, 5ml every 6 hours, and placebo, 400mg b.d.,

(2) saline, 5ml every 6 hours, and cimetidine, 400mg b.d. , or

(3) the formulation of Example l.A, 5ml every 6 hours , and cimetidine, 400mg b.d. After treatment for 4 weeks endoscopy was repeated.

While cimetidine (n=25, 18 men and 7 women, age range 24 to 71 years, mean 43) was significantly (p<0.01) more effective than placebo (n=22, 14 men and 8 women, age range 27 to 68 years, mean 45) in stimulating the healing of reflux oesophagitis (5(23%) vs 15(60%)), this advantage was significantly (p<0.01) heightened by the addition of the composition (n=24, 17 men and 7 women, age range 22 to 65 years, mean 40) in that all the patients achieved complete healing and the oesophagus showed an intact mucosa in all these cases.

B. Consecutive patients who presented with a significant degree of dyspepsia existing over a period of a few weeks and who were smokers, were endoscoped and when no apparent upper gastrointestinal pathology was detected (non-ulcer dyspepsia) , they were randomized into one of the following 3 groups and treated for one week then endoscoped again: (1) saline, 5ml every six hours, and placebo, 400mg b.d., (2) saline, 5ml every six hours, and cimetidine, 400mg b.d., or (3) the formulation listed in Example l.A, 5ml every six hours, and cimetidine, 400mg b.d. While cimetidine (n=20, 15 men and 5 women, age range 25 to 66 years, mean 39) was significantly (p<0.01) more effective than placebo (n=22, 14 men and 8 women, age range 21 to 72 years, mean 37) in exhibiting symptomatic relief (3(14%) vs 11 (55%)), addition of the composition siginificantly (p<0.01) enhanced this action and afforded complete symptomatic relief in all cases (n=23, 16 men and 7 women, age range 24 to 67 years, mean 38) .

C. Consecutive patients who were smokers and who had endoscopy proven duodenal ulceration occurring for the first time were randomized into one of 3 groups provided the ulceration was larger than 0.5cm in diameter but not of the giant variety, i.e. >2.5cm in diameter, and treated for 8 weeks then endoscoped again. The study groups received the following treatments: (1) saline, 5ml every 6 hours, and placebo, 400mg b.d., (2) saline, 5ml every 6 hours and cimetidine, 400mg b.d., and (3) the composition listed under Example l.B, 5ml every 6 hours, and cimetidine, 400mg b.d. Thirty-seven patients were randomized to the control group (26 men and 11 women, age range 21 to 70 years, mean 45) , 35 patients were randomized to the cimetidine group (25 men and 10 women, age range 22 to 69 years, mean 47) and 38 patients were randomized to the group receiving the composition of Example IB (27 men and 11 women, age range 20 to 71 years, mean 44) . Cimetidine was significantly more effective than placebo in stimulating the healing of peptic ulceration (25(71%) vs 11 (30%)), an action which was significantly (p<0.01) heightened by the addition of the present invention where complete healing with an intact duodenal mucosa was observed in all the patients at the end of the study. D. Following cimetidine-induced and endoscopy proven healing of duodenal ulceration in smokers, randomization into one of 3 groups was carried out and the patients were instituted on a one year's maintenance therapy. The study groups were: (1) saline, 5ml every six hours, and placebo, 400mg at bedtime, (2)saline, 5ml every 6 hours, and cimetidine, 400mg at bedtime, and (3) the composition described under Example l.A, 5ml every 6 hours, and cimetidine, 400mg at bedtime. Endoscopy was repeated at the end of the maintenance therapy year or earlier whenever symptoms recurred (one or more days of typical ulcer pain) . Twenty-seven patients were randomized to the control group (21 men and 6 women, age range 22 to 68 years, mean 43) , 26 patients were randomized to the cimetidine group (20 men and 6 women, age range 20 to 69 years, mean 46) , and 29 patients were randomized to the group receiving the composition of Example 1A (22 men and 7 women, age range 25 to 71 years, mean 41) . The cumulative relapse rate in the control group during the maintenance therapy year was 63% (17 cases). While cimetidine significantly (p<0.01) reduced this rate (31%, 8 cases), its efficacy was further increased (p<0.01) by addition of the novel composition of Example l.A where the overall relapse rate decreased to 7% (2 cases) .

E. Consecutive patients with multiple simple fractures of the legs and pelvis with signs of haemorrhagic shock were resuscitated using blood and fluids under central venous pressure monitoring, then endoscopy under sedation was performed. Patients having no upper gastrointestinal pathology were randomized to the control (5ml saline every 6 hours) or active treatment (5ml of the composition described in Example l.A every 6 hours) groups. A nasogastric tube was placed in the stomach and aspiration was carried out every 2 hours for 5 days. Patients were allowed restricted fluids orally if there was no contraindication and were given intravenous fluid replacement. All the patients required a general anaesthetic to reduce or internally fix their fractures.

Stress-induced acute gastric mucosal injury in patients showing blood in the aspirate was diagnosed if, at immediate endoscopy under sedation, multiple haemorrhagic ulcers affecting most of the stomach were seen. Fifteen patients were randomized to the control group (10 men and 5 women, age range 23 to 56 years, mean 31) and 16 patients were randomized to the active therapy group (12 men and 4 women, age range 19 to 59 years, mean 29) and treatment lasted for 5 days. Three patients in the control group (20%) developed stress injury of the gastric mucosa 2-4 days after entry into the study. None of the patients in the active treatment group developed this injury, thus reflecting the protective ability of the formulation used.

F. Consecutive patients presenting with haematemesis with or without melena stools after using asprin or other NSAIDs in the previous week were resuscitated, if necessary, then endoscoped under sedation. Erosive gastritis was diagnosed when most of the gastric mucosa showed haemorrhagic inflammation studded with erosions. Patients with this gastritis were randomized to the control (5ml saline every 6 hours) or active treatment (5ml of the formulation listed under example l.A every 6 hours) groups and allowed free fluids by mouth. Patients remaining stable with no further haematemesis were endoscoped again 2 days after commencing treatment to examine the gastric mucosal integrity. These patients were then allowed to start eating solid food. Treatment lasted for 5 days. Twenty patients were randomized to the control group (14 women and 6 men, age range 25 to 70 years, mean 57) and 22 patients were randomized to the active therapy group (17 women and 5 men, age range 23 to 69 years, mean 54) .

Administration of the formulation of this invention was extremely effective in protecting patients against the complications of erosive gastritis and in stimulating its healing.

Further episodes of haematemesis occured in 7 controls (35%) and in 2 active treatment cases (9%) (p<0.01). Of these patients, 4 controls (20%) deteriorated because of large volumes of haematemesis producing shock. Surgical intervention was necessary in 3 of these patients and one of them died in the immediate postoperative period.

The second endoscopy for the cases which remained stable showed evidence of haemorrhagic inflammation, but no erosions, in the stomachs of 7 controls (50%) and 2 active treatment cases (10%) (p<0.01).

G. Consecutive patients with signs and symptoms of an acute attack of moderate severity proctosigmoidal ulcerative colitis which was confirmed histologically, were randomized to the control group (prednisolone lOmg every 6 hours, sulphasalazine 500mg every 6 hours, prednisolone enema 20mg twice every day and placebo-identical in appearance to the capsules of Example 2B - one capsule every 6 hours) or to the active treatment group (same treatment but the placebo was replaced with the capsules listed under Example 2B, one capsule every 6 hours) . Remission or recovery from attacks indicates that the patient has become free of symptoms and has no diarrhoea; flexible sigmoidoscopy shows no contact bleeding or deeply congested mucosa discharging blood, mucus, or pus; haematological and biochemical data return to normal values; and histological examination shows the disease to be inactive. Patients were given a low residue and milk-free diet, which is high in protein and calories, until their attack had subsided. Progress was determined by monitoring the physical condition of the patient, the bowel frequency, passage of blood, mucus or pus via the rectum, by sigmoidoscopy (once every week over the first 4 weeks and then at 6 weeks and 8 weeks after commencing treatment; the colorectal mucosa was always biopsied after clinical recovery from the attack) ; and by regular haematological and biochemical investigations. Once the symptoms ceased, the patients continued using their therapeutic regimen for another month (end point of the study) and thereafter the administration of corticosteroids was tapered off over the following 3 weeks.

Fifteen patients were randomized to the active treatment group (8 women and 7 men, age range 18 to 59 years, mean 31) and 17 patients were randomized to the control group (9 women and 8 men, age range 20 to 61 years, mean 34) remission and complete recovery from the acute attack of ulcerative colitis was achieved within 3 weeks in all the active therapy cases (100%) , an event occurring in only 10 controls (59%) at the end of this time period (p<0.01). The ability of the composition of the invention to control the acute attacks of ulcerative colitis and to enhance the colitis healing is, thus, demonstrated. Example 6: Toxicity studies

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

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 using animals 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 0.25ml of each preparation were administered.

No deaths occurred among 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 confirming that the therapeutic doses used in Examples 3 and 5 of the present invention are safe to administer.

In groups of ten healthy male volunteers of an age range between 18 to 30 years, the safety of 5ml 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 undertaken twice daily and standard haematology and biochemistry tests (including liver and renal 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 for the compositions of this invention 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 prophylaxis or treatment of gastrointestinal injury.

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 or prophylaxis of gastro-intestinal injury.

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. An inhalation formulation according to claim 5 which includes a smoking product, formed and arranged for delivery of the methylsulphonylmethane and dimethylsulphoxide in the smoking product smoke, in use thereof.

10. A method of treatment or prophylaxis of gastro intestinal injury which method comprises administering an effective dosage of a formulation according to claim 5.

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

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

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