IE46952B1 - Method of treating animals - Google Patents

Abstract

Prophylactic and curative treatment of allergic disorders in cats, dogs, pigs, horses and cattle comprises administering a cpd. having activity similar to that of sodium cromoglycate, esp. one of formula (I) or one of their salts (where X is a 3-7C polymethylene chain opt. substd. by OH). Cpds. are used for the relief or prevention of respiratory and pulmonary disorders, neonatal diarrhoea in pigs and calves etc. Pref. dose is 40-80 mg daily by inhalation in calves and pigs. For gastrointestinal disorders the oral dose is preferably 10-200 mg for pigs and 50-500 mg for cattle. For cats and dogs the daily dose is 25-250 mg orally. In an example, epidemic diarrhoea in calves was prevented by treating 10 calves with 100 mg/day of disodium cromoglycate in 100 ml of milk from birth to day 21.

Description

A61K 31/35 O GvvarwMCiM ef lr«Un4 19θ3 complete specification HE BRITISH LIBRAR1 MAR 1984 (34) METHOD OF TREATING ANIMALS SCIENCE REFERENCE LIBRARY PATENT APPLICATION BY (71) FISONS LIMITED, A BRITISH COMPANY, OF FISON HOUSE, 9 GROSVENOR STREET, LONDON, ENGLAND.

Prtct »2ip This invention, relates to a novel method of treatment of animals.

According to the invention we provide a method for the prophylactic or curative treatment of a disease condition 5 having ah allergic basis in cattle, horses, pigs, cats or dogs fchich comprises administering an active ingredient having sodium cromoglycate like activity to cattle or a horse, pig, cat or dog suffering, or liable to suffer, from such a condition.

A compound having sodium cromoglycate like activity is able to inhibit the release of pharmacological mediators which result from the in vivo combination of certain types of anti-body and specific antigen, for example the combination of reaginic antibody and specific antigen (see Exanple 27 of British Patent Specification No 1,292,601 - the rat passive cutaneous anaphylaxis test), the active ingredients may be characterised by the following biological tests and results thereof.

The compound is first tested in the rat passive cutaneous anaphylaxis test. If the compound does not show significant inhibition of allergic manifestations at 20 mg/kg intraperitoneally (i.p.) or intravenously (i.v.) in this test, its activity is generally too low. Various other biological tests may he used to show that the compound exhibits its anti-allergy activity as an inhibitor of mediators of anaphylaxis rather than as, for example an end organ antagonist or anti-cholinergic and adenyl cyclase - 2 4 6952 stimulator. Therefore, tests to see if the compound inhibits the effect of histamine, serotonin, and slow reacting substance of anaphylaxis (SRSA), that is, that the compound is an end organ antagonist of the mediators, may be employed. Such tests are well known and include contraction of guinea pig ileum in the presence of methysergide for serotonin activity. If activity is still observed in these systems, it is due to histamine action. A further check on histamine is through the spectrofluorimetric assay described by Shore, Burkhalter and Cohn, Journal of Pharmacology and Experimental Therapeutics, Vol 127 page 182. Active ingredients according to the invention are not end organ antagonists.

If the results from these tests show that the active ingredient is not an end organ antagonist further tests may be run to show that the compound is not exhibiting its activity through anti-cholinergicity, e.g. by the reversal of acetylcholine induced guinea pig tracheal chain contraction. An active ingredient will not be an anti-cholineTgic.

Specific groups of active ingredients are to be found among the chromone-2-carboxylic acids, and suitable derivatives thereof, e.g. those described in Patent Specification Nos. 3.55Θ6; 29563; 32345 and lfest German Patent Specification No 2,553,688. Other active ingredients are to be found among the xanthones, e.g. of Belgian Patent Nos 759,292 and 787,843 and Dutch Patent Specification Nos 72,09622 and 73,06958; among the compounds of Belgian Patent No 792,867; among the azapurines, e.g. of Belgian Patent No 776,683; the oxazoles, e.g. of lfest German OLS 2,459,380; - 3 46953 and the flavones, e.g. of Belgian Patent No 823,875.

Particularly preferred are the chromones and chxomone like compounds of Patent Specification Nos. 29563; and 32345 and West German Patent Specification No 2,553,688. More specifically we prefer compounds of formula I, therein X is a polymethylene chain containing 3 to 7 carbon atoms inclusive, which chain may be substituted by an -CH group, or a pharmaceutically acceptable derivative thereof.

We particularly prefer l,3-bis(2~carboxychromon-5-yloxy)propan 2-ol or a pharmaceutically acceptable derivative, e.g. salt such as the disodium salt, thereof; this latter is coranonly known as sodium cromoglycate or cromolyn sodium. As further preferred compounds there may be mentioned 6,7,8,9-tetrahydro-4-oxo-10-propyl· 4H-naphtho£T2,3-bJ7pyran-2-carboxylic acid and 6,7,8,9-tetrahydro-S· hydroxy-4-oxo-10-propyl-4H-naphthoZZ2,3-b_Z7pyran-2-carboxylic acid and pharmaceutically acceptable derivatives of either thereof. Suitable pharmaceutically acceptable derivatives include salts, alkyl C I to 10 esters, mono-alkyl C 1 to 10 amides, di-alkyl G 1 to 10 amides or an unsubstituted amide of the 2-carboxylic acid groups. - 4 Specific conditions to be treated by the method of the invention include those in which allergy or immune reactions play a contributory part, for example certain respiratory or pulmonary conditions. In particular there may be mentioned conditions in which antigens are involved and in which there is a shock reaction and slow reacting substance of anaphylaxis (SRS-A) is released. Specifically there may be mentioned broken wind, heaves, chronic obstructive pulmonary disease, laminitis and sweat itch in horses; and fog fever, husk, acute bovine pulmonary emphysema, bovine farmer's lung and respiratory diseases which are due, at least in part, to Respiratory Syncytial Bovine Virus (RSB) in cattle. Ibis latter condition takes tiie form of an influenza like disease with dyspnoea, emphysema and foaming at the mouth. Death occurs within a few hours if no efficient treatment is given. Respiratory conditions in cattle and horses are often associated with damp climates and the feeding or presence of mouldy hay.

In cats and dogs the method of the invention may be used, particularly on oral or topical administration, to treat allergic conditions produced as a response to allergens contained in foods and food additives, in therapeutic agents, in parasitic fungi, produced by bacterial or fungal infection, or as a response to inhaled or contact antigens. Specific symptoms which may be mentioned include pruritis, characterised by excessive scratching, chewing, biting, licking or rubbing at the skin and an exaggerated scratch reflex or skin twitching; self inflicted lesions which vary in shape, size - 5 46952 and distribution; other skin changes, characterised by generalised hyperaemia, papular reaction, oedematous plaques, oedema of head, vulva or extremities; and severe inflammatory changes leading to serous exudation and exfoliation over part of the body. Lesions are most commonly noted on the less hairy areas of the body, but their distribution varies with the agent concerned and the part of the body which comes into direct contact with the allergen. Inhaled allergens can produce ’hay fever' and 'asthma' type reactions· and also conjunctivitis especially in the dog. Allergic contact Τθ dermatitis is encountered most frequently in the dog.

Gastrointestinal disturbances and enteritis in young pigs and cattle can result in neo-natal diarrhoea and fluid loss often leading to death. . Such conditions may be treated by the method of the invention (especially oral administration of active ingredient) as may also diarrhoeas of somewhat older animals which may occur during, or shortly after, the period of liquid feeding.

Such diarrhoeas have an infective and/or viral (e.g. Rotavirus and Coronavirus) and/or hypersensitive aetiology, e.g. caused by soya bean meal, or by endotoxins produced by certain pathogenic serotypes Ζθ of E. coli, or by viruses associated with transmissible gastroenteritis The active ingredient may be administered by any convenient route which will produce adequate blood levels of the active ingredient or which will treat the organ causing the condition, e.g. the respiratory tract,the gut, or the skin, directly. When the 2S condition to be treated is a condition of the respiratory tract the - 6 4 6932 - 7 active ingredient may be administered directly to the respiratory tract, e.g. as a nebulised solution or as a powder aerosol which the animal is caused or forced to inhale. The powder aerosol or the nebulised solution may be administered through the mouth or nose.

Thus the nebulised cloud may be produced by a conventional nebuliser, e.g. comprising an air jet blowing across the open end of a tube the other end of which is situated in the solution to be nebulised, and an inpinger on which the larger drops of nebulised solution are collected. The nebuliser may be powered by a compressed air, nitrogen or oxygen supply or by a hand operated, mechanical or preferably by an electrical pump.

Ihe nebuliser or nebulisers are preferably mounted in a device comprising an inhalation chamber which is adapted to fit over the animals nose and mouth. The device is preferably cylindrical or bag shaped and is preferably made from material, and preferably fairly rigid material, which will be sufficiently robust to be used in veterinary practice, e.g. fiberglass or polypropylene. The device is also preferably provided with one or more ports or valves permitting the animal to exhale with reasonable ease. Ihe device is also preferably provided with means for fixing it over the animal's nose and mouth, e.g. straps to tie behind the head and ears. In order to minimise the loss of nebulised solution from the device, other than by inhalation, the device may comprise means for sealing the inhalation chamber over the animal's face, for example a rubber or flexible seal which fits and can optionally be tightened around the - 7 46952 animal's head, e.g. by means of draw straps. Ihe powder aerosol may be produced by a pressure pack formulation of the active ingredient or by wans of the device of Patent Specification No. 31505, which is commercially available under the Trade Mark 'Spinhaler'. The nebulised solution or the powder aerosol may be transferred from the generating device to the animal's nose or mouth as described above or by means of a flexible tube provided in the case of nasal administration with adaptors for insertion in one or more nostrils, and, in the case of oral inhalation administration with means that will not be crushed in the mouth for transferring the nebulised solution or the powder aerosol to the animal's airways. Ihe active ingredient may also bs administered intravenously, intramuscularly or preferably subcutaneously.

The active ingredient to be administered by the method of the IS invention may if desired be admixed with one or more other conpounds which are tolerated by the animal by the chosen method of administration, for example fcr inhalation administration with water, coarse lactose or, for pressurised aerosol fornulations, with suitable propellants and surfactants. Ihe active ingredient may also be admixed with a compound which prevents the release of SRS-A (Slow Releasing Substance of Anaphylaxis) or antagonises SRS-A when released. Suitable anti SRS-A compounds include diethylcarbamazine. Such mixtures may be used in accordance with the method of the invention. Alternatively the active ingredient may be administered within a short time of, or simultaneously with, ihe administration - 8 46952 of the anti SRS-A compound. Wien diethylcarbamazine is used a dosage of from 15 to 25 ngAg, e.g. 20 mgAg, of animal body weight may be used. For oral administration the active ingredient may be admixed with inert diluents, such as talc, dextran, lactose, calcium phosphate or water, lhe active ingredient may also be admixed with the animal's foodstuff, e.g. milk, or with other matter which it is desired to administer to the animal orally.

Ihus the active ingredient may be admixed with desirable trace elements such as copper, cobalt, manganese or a mixture thereof; with one or more vitamins, e.g. vitamins A, D, Bp B2, Bg, B12, E (or other anti-oxidants) or a mixture thereof; antibiotics (to assist in the prevention of a neonatal scour), for example broad spectrum antibiotics such as chlortetracycline hydrochloride, oxytetracyclin and nitrofurans; absorption aids, e.g. certain amino acids and/or electrolytes; immunoglobulins; or corticosteroids.

Particular compositions for oral administration which may be mentioned are fluid compositions, e.g. a drench, which may be administered with a drenching gun or bottle or a similar device adapted to administer a metered dose to the animal. The drench may be supplied in the form of a wettable powder which can then be dispersed or dissolved in water by the user. Such a powder may compromise the active ingredient, a colloid to make the drench of suitable viscosity for the gun, and a surface active agent to assist dispersion or dissolution of the powder in water. The drench may also be supplied in liquid form in which case it is desirable to - 9 - 10 46952 incorporate a preservative, e.g. chloroform, glycerin or sodium benzoate. The active ingredient may also be presented in the following forms:as a tablet containing active ingredient, binder, moistening 5 agent, disintegrant and lubricant; or as a capsule containing active ingredient, binder, moistening agent and lubricant; or as a pill or bolus containing active ingredient and syrup or treacle; or as a paste containing active ingredient, gum and preservative; or as an aerosol pack containing active ingredient, surface active agent, propellant and optionally water.

The aerosol, drench and paste compositions may also, if 15 desired, contain a suitable flavouring to help prevent rejection of the composition by the animal. The compositions should of course be in such a form that the dosage-required may be administered easily, e.g. as a single unit dose, to the animal. Preferred compositions from the point of view of ease and certainty of oral administration are those which are solids or pastes.

The active ingredient may be administered orally to the animal in conventional manner, for exanple tablets, capsules, pills and boluses may be placed at, or shot or flicked into the back of the animals mouth and pastes may be smeared carefully on tongue, teeth and the inside of the animals mouth. The active ingredient may - 10 > 46953 - 11 also be administered by other teclmiques, for example liquids and pastes may be administered from a bottle or gun adapted to eject a metered dose, and aerosol compositions may also be put up in containers adapted to eject a metered dose. Such bottles, guns s and containers containing a composition comprising the active ingredient form a further feature of our invention.

The oral treatment of gastrointestinal disturbances is most appropriately carried out on young calves and pigs, e.g. during the first 12 weeks, and preferably during the first 21 days, of the animal's life. The calves to be treated for gastrointestinal disturbances are preferably in the weight range 40-60 kg and may be of the type suitable for rearing in intensive fattening units.

Such calves are usually male.

The dosage of active ingredient to be administered will of course vary with the active ingredient, the condition to be treated, with its location and severity, with the method of administration and the size of the animal. However we have found that in general the active ingredient may be administered intravenously, intramuscularly or subcutaneously at a daily dosage of up to about 15 mg/kg, e.g. from 5 to 15 mg/kg, and preferably about 10 mg/kg of animal body weight. Mien i.v. administration is used the administration preferably takes at least 60 seconds. Suitable daily dosages for inhalation administration, e.g. as a nebulised solution, are generally up to 160 mg and are preferably in the range 40 to 160 mg, and more preferably 40 to 80 mg per animal per day. - 11 46858 - 12 For gastrointestinal disturbances we prefer to administer the active ingredient orally. Thus we prefer to administer a daily dosage of up to 1500, preferably from 10 to 500 and more preferably 10 to 200 mg of active ingredient to piglets, and from 50 to 1000 mg, preferably 50 to 500 mg and more preferably about 100 mg of active ingredient to calves. For cats and dogs we prefer to administer a daily dosage of up to 250 mg, and preferably from 25 to 250 mg of active ingredient.

The dosages mentioned above may be administered as split doses 10 froml to 4 times, and preferably once or twice, a day.

Ihe method of the invention when applied to cattle, pigs or horses enhances the weight gain of the animal as compared to untreated animals.

Ihe invention is illustrated, but in no way limited by the 15 following Examples.

Example 1 Chronic Obstructive Pulmonary Disease in the Horse Two horses sensitised to M. faeni were used. The M. faeni challenge is given by nebulising a suspension of spoTes in a Wright nebuliser; directing this spore laden atmosphere via a length of rubber .tubing into a bucket secured to the muzzle of the horse; and finally by the normal inhalation of the animal to the respiratory tract.

Nebulised disodium cromoglycate is administered to the horse by inhalation from a mask attached and sealed to the muz2le. This - 12 4βΑ8» - 13 consists of a plastic bucket into the walls of which, are welded 4 nebuliser units. These are positioned opposite the external nares of the horse and 3-4 inches from the base of the bucket. Into tiie base of the bucket is secured a one way valve to allow exhalation.

S The nebuliser units are situated such that in use they are in the horizontal position. Each unit is charged with 2 mis of disodium cromoglycate It w/v aqueous solution and operated fran a Wright puip from which the flow rate is reduced to 9 litres/idnute by means of a bleed valve.

For the initial trial the horse was treated for four days receiving 80 mg of disodium cromoglycate as a single dose on each of the days. It was then challenged at intervals after the treatment period with M. faeni using clinical appearance, auscultation of the chest and changes in intra-thoracic pressure and in arterial oxygen pressure as the main indicators of response to challenge.

The horse did not react to challenge tp to seven days post treatment period, but was not protected at 4 weeks after the treatment period.

In the second trial the 4 day treatment period with the same levels of disodium cromoglycate afforded protection to the M. faeni challenge at 10 days, but not at 17 days post treatment.

The final trials involved the determination of the protective period of a single treatment of disodium cromoglycate.

In the first of these trials a single dose of 80 mg of disodium - 13 46952 - 14 cromoglycate was protective at 2 days, but not at 4 days post treatment. In the second, a single dose of 160 ng of disodium cromoglycate was protective at 2 days, but not at 4 days post treatment. In the second, a single dose of 160 mg of disodium cromoglycate was not protective 4 days post treatment.

In a second horse the 4 day treatment schedule as above was protective at 10 days post treatment.

Example 2 A diarrhoea epidemic effecting 50¾ of the calves and causing 10 a 101 mortality, despite antibiotic treatment, was experienced in an organisation raising calves for slaughter. of the calves were treated from birth for 21 days with disodium cromoglycate at a daily dose of 100 mg (administered as a single daily dose dissolved in 100 ml of milk).

None of these calves contracted diarrhoea and no cases of death were noted amongst them.

Example 3 A litter of 6 pigs of 3 weeks of age were used. These animals had suffered from diarrhoea since birth and had been treated on two occasions with antibiotics. Each treatment was of 3 days duration and resulted in cessation of diarrhoea for one or two days. pigs were treated with disodium cromoglycate at the rate of 25 mg daily for 3 days, the conpound being administered as a single daily dose dissolved in 5 ml of water.

The diarrhoea ceased in the treated pigs after two treatments - 14 '4 69 52 - 15 and did not recur during the period of observation i.e. 1 week. Exanple 4 Six dogs and one cat were used. Disodium cromoglycate in gelatin capsules containing 25 ng or 100 mg active material were administered orally once a day for the trial period.

Daily clinical observations were made for all animals and changes in skin condition recorded.

Results The response of the individual cases to treatment are detailed below: 1. Cat - Food allergy - Beef Generalised pruritis. Skin macroscopically normal but irritation leading to self-inflicted skin damage following challenge with cooked beef.

Treatment 1 x 25 mg disodium cromoglycate per day, starting 24 hours after the animal was placed on a beef diet. All irritation resulting from the beef was resolved within the following 24 hours. The treatment was continued far seven days during which tine the animal remained in good health with no evidence of irritation despite being kept on the beef diet. Cessation of treatment resulted in a recurrence of irritation. 3. Dog - Retriever Allergy - Severe pollen contact allergy not controlled by steroids after initial success on that therapy. Treatment 1 x 100 mg disodium cromoglycate per day initially, increased to 1 x 200 mg per day. No improvement noted on the lower dose. Seven days later the dose was increased to 200 mg - 15 46952 - 16 disodium cromoglycate per day, when some improvement was obtained. However, the skin thickening and hyperaemia remained and the animal indulged in bouts of scratching. 4. Dog - Alsation Food Allergy - Pork Allergy present for at 5 least twelve months with marked secondary changes and extensive cutaneous staphylococcal infection.

Treatment 1 x 100 mg disodium cromoglycate per day. A slight improvement was noted over the seven day trial.

. Dog - Terrier Food Allergy - cows milk The allergy had previously been well controlled on betamethasone treatment.

Treatment 1 x 100 mg disodium cromoglycate per day. Steroid therapy was replaced by disodium cromoglycate for a four day period. Ihe skin irritation returned but was not severe. 6. Dog - Setter Food Allergy - cows milk The allergy caused generalised skin irritation plus a pollen contact allergy producing regional changes. The animal did not tolerate steroid therapy which resulted in excessive thirst, urination and pseudo pregnancy. Treatment 1 x 100 mg disodium cromoglycate per day. Ihe irritation appeared to lessen over the back during the seven day trial. 7. Dog - Terrier Food Allergy - mutton The condition was well controlled with steroids.

Treatment 1 x 100 mg disodium cromoglycate per day. Fairly good control was obtained during the five day trial after the first 48 hours. 8. Dog - Retriever/Labrador Food Allergy - beef The allergic skin - 16 - 17 46853 condition had an associated bacterial infection.

Treatment 1 x 100 mg disodium cromoglycate per day. lhe clinical allergic condition and bacterial infection responded very well to the treatment.

A device suitable for administration of a nebulised solution to an animal is illustrated in the attached Figure which represents an exploded view of the device.

In the Figure a base plate 1 is provided with two nebuliser nozzle retaining holes 2 into which two nebulisers 3 are adapted to fit. The nebulisers are connected to a compressed air delivery system 4. The base plate 1 is mounted in a frame S in which the compressed air delivery system 4 is supported, lhe frame 5*is provided with toggle clamps 7 which are adapted to fit over the toggle clamp hooks 8 on the inhalation chamber 9. The inhalation chamber 9 is provided wfith two exhalation valves 10, v/ith head strap slots 11 and with press studs 12. lhe inhalation chamber 9 is adapted to fit onto the flexible (rubber) seal 13 by means of the press studs 12 and the flexible seal 13 is provided with a draw tape 14.

In operation the inhalation chamber 9 and the flexible seal 13 are placed owrer the animals head and the frame 5 in which the nebulisers 3 (which hawre been filled v/ith an aqueous solution of active ingredient), the base plate 1 and the compressed air delivery system 4 are mounted is clipped onto the inhalation chamber by means of the clips 7 and the hooks 8. The nebulisers are then - 17 469*3 - 18 actuated and a supply of nebulised solution provided for the animal to inhale for the appropriate time to provide the required dose of active ingredient.

Claims (38)

1. CLAIMS:1. A method for prophylactic or curative treatment of a disease condition having an allergic basis in cattle, hiorses, pigs, cats or dogs which comprises administering an active ingredient having 5 sodium cromoglycate like activity to cattle or a horse, pig, cat or dog suffering, or liable to suffer, from such a condition.

2. A method according to Claim 1, therein the active ingredient is a chromone-2-carbaxylic acid.

3. A method according to Claim 1 therein the active ingredient 10 is a compound of formula I, 0 0 wherein X is a polymethylene chain containing 3 to 7 carbon atoms inclusive, which chain may be substituted by an -CH group, or a pharmaceutically acceptable derivative thereof.

4. A method according to Claim 3, wherein the active ingredient 20 is l,3-bis(2-carboxychromon-5-yloxy)propan-2-ol or a pharmaceutically acceptable derivative thereof.

5. A method according to any one of the preceding claims, wherein the active ingredient is sodium cromoglycate,

6. A method according to Claim 1, wherein the active ingredient is 25 6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho£ 2,3-b_7pyran- 2- 19 469*2 - 20 carboxylic acid or 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl4H-naphthoZ72,3-bJ7pyran-2-carboxylic acid or a pharmaceutically acceptable derivative of either,

7. A method according to any one of the preceding claims, wherein the condition treated is a respiratory condition.

8. A method according to any one of the preceding claims, wherein the condition is a pulmonary condition in which allergy or immune reactions play a contributory part.

9. A method according to Claim 8, wherein the condition is a condition in which antigens are involved and in which there is a shock reaction and slow reacting substance of anaphylaxis is released.

10. A method according to any one of Claims 1 to 6 wherein broken wind, heaves, chronic pulmonary disease, laminitis or sweat itch, is treated in a horse.

11. A method according to any one of Claims 1 to 9, wherein fog fever, husk, acute bovine pulmonary emphysema, bovine farmer's lung or a respiratory disease due to Respiratory Syncytial Bovine Virus is treated in cattle.

12. A method according to any one of Claims 1 to 6, wherein an allergic condition produced as a response to allergens contained in foods and food additives, in therapeutic agents, in parasitic fungi, produced by bacterial or fungal infection, or as a response to inhaled or contact antigens is treated in a cat or dog.

13. A method according to any one of Claims 1 to 6, wherein the - 20 - 21 469S2 condition is a gastrointestinal disturbance or enteritis in pigs or cattle.

14. A method according to Claim 13, wherein the animal is a neo-nate. 5 15. A method according to Claim 13 or 14, wherein the condition has an infective and/or viral, and/or hypersensitive aetiology. 16. A method according to any one of the preceding claims, wherein the active ingredient is administered directly to the oigan causing the condition. 10 17. A method according to Claim 16, wherein the active ingredient is administered directly to the respiratory tract, the gut or the skin. 18. A method according to Claim 17, wherein the condition is of the respiratory tract and the active ingredient is administered

15. As a nebulised solution or as a powder aerosol.

16. 19. A method according to any one of Claims 1 to 15, wherein the active ingredient is administered intravenously, intramuscularly or subcutaneously.

17. 20. A method according to Claim 17, wherein the active 20 ingredient is administered in admixture with,simultaneously with, or within a short time of, a compound which prevents the release of SRS-A or antagonises SRS-A when released.

18. 21. A method according to any one of the preceding claims, wherein the active ingredient is administered in admixture with one or more 25 other compounds which are tolerated by the animal by the chosen - 21 46953 - 22 method of administration.

19. 22. A method according to Claim 21, wherein the active ingredient is administered orally in admixture with talc, dextran, lactose, calcium phosphate, water, the animal's foodstuff, copper, cobalt, manganese or a mixture thereof; one or more vitamins; an antibiotic; an absorption aid; an imunoglobulin; or a corticosteroid.

20. 23. A method according to Claim 21 or 22, wherein the active ingredient is administered in the form of a drench, tablet, capsule, pill, bolus, paste or aerosol.

21. 24. A method according to any one of Claims 1 to 6, 13 to 17 or 21 to 23, wherein a gastrointestinal disturbance is treated in a calf or pig during the first 12 weeks of its life.

22. 25. A method according to Claim 24, wherein the treatment is carried out during the first 21 days of the animal's life.

23. 26. A method according to Claim 24, wherein a gastrointestinal disturbance is treated in a calf in the weight range 40-60 kg.

24. 27. A method according to any one of Claims 1 to 15, 19 or 24 to 26, wherein the active ingredient is administered intravenously, intranuscularly or subcutaneously at a dosage of up to 15 ng per kg of animal body weight.

25. 28. A method according to Claim 27, wherein the dosage is from 5 to 15 mg per kg of animal body weight.

26. 29. A method according to any one of Claims 1 to 18, wherein a dosage of up to 160 mg of active ingredient per animal per day is - 22 48882 23 administered by inhalation.

27. 30. A method according to Claim 29, wherein a dosage of 40 to 160 mg is administered.

28. 31. A method according to Claim 30, wherein a dosage of 40 to 5 80 mg is administered.

29. 32. A method according to any one of Claims 1 to 6 or 13 to 17, wherein a daily dosage of up to 1500 mg of active ingredient is administered to a piglet orally.

30. 33. A method according to Claim 32, wherein the daily dosage is 10 10 to 500 mg.

31. 34. A method according to Claim 33, wherein the daily dosage is from 10 to 200 mg.

32. 35. A method according to any one of Claims 1 to 6, 13 to 17, 19 or 24 to 26, wherein a daily dosage of from 50 to 1,000 mg 15 of active ingredient is administered to a calf.

33. 36. A method according to Claim 35, wherein the daily dosage is 50 to 500 mg.

34. 37. A method according to any one of Claims 1 to 6, 12, 16 or 17, wherein a daily dosage of up to 250 mg of active ingredient 20 is administered to a cat or dog.

35. 38. A method according to Claim 37, wherein a dosage of from 25 to 250 mg is administered.

36. 39. A method according to any one of the preceding claims, wherein the weight gain of cattle, a pig or a horse is enhanced. 25

37. 40. A method according to Claim 1 and substantially as herein - 23 46952 - 24 before described in any one of the Examples.

38. 41. Cattle, horses, pigs, cats or dogs when treated by a method according to any one of the preceding claims.