GB2281207A

GB2281207A - Treatment of laminitis with l-arginine

Info

Publication number: GB2281207A
Application number: GB9317943A
Authority: GB
Inventors: Ian William Henderson; Karen Ann Hinckley
Original assignee: University of Sheffield
Current assignee: University of Sheffield
Priority date: 1993-08-28
Filing date: 1993-08-28
Publication date: 1995-03-01
Also published as: GB9317943D0

Abstract

A composition for the treatment of laminitis in animals which comprises an effective amount of l-arginine, or a precursor of the biosynthesis of arginine, in a physiologically acceptable diluent. Preferably l-arginine hydrochloride or the precursor l-citrulline are used.

Description

TREATMENT OF LAMINITIS This invention relates to the treatment of laminitis and is more particularly concerned with novel compositions for the prevention and control of the disease and to a method of treatment involving the administration of certain amino acids and precursors thereof.

Laminitis is a disease affecting the peripheral vasculature of the feet in hooved animals. It is common in cattle and horses, and is a major cause of temporary and permanent lameness. Laminitis can be extreme in horses and euthanasia is often justified. The severity of the disease varies but can be most severe in horses because of the anatomical arrangement of the vasculature within the equine hoof. Cattle and horses have a high incidence of the disease which results in considerable economic losses.

The pathophysiology of the developmental, acute and chronic stages of the disease are not known. However, the pathogenesis of the condition in all species seems to be similar. For example, there is a strong association between dietary habits and the onset of the disease. The nutritional aspects of laminitis are akin in both horses and cattle; high protein and/or carbohydrate diets are aetiological factors in the condition.

In a review of the concepts and current therapy of the condition, Yelle in Equine Veterinary Journal (1986) 18, 156 - 158 concluded that laminitis should be considered as an emergency condition requiring immediate therapy. The acute phase of the disease may be protracted and incur large expenses usually with a poor prognosis. Nany laminitic horses require life long attention. A variety of treatments are proposed, including local nerve blocks and systemic analgesics to control pain, antibiotics to control infection, non-steroidal anti-inflammatory drugs (NSAIDs) to control shock and padding to maintain local hoof integrity.

Nevertheless, as will be appreciated from the above, there is still no effective treatment for laminitis which continues to cause considerable suffering in animals and substantial expenses to their owners. There is therefore a need for more efficacious treatment, control and prevention of the condition.

According to the present invention the onset of laminitis in susceptible animals is delayed or substantially prevented, and the condition substantially improved by administration of l-arginine or an l-arginine pre-cursor.

In one aspect, the invention provides a composition for the treatment of laminitis in animals which comprises an effective amount of l-arginine, or a precursor of the biosynthesis of l-arginine, in a physiologically acceptable diluent.

In another aspect the invention provides a method for the prevention, treatment, or control of laminitis in animals, which comprises administering an effective amount of l-arginine or a precursor of the biosynthesis of 1arginine.

In a further aspect the invention comprises the use of l-arginine or a precursor of the biosynthesis of l-arginine in the prevention, treatment, or control of laminitis in animals.

In a still further aspect, the invention provides a dietary supplement for the prevention, treatment or control of laminitis in animals which comprises an effective amount of l-arginine, or a precursor of the biosynthesis of 1arginine.

In this specification the term "precursor of the biosynthesis of l-arginine" includes physiologicallyacceptable salts of l-arginine such as, for example, 1argine hydrochloride and compounds which can be metabolised into l-arginine in the body. Of particular significance in this latter connection is l-citrulline which is metabolised to produce l-arginine, and this is the preferred compound for administration in accordance with the invention. L citrulline is preferred because l-arginine is rapidly metabolised, especially if administered orally.

The l-arginine or pre-cursor can be administered as a systemic treatment for example in a buffered aqueous saline and/or glucose isotonic solution. The equine dose is preferably in the range of from 0.072g/Kg body weight to 0.4g/Kg body weight per treatment. The solution can, for example, comprise from 3 to 15% by weight (0.l4mol/L to 0.7lmol/L) of l-arginine, or its precursor, preferably around 15% by weight, in a solution of pH from 7.2 to 7.6.

Solutions of physiologically-acceptable salts of 1arginine, such as, for example, l-arginine hydrochloride are preferred, as the free base is strongly alkaline.

Intravenous treatment will normally be via the jugular vein, with a daily dose of from 500ml to 3 litres of solution. Systemic treatment can also be applied by oral administration, by intramuscular administration, or by intra-nasal spray.

Oral administration of l-arginine, or a pre-cursor thereof, in a daily amount of, for example, from 10 to 500 grams, can be used for control of the condition and as a prophylactic treatment.

As a dietary supplement the l-arginine, or pre-cursor thereof, can be admixed with the animal's daily feed or formulated as an oral paste. A suitable dietary supplement for admixture with the feed may comprise, for example, 1citrulline, electrolytes such as sodium chloride, methionine and biotin (hoof growth promoters/enhancers), calcium carbonate or calcium gluconate, and preferably also l-arginine. Lysine in the feed of animals suffering from laminitis should be eliminated or at least substantially minimised.

A typical daily dietary supplement for horses suffering from laminitis may include, for example: Compound Amount gmsiKa bodv weight l-citrulline 100.0 sodium chloride 11.0 potassium chloride 11.0 methionine 3.0 calcium carbonate 22.0 calcium gluconate 15.0 l-arginine 30.0 biotin 8.0 This may be administered together with a feed comprising a mixture of chopped and dried Alfalfa together with small quantities of low protein horse and pony cubes; and hay.

For an animal suffering from the acute or chronic stages of the disease, the amount of l-citrulline may be increased to up to 1000 gms/day, although the daily dose for an average weight horse is usually about 200gms/day.

As a prophylactic, an average daily dietary supplement may comprise, for example: Compound Amount qms/Kq bodv weight l-citrulline 60.0 sodium chloride 11.0 potassium chloride 11.0 methionine 3.0 calcium carbonate 22.0 calcium gluconate 15.0 l-arginine 20.0 biotin 8.0 For an average weight horse, this would provide a daily dose of l-citrulline of about 150 grams.

In addition to the treatment with l-arginine, or a pre-cursor thereof, it is also frequently found to be advantageous to use additionally an agent capable of reducing vasoconstriction, for example by opposing the synthesis of angiotensin, and particularly an Angiotensin Converting Enzyme (ACE) inhibitor, for example in tablet form. Treatment with ACE inhibitors and other opponents of angiotensin synthesis is described in more detail in our co-pending patent application number t ) entitled "Treatment of Laminitis". Suitable ACE inhibitors include Captopril, Lysinopril, and Enalapril maleate, and other suitable agents include non-peptide angiotensin antagonists such as Losartan.

Treatment with short-acting ACE inhibitors such as, for example, Captopril can be given at a dose of about 0.72mg/Kg body weight three times daily. Preferably, however, longer-acting ACE inhibitors are given, at a daily dose of from 10 to 250yg/Kg body weight.

It is often found advantageous to include in the composition or dietary supplement of the invention or to administer in conjunction therewith, an agent capable of reducing blood plasma levels of orotic acid. Suitable orotic acid level lowering agents include, for example, sodium benzoate and sodium phenylacetate. Preferred dosage levels are in the range of from 0.25 to 10 milligrams/Kg body weight.

It may also be found to be useful to include in the treatment potentiated charcoal, which can be administered orally and which can reduce levels of toxins in the gut.

A further group of compounds which may usefully be included in the treatment are non-peptide endothelin (ET-1) antagonists. Such compounds may be added to the compositions of the invention for intravenous, intravascular, or intra-nasal sprays, or administered orally or as part of a dietary supplement.

Oral administration of l-citrulline can conveniently be achieved by feeding the animal water melon (citrullis vulgaris) in which it is present in substantial quantities (100mg per bog), and this is accordingly a further aspect of the invention.

Where sodium benzoate is administered orally, this may be done by feeding cranberries, which contain high levels of this compound.

The invention can be applied to the treatment of cattle and horses, and is of particular value in the treatment of many equine breeds.

The reader's attention is directed to all papers and documents which are filed concurrently with this specification and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

All the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps or any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive.

Each feature disclosed in this specification (including any accompanying claims, abstract and drawings), may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

Claims

1. A composition for the treatment of laminitis in animals which comprises an effective amount of l-arginine, or a precursor of the biosynthesis of arginine , in a physiologically acceptable diluent.

2. A composition according to claim 1, in which the 1argine precursor is l-arginine hydrochloride.

3. A composition according to claim 1 in which the 1arginine precursor is l-citrulline.

4. A composition according to any of the preceding claims, in which the l-arginine, or l-arginine precursor, is present in an amount of from to 3 to 15% by weight.

5. a composition according to any of the preceding claims, in which the physiologically acceptable diluent is a buffered aqueous saline or glucose isotonic solution.

6. A composition according to claim 5, in which the solution has a pH of from 7.2 to 7.6.

7. A composition according to claim 5 or 6, which comprises a daily dose of from 500ml to 3 litres of the solution.

8. A composition according to any of the preceding claims that is formulated for intravenous or intramuscular administration, or as an intra-nasal spray.

9. A composition according to any of the preceding claims, that also comprises sodium benzoate or sodium phenylacetate.

10. A composition according to any of the preceding claims substantially as hereinbefore described.

11. A method for the prevention, treatment, or control of laminitis in animals, which comprises administering an effective amount of 1-arginine or a precursor of the biosynthesis of l-arginine.

12. A method according to claim 11, in which the 1arginine precursor is l-arginine hydrochloride.

13. A method according to claim 11, in which the 1arginine precursor is 1-citrulline.

14. A method according to any of claims 11 to 13 in which the 1-arginine, or 1-arginine precursor, is administered as a systemic treatment.

15. A method according to claim 14, in which the 1arginine, or l-arginine precursor is administered by intravenous or intramuscular injection, or by an intranasal spray.

16. A method according to any of claims 11 to 14, in which the 1-arginine, or 1-arginine precursor, is administered orally.

17. A method according to claim 16, in which the 1arginine, or l-arginine precursor, is administered in a daily amount of from 10 to 500 gms.

18. A method according to any of claims 11 to 17, in which there is also administered sodium benzoate or sodium phenylacetate.

19. A method according to any of claims 11 to 18 in which there is additionally administered an Angiotensin Converting Enzyme (ACE) inhibitor.

20. A method according to claim 19, in which the ACE inhibitor is administered in a daily dose of from 10 to 250 yg/Kg body weight.

21. A method according to any of claims 11 to 20 substantially as hereinbefore described.

22. A method according to any of claims 11 to 21 in which there is used a composition according to any of claims 1 to 10.

23. The use of 1-arginine, or a precursor of the biosynthesis of 1-arginine, in the prevention, treatment, or control of laminitis in animals.

24. A dietary supplement for the prevention, treatment, or control of laminitis in animals, which comprises an effective amount of 1-arginine, or a precursor of the biosynthesis of 1-arginine.

25. A dietary supplement according to claim 24, in which the 1-arginine precursor is 1-arginine hydrochloride.

26. A dietary supplement according to claim 24, in which the l-arginine precursor is l-citrulline.

27. A dietary supplement according to claim 26, which comprises: Compound Amount amstRa body weight 1-citrulline 100.0 sodium chloride 11.0 potassium chloride 11.0 methionine 3.0 biotin 8.0 calcium carbonate 22.0 calcium gluconate 15.0 l-arginine 30.0

28. A dietary supplement according to claim 26, which comprises: Compound Amount amsiK bodv weight l-citrulline 60.0 sodium chloride 11.0 potassium chloride 11.0 methionine 3.0 calcium carbonate 22.0 calcium gluconate 15.0 l-arginine 20.0 biotin 8.0

29. A dietary supplement according to any of claims 24 to 28, that also comprises sodium benzoate or sodium phenylacetate.

30. A dietary supplement according to any of claims 24 to 29 substantially as hereinbefore described.

31. A composition according to any of claims 1 to 10, that also comprises a non-peptide endothelin (ET-1) antagonist.

32. A method according to any of Claims 11 to 22, in which there is also administered a non-peptide endothelin (ET-1) antagonist.

33. A dietary supplement according to any of claims 24 to 30, which also comprises a non-peptide endothelin (ET-1) antagonist.