GB2281208A

GB2281208A - Treatment of laminitis

Info

Publication number: GB2281208A
Application number: GB9317989A
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: GB9317989D0

Abstract

A composition for the treatment of laminitis in animals which comprises an effective amount of an agent capable of opposing the synthesis of angiotensin, in a physiologically acceptable diluent. The agent may be an ACE inhibitor such as captopril, lisinopril, quinapril, perindopril, fosinopril, ramipril or cilazapril or may be a non-peptide angiotensin receptor antagonist such as losartan.

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 condition and to a method of treatment involving the administration of certain vaso-active agents.

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 enormously 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 disease 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 disease, Yelle in Equine Veterinary Journal (1986) 18(2), 156 - 158 concludes 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. Many laminitic horses require life long attention. A variety of treatments are proposed, including local nerve blocks and analgesics to control pain, antibiotics to control infection, anti-prostaglandins 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 certain agents that oppose the synthesis of angiotensin.

In one aspect, the invention provides a composition for the treatment of laminitis in animals which comprises an effective amount of an agent capable of opposing the synthesis of angiotensin, 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 an agent capable of opposing the synthesis of angiotensin.

In a further aspect the invention comprises the use of an agent capable of opposing the synthesis of angiotensin in the prevention, treatment, or control of laminitis in animals.

Agents capable of opposing the synthesis of angiotensin and of reducing vasoconstriction suitable for use in the present invention can be of several different types but are preferably Angiotensin Converting Enzyme (ACE) inhibitors. It is believed that one of the mechanisms by which vasoconstriction is propagated is that the kidneys become constricted and oversecrete renin. This enzyme cleaves the decapeptide Angiotensin I from the substrate Angiotensinogen. The decapeptide is converted to the potent vasoconstrictor Angiotensin II by Angiotensin Converting Enzyme (ACE). Some of the vasoconstrictor actions can be reversed by the administration of inhibitors which block the receptors and act on the enzymes, especially ACE, involved.A full chemical numbering for the enzymes and ACE inhibitors is given in Figure 11.1 of "The Renin-Angiotensin System" Vol I 1993 Robertson & BR< Nicholls published by Gower; London.

The ACE inhibitor used must, of course, be physiologically acceptable, and have an effect which is not permanent or deleterious. Suitable ACE inhibitors can include short-term activity compounds such as Captopril, but preferably longer-acting compounds such as Enalapril maleate and Lisinopril are used.

The ACE inhibitors can be administered orally, for example in tablet or powder form. In the case of a shortterm activity compound such as Captopril a dose of about 0.71mg/Kg body weight three times daily is preferred during the acute stages of the condition. For a prophylactic dose, an amount of about 0.358mg/Kg body weight three times daily is usually sufficient. For a longer-term activity compound the dose during the acute stage is preferably about 250zg/Kg body weight once daily, and a prophylactic dose is preferably about 10yg/Kg body weight once daily.

Other ACE inhibitors which can be used include, for example, Quinapril, Perindopril, Enalapril maleate, Fosinopril, Ramipril and Cilazapril.

Another group of agents which are capable of opposing the synthesis of angiotensin and reducing vasoconstriction are the non-peptide angiotensin receptor antagonists such as, for example, Losartan.

Treatment with an agent capable of opposing the synthesis of angiotensin can also be used in conjunction with a treatment with l-arginine, or an l-arginine precursor, as described in our copending UK patent application no. entitled "Treatment of Laminitis" the entire disclosure of which is included herein by reference.

In this specification the term "precursor of the biosynthesis of l-arginine" includes physiologicallyacceptable salts of l-arginine such as for example 1arginine 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 1arginine is rapidly metabolised, especially if administered orally.

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 an agent capable of opposing the synthesis of angiotensin, in a physiologically acceptable diluent.

2. A composition according to claim 1, in which the agent is an ACE inhibitor.

3. A composition according to claim 2, in which the ACE inhibitor is Captopril.

4. A composition according to claim 2, in which the ACE inhibitor is Enalapril maleate or Lisinopril.

5. A composition according to claim 2, in which the ACE inhibitor is Quinapril, Perindopril, Fosinopril, Ramipril or Cilazapril.

6. A composition according to claim 1, in which the agent is a non-peptide angiotensin receptor antagonist.

7. A composition according to claim 6, in which the agent is Losartan.

8. A composition according to any of the preceding claims, in which the physiologically acceptable diluent is a tablet base.

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

10. A method for the prevention, treatment, or control of laminitis in animals, which comprises administering an effective amount of an agent capable of opposing the synthesis of angiotensin.

11. A method according to claim 10, in which the agent is an ACE inhibitor.

12. A method according to claim 11, in which the ACE inhibitor is Captopril.

13. A method according to claim 11, in which the ACE inhibitor is Enalapril maleate or Lisinopril.

14. A method according to claim 11, in which the ACE inhibitor is Quinapril, Perindopril, Fosinopril, Ramipril or Cilazapril.

15. A method according to claim 10, in which the agent is a non-peptide angiotensin antagonist.

16. A method according to claim 15, in which the agent is Losartan.

17. A method according to any of claims 10 to 16, in which the agent is administered orally.

18. A method according to any of claims 10 to 17, in which there is additionally administered to the animal l-arginine or an l-arginine precursor.

19. A method according to any of claims 10 to 18, substantially as hereinbefore described.

20. A method according to any of claims 10 to 19, in which there is used a composition according to any of claims 1 to 9.

21. The use of an agent capable of reducing vasoconstriction in the prevention, treatment,or control of laminitis in animals.