| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | March 1, 1994 |
| PATENT TITLE |
Method for treating laminitis in equine livestock |
| PATENT ABSTRACT | A method for treating laminitis in equine livestock with tylosin which comprises dosing the equine or delivering to the lower alimentary canal a pharmaceutically effective quantity of an agent comprising tylosin. The method may be used for treating equine livestock which are subjected to a high carbohydrate diet by controlling lactic acid concentration in the hind gut. The agent acts to improve efficiency of feed utilization in the equine by increasing the production of propionate during fermentative digestion in the hind gut and allows feeding to the equine diets containing high levels of a readily fermentable carbohydrate |
| PATENT INVENTORS | This data is not available for free |
| PATENT FILE DATE | September 30, 1992 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED | Rowe, James Baber, Prior Art With Respect to the U.S. Patent application "Treatment of Equine Livestock". |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
I claim: 1. A method of treating laminitis in equine livestock which comprises dosing said equine with a pharmaceutically effective quantity of an agent comprising tylosin. 2. A method as claimed in claim 1 wherein said method is for treating equine livestock which are subjected to a high carbohydrate diet by controlling lactic acid concentration in the hind gut of the animal. 3. A method as claimed in claim 2 wherein said agent is administered regularly throughout the period the animal is subjected to a high carbohydrate diet. 4. A method as claimed in claim 2 wherein said agent is administered in a single dose subsequent to the animal's consumption of an excess quantity of high carbohydrate foodstuff. 5. A method as claimed in claim 1 wherein said agent is administered in a particulate form able to withstand enzymatic digestion in the upper alimentary canal of the animal. 6. A method as claimed in claim 1 wherein uptake of said agent in the caecum is enhanced by administering the agent in a particulate form. 7. A method as claimed in claim 1 wherein said agent is administered in the form of particles of at least 1 mm in size. 8. A method as claimed in claim 1 wherein said agent is administered in the form of particles which are fibrous. 9. A method as claimed in claim 1 wherein said agent is administered orally. 10. A method of treating laminitis as claimed in claim 1, wherein said agent acts to treat laminitis by controlling lactic acid concentration in the hind gut. 11. A method of treating laminitis as claimed in claim 1, wherein said agent acts to improve the efficiency of feed utilization in the equine livestock by increasing the production of proprionate during fermentative digestion in the hind gut and allows feeding to the equine livestock diets containing high levels of a readily fermentable carbohydrate. 12. A method for treating equine livestock which comprises delivering to the lower alimentary canal a pharmaceutically effective quantity of an agent comprising tylosin to increase the production of propionate during fermentative digestion in the hind gut. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
This invention relates to the treatment of equine livestock such as horses, donkeys, ponies, mules and like livestock. In one form the invention resides in an agent for the treatment of equine livestock comprising a glycopeptide antibiotic or a glycolipid antibiotic or a staphylomycin antibiotic or a polypeptide antibiotic or a macrolide antibiotic or a sulphur-containing peptide antibiotic or a lincosamide antibiotic, or tiamulin or a nitrofuran antibiotic or a tetracycline antibiotic or a penicillin antibiotic or a polythiazole antibiotic or ionophore antibiotic or any other antibiotic which are active against gram-positive bacteria or any combination thereof. According to a preferred feature of the invention the agent is for the treatment of laminitis in equine livestock by controlling lactic acid concentration in the hind gut. According to a preferred feature of the invention the agent is for improving the efficiency of feed utilization in equine livestock by increasing the production of propionate during fermentative digestion in the hind gut. According to a preferred feature of the invention the agent is presented in a particulate form which is able to withstand the enzymatic digestion of the upper alimentary canal and enhances its uptake into the caecum. According to a preferred feature of the previous feature the particle size is as least approximately 1 mm in size. According to a preferred feature of the previous feature the particles are of a fibrous nature. According to a preferred feature of the invention the glycopeptide antibiotic comprises avoparcin. According to a preferred feature of the invention the glycopeptide antibiotic comprises vancomycin. According to a preferred feature of the invention the glycolipid antibiotic comprises flavomycin (bambermycin). According to a preferred feature of the invention staphylomycin antibiotic comprises virginiamycin. According to a preferred option of the invention the polypeptide antibiotic comprises bacitracin zinc. According to a preferred option of the invention the polypeptide antibiotic comprises bacitracin methylene disalicylate. According to a preferred option of the invention the polypeptide antibiotic comprises virginiamycin A. According to a preferred option of the invention the polypeptide antibiotic comprises polymixins (B & E). According to a preferred feature of the invention the macrolide antibiotic comprises tylosin. According to a preferred feature of the invention the macrolide antibiotic comprises spiramycin. According to a preferred feature of the invention the macrolide antibiotic comprises virginiamycin M. According to a preferred feature of the invention the macrolide antibiotic comprises josamycin. According to a preferred feature of the invention the macrolide antibiotic comprises spectinomycin. According to a preferred feature of the invention the macrolide antibiotic comprises erythromycin. According to a preferred feature of the invention the sulphur-containing peptide antibiotic comprises thiopeptone. According to a preferred feature of the invention the sulphur-containing peptide antibiotic comprises sulfomycin. According to a preferred feature of the invention the sulphur-containing peptide antibiotic comprises thiostrepton. According to a preferred feature of the invention the sulphur-containing peptide antibiotic comprises sporangiomycin. According to a preferred feature of the invention the sulphur-containing peptide antibiotic comprises siomycin. According to a preferred feature of the invention the sulphur-containing peptide antibiotic comprises taitomycin. According to a preferred feature of the invention the lincosamide antibiotic comprises lincomycin. According to a preferred feature of the invention the lincosamide antibiotic comprises clindamycin. According to a preferred feature of the invention the agent comprises tiamulin. According to a preferred feature of the invention the nitrofuran antibiotic comprises nitrofurantoin. According to a preferred feature of the invention the nitrofuran antibiotic comprises nitrofurazone. According to a preferred feature of the invention the nitrofuran antibiotic comprises furazolidone. According to a preferred feature of the invention the tetracycline antibiotic comprises chlortetracycline. According to a preferred feature of the invention the tetracycline antibiotic comprises oxytetracycline. According to a preferred feature of the invention the polythiazole antibiotic comprises nosiheptide. According to a preferred feature of the invention the antibiotic comprises novobiocin sodium. According to a preferred feature of the invention the antibiotic comprises bottromycin tartrate. According to a preferred feature of the invention the antibiotic comprises streptogramin. According to a preferred feature of the invention the antibiotic comprises nitrovin (payzone). According to a preferred feature of the invention the antibiotic comprises enramycin. According to a preferred feature of the invention the penicillin antibiotic comprises penicillin V. According to a preferred feature of the invention the inophore antibiotic comprises lasalocid. According to a preferred feature of the invention the ionophore antibiotic comprises tetronasin. According to a preferred feature of the invention the ionophore antibiotic comprises naracin. According to a preferred feature of the invention the ionophore antibiotic comprises salinomycin. According to a preferred feature of the invention the penicillin antibiotic comprises ampicillin. In another form the invention resides in a method of treating equine livestock which comprises delivering to the lower alimentary canal a quantity of an agent of the form described above. According to a preferred feature of the invention the method is for treating equine livestock which are the subject of a high carbohydrate diet by controlling lactic acid concentration in the hind gut to prevent laminitis. According to a preferred feature of the invention the agent is administered regularly throughout the period the animal is subjected to a high carbohydrate diet. According to a preferred feature of the invention the agent is administered in a single dose subsequent to the consumption of an excessive quantity of high carbohydrate food stuff. According to a preferred feature of the invention the method is for treating equine livestock to increase the production of proprionate during fermentation digestion in the hind gut. According to a preferred feature of the invention the agent is administered orally. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graphic illustration showing the changes with time of blood D- and L-lactate in four horses dosed with ground wheat (Expt. 1). FIG. 2 is a graphic illustration showing the relationship between blood D-lactate concentration and blood bicarbonate concentration in horses dosed with ground wheat. Samples of blood were taken at 8-hour intervals for 24 hours after dosing (Expt. 1). FIG. 3(a) is a graphic illustration showing the change with time in D-lactate measured in the blood of horses following dosing with ground wheat. The horses in one group (n=5) were treated with virginiamycin (VM) and those in the other received no medication (Control). FIG. 3(b) is a graphic illustration showing the change with time in L-lactate measured in the blood of horses following dosing with ground wheat. The horses in one group (n=5) were treated with virginiamycin (VM) and those in the other received no medication (Control). FIG. 4(a) is a graphic illustration showing the change with time in blood bicarbonate concentration following dosing with ground wheat. The horses in one group (n=5) were treated with virginiamycin (VM) and those in the other received no medication (Control). FIG. 4(b) is a graphic illustration showing the change with time in faecal pH following dosing with ground wheat. The horses in one group (n=5) were treated with virginiamycin (VM) and those in the other received no medication (Control). FIG. 5 is a graphic illustration showing the change with time in heart rate following dosing with ground wheat. The horses in one group (n=5) were treated with virginiamycin (VM) and those in the other received no medication (Control). FIG. 6 is a graphic illustration showing the change in L-lactate concentration with time after the start of incubation of glucose solution with strained equine hindgut digesta. The straight lines show the change in L-lactate concentration following the addition of virginiamycin (10 .mu.g/ml) to the incubation mixture. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The digestive processes in the horse include gastric digestion where enzymes act on the ingested feed in an acid stomach followed by absorption of nutrients from the small intestine and then fermentative digestion in the caecum, colon and large intestine. The volume of the caecum, colon and large intestine can be around 50 to 60 liters and on most diets the end products of fermentation in these parts of the tract provide more than half of the energy available to the animal. The principal end products of fermentation are three volatile fatty acids: acetic acid; propionic acid; and butyric acid. A description of the pathways by which these acids are produced is required in order to understand how modification of their relative importance as end products of fermentation can enhance equine performance. During microbial fermentation, carbohydrates including cellulose, hemicellulose, starch and sugars are first broken down to 6-carbon compounds (hexose). These are then fermented through pyruvate to the volatile fatty acids. From 1 mole of hexose it is possible to obtain 2 moles of acetic acid, or two moles of propionic acid or one mole of butyric acid. When acetic acid is the end product, 2 moles contain 1.75 MJ of energy compared to 3.08 MJ contained in 2 moles of propionic acid and 2.20 MJ contained in one mole of butyric acid. Therefore when the production of propionic acid increase relative to that of acetic and butyric acids, there is more energy available to the animal per unit of carbohydrate fermented. The volatile fatty acids are utilized by the animal through different biochemical pathways in the liver and the body tissues. Acetic and butyric acids cannot be used for the synthesis of glucose. On the other hand, propionic acid is converted by the liver to glucose. Glucose is an essential nutrient for many of the body tissues such as the brain and the kidneys and is also the basic component of glycogen which is the principal store of biochemical energy in the muscle. Glycogen is rapidly broken down to glucose for use by muscle when animals are exercising and its availability may influence the performance of an animal where speed and/or endurance are being tested. Increased propionic acid production in the caecum and colon may therefore enhance the deposition of glycogen. When acetic or butyric acids are produced during fermentation the gas, carbon dioxide, is also produced. Part of this carbon dioxide is converted to the gas methane. Some of these said gasses are absorbed from the gastrointestinal tract and some are expelled as flatus. Under some conditions the gas is produced more rapidly than it is removed and the build-up of gas results in distension of the bowel which causes severe pain (colic) to the animal. A pattern of fermentation where propionic acid production is increased results in less gas being produced and thereby decreases the amount of gas expelled as flatus and also decreases the likelihood of gas accumulation causing colic. When horses consume grain, or any other feed which contains starch or soluble carbohydrate, part of this is digested by fermentation in the caecum and colon. Starch and soluble carbohydrate provide a substrate for bacteria which is rapidly fermented. The direct results of this rapid fermentation include the following changes: increased rate of volatile fatty acid production; decreased pH; increased molar proportion of propionic acid relative to acetic acid and butyric acid; and the accumulation of lactic acid. It is known that associated with the feeding of high levels of starch or soluble carbohydrate to horses are a number of adverse effects on the animal. These (carbohydrate overload) effects on the animal include: adverse behaviour (more time eating wood, and coprophagia); increased testosterone levels; lowered blood pH; decreased blood bicarbonate concentration; a deficit in blood bases; increased body temperature; increased blood lactic concentration and laminitis which can lead to lameness. Laminitis, or founder, is an inflammation of the horses foot. Laminae are located between the bone and the hoof and contain the blood vessels "servicing" the hoof. When inflamed the laminae between these two rigid surfaces swell, causing pressure, pain and tissue damage. Through anterio-venous shunts blood supply to the inflamed tissue is cut off and this results in ischaemic necrosis of the laminae at the front of the hoof. In severe cases the hoof may separate from the underlying laminae or downward rotation of the "coffin" bone in the foot may occur. The biological pathway linking carbohydrate overload with laminitis is not known but there is clear evidence that when high levels of grain or lush green grass are fed laminitis and lameness can result. It has been found that these adverse effects are closely correlated with low pH, and high lactic acid in the caecum and colon. Therefore it is preferred that control of low pH and high levels of lactic acid in the caecum and colon would therefore reduce or remove the adverse effects on the animal when starch or soluble carbohydrate are fed as a major component of the diet. Current nutritional management of equine animals requires that approximately half of the diet is roughage and that only limited amounts of starch are fed. This feeding regime is designed to avoid laminitis which is well known to be associated with too much starch in the diet. If it were possible to feed additional grain (starch) and less roughage, there would be a number of advantages. These are listed below: (i) Reduce the amount of digesta in the hind gut of the horse and thereby reduce the total body weight of the animal without affecting the muscle mass. (ii) Facilitate the practice of "carbohydrate loading" used in the nutritional management of athletes. This practice requires the feeding of starch and soluble carbohydrate prior to racing or performance in order to boost muscle glycogen reserves. (iii) Reduce the cost of feeding horses. Starch-rich grains are cheaper sources of digestible energy than the high quality roughages (hay and chaff) normally required for horse feeding. Lactic acid in the blood and tissues of horses can originate from two sources. (i) It can be formed when glucose is used as an energy source by muscle in the presence of insufficient oxygen for complete oxidation of the glucose to carbon dioxide. (ii) When lactic acid accumulates in the caecum and colon it is absorbed and contributes to total blood lactic acid concentration. A build up of lactic acid in the blood reduces the animal's ability to perform at its full potential and causes pain in the muscles. A secondary effect of blood lactic acid is to reduce appetite and thereby decrease feed intake. Reduced appetite can be an important factor in situations where horses are in training and have extremely high requirements for energy in order to maintain body condition and support extended periods of exercise. Control of lactic acid production during fermentation of carbohydrate in the caecum and colon would reduce the total concentration of lactic acid in the blood and thereby contribute to a reduction in the secondary effects of this metabolite on the animal. There have been a number of studies on development and control of lactic acidosis in sheep and cattle given excessive quantities of readily fermentable carbohydrate. The main lactate-producing bacteria are Streptococcus bovis and Lactobacillus spp. These are Gram+ve organisms and it has been shown that the build up of lactic acid may be controlled through the use of a range of antibiotic compounds specifically active against the Gram+ve bacteria. Nagaraja et al. (1981) reported that lactic acidosis could be controlled in cattle by using the ionophore compounds lasalocid or monensin. Muir et al (1980) demonstrated the control of wheat-induced acidosis in sheep using thiopeptin and related antibiotics, and Aitchison et al. (1986) found avoparcin to be particularly effective in controlling lactic acid in sheep dosed with round wheat. In all of these studies the "end-point" of lactic acidosis control was taken to be an inhibition of lactic acid build up in the rumen fluid. Laminitis is not a major problem in ruminants and in the studies mentioned above no observations were reported on the effect of the antibiotic treatments on any signs of lameness in the animals studied. In addition to the question of whether controlling lactic acid production in the large intestine of horses will protect against laminitis there are also uncertainties in the extrapolation of the use of specific antibiotics, effective in ruminants, to equine livestock. The ruminant is a forestomach fermentor whereas the horse's fermentation compartments are in the hind gut. In the horse all material (feed, bacteria and antibiotics) pass through enzymic digestion in the stomach and small intestine before reaching the main fermentation compartments of the caecum and the large colon. Difference between the two species may therefore be expected in relation to the toxicity of the antibiotics on the host (e.g. monenesin is highly toxic to horses), the substrate to be fermented and the composition of the microbial population carrying out the fermentation. An object of the invention is to modify the pattern of fermentation in the caecum and colon in such a way that: (i) little or no lactic acid is produced; (ii) and the pH remains within normal limits. A second object of the invention is to increase propionate production, relative to acetate and butyrate, during hind gut fermentation. A series of three experiments is hereinafter described which were designed to determine; (i) whether it is possible to control lactic acid accumulation in the hind gut of horses using antibiotics selective against the Gram positive organisms; (ii) whether, by preventing lactic acid accumulation during starch fermentation, laminitis could be controlled; and (iii) whether the production of propionate, during hind gut fermentation, can be increased relative to acetate or butyrate by the action of antibiotics active against Gram+ve organisms. MATERIALS AND METHODS In the first experiment animals were dosed with wheat slurry with and without avoparcin. Lactic acid accumulation in the hind-gut and lameness developed irrespective of the presence of avoparcin. This effectively demonstrated that the results obtained in ruminants could not necessarily be extrapolated to events in the hind gut or large intestine of the equine animal. Based on this result, the second experiment was carried out to screen a range of antibiotics for their effectiveness in controlling lactic acid production in digesta taken from the caecum and large colon of horses. This experimental programme identified virginiamycin as a compound which achieved consistent and effective control of lactic acid build up. The third experiment was conducted to investigate the effectiveness of virginiamycin in controlling lactic acid and laminitis in horses given controlled doses of ground wheat. |
| PATENT EXAMPLES | available on request |
| PATENT PHOTOCOPY | available on request |
|
Want more information ? Interested in the hidden information ? Click here and do your request. |