NZ231758A - Treating bloat and/or increasing milk yield using crystalline monensin - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £31 753 231758 XX/We,- ELI LILLY AND COMPANY a Corporation organised and existing under the laws of the State of Indiana of Lilly Corporate Center, City of Indianapolis State of Indiana, United States of America, hereby declare the invention for whichxi / we pray that a patent may be granted to rt4*/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - , v~.v,."w"*-''v \ - - " 23175 o o TECHNICAL FIELD The present Invention relates to methods of treating bloat in cattle and also to methods of improving milk yield in dairy cattle. 5 BACKGROUND ART For most dairy farmers, and some beef farmers bloat is part of farming. In some herds it is a daily problem and a major threat to herd profitability.

Bloat is a disease affecting cattle and in severe seasons, upto 5°/. of 10 animal losses can be expected. Many chemical treatments have been tested for bloat control and several non-ionic detergents have been licensed as effective safeguards. A current treatment such as bloat blocks is used but with limited effects. Various bloat prevention measures have also been considered by many cattle producers including grazing management to avoid 15 clover dominant areas. In extreme cases, herbicides are also used to suppress clover growth.

Monensin, 2-[5-ethyltetrahydro-5-Ctetrahydro-3-methyl-5-[tetrahydro-6-hydroxy-6-(hydroxymethyl )-3,5-dimethyl-2H-pyran-2-yl ]-2-furyl ]-2-furyl 3-9-hydroxy-beta-methoxy-alpha, gamma, 2,8-tetramethyl-l,6-dioxasp1ro[4.5] 20 decane-7-butyric acid is described in Australian Patent No. 290 883 as an anticoccidiostat. The compound is used in lot fed cattle operations around the world to improve feed efficiency and weight gains (growth promotant for ruminants). That patent also describes the crystalline form of monensin.

Monensin alters the microbial population and the fermentation pattern O/ 25 in the rumen. The natural end products of the fermentation processes are a range of volatile fatty acids that the ruminant uses as a source of energy. The addition of the monensin: 1. Improves the efficiency of conversion of feed to fatty acids and produces a greater proportion of propionic acid which is a superior energy O 30 source for growth. This accounts for greater growth rates of treated cattle. 2. Decreases the production of gas particularly methane and thus reduces the chances of bloat. Reduction of methane production and expulsion by ruminants is very desirable from an environmental view point as It is a "greenhouse" effect gas. 3. Controls the rate of fermentation in the rumen to prevent the "rush" of fermentation thought to contribute to bloat.

TCW/723v 231 4. Controls the rumen protozoal population preventing the rapid proliferation of protoza thought to contribute to bloat.

The carrier material in the capsule, a non-ionic hydrophilic polyglycerol ester, reduces surface tension, hence foam does not build up in large volumes.

The fear of bloat is a major factor in preventing cattlemen from undertaking pasture improvement programs based on leguminous plant species for these can precipitate bloat. As well, to protect the cash flow of an efficient beef cattle enterprise, many cattlemen put their best cattle on their worst pastures in bad bloat times. Both these management decisions markedly reduce the potential efficiency of beef cattle enterprises. This invention allows major production improvements to occur with pasture fed beef cattle for the first time.

Milk Yield The increasing of milk yield from dairy cows has been the focus of great attention for decades if not hundreds of years. The use of breeding genetics and elaborate government backed recording systems together with pasture improvement schemes has allowed much progress and has kept whole, fresh milk affordable by all. Being able to increase milk yield at strategic times of the year is a very desirable goal. Premium prices are paid to dairy farmers who can produce more milk in winter (say) or to allow factory processing efficiencies. This is partially achieved today by supplying concentrate feed and feed silage to the dairy cows.

DISCLOSURE OF THE INVENTION Cattle suffering from clinical and sub-clinical bloat show a decrease in growth rate (0.2 kg/animal/day) and in milk production.

The present invention provides a method of treating bloat in pasture-fed cattle requiring said treatment which method comprises administering to the rumen Of said cattle, crystalline monensin, in a sustained release capsule, in an amount effective to control bloat.

The invention also provides a method of increasing milk yield in dairy cows which comprises administering to the rumen of said dairy cows a milk production enhancing amount Of crystalline monensin in a sustained release capsule. 231758 As indicated above, the monensin is administered in a sustained release capsule. The capsule may be a device as described in US 4 312 347, US 4 381 780, US 4 439 197, US 4 507 115, US 4 642 230, US 4 671 789, US 4 675 174, US 4 717 718, US 4 867 980, .EP 0 016 241, EP 0 061 783, EP 0 062 391, EP 0 079 724, GB 1 316 998, WO 82/00094, AU 539 868, AU 558 009, AU 580 782, AU-A 90108/82 or the anti-bloat capsule described herein. Preferably the capsule is the anti-bloat capsule described herein.

Dosage The Anti-Bloat Capsule provides a continuous release of monensin into the rumen of cattle for a period of approximately 100 days with only one dosing of the animal. We have determined that dosage rates from 170 mg/day 23175 to over 380mg/day have a significant effect on bloat and also result 1n weight gain of beef cattle. We have determined that 300mg/day is a preferred dosage rate and that this rate provides an increase in milk, production of economic significance. ^ 5 It is important that 7 days be allowed after administration to allow the optimum concentration of monensin to be achieved in the rumen from the constant payout of the device.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is an illustration of a bloat capsule capable of being used in 10 the practice of the invention.

^ BEST MODE AND OTHER MODES FOR CARRYING OUT THE INVENTION The capsule illustrated in Figure 1 can be filled with the appropriate dose for use in treating bloat or for improving milk, yield. Figure 1 shows a capsule 1 having a roughly cylindrical body 2 and 15 including wings 3 at one end and an opening 4 at the other end. The opening 4 is covered with a cap 5 which is removed prior to administering the capsule 1 to the animal. The body 2 includes a piston like member 6 and a spring 7 which forces the monensin 8 towards the opening 4 when the capsule 1 is in the animal's rumen. A hole 9 is provided adjacent wings 3 20 to permit pressure equalization.

In use, plastic cap 5 is removed from the capsule 1. The wings 3 are folded along the capsule body 2 and secured in place by means of a cardboard ring (not shown). The capsule is administered by means of a tool comprising a cavity adapted to hold the capsule and a plunger adapted to v-' 25 insert the capsule into the animal's throat.

For administration of the capsule, the animal is restrained and the head of the tool containing the capsule is introduced into the animal's mouth avoiding the front teeth. Once inside the animal's mouth, the tool ^ is straightened so as to avoid the back teeth. The tool is then inserted past the base of the tongue. As the animal swallows, its tongue comes forward and the tool is able to be moved over the base of the tongue. Once the tool is passed the base of the tongue, the capsule is ejected from the tool by slowly pressing the plunger without applying force. The animal is permitted to swallow before the tool is removed to ensure that the capsule 35 reaches the rumen. In some instances, the animal may disgorge the capsule. It is thus preferred that the treated animals be kept in pens under observation for a short period following administration of the TCW/723V 23175 capsule.

The preferred capsule according to the invention is approximately 16cm long and contains 32g monensin as the sodium salt. Such a capsule is capable of continuously administering monensin into the rumen at a 5 regulated rate for about 100 days. The capsules can be conveniently moulded from a flexible plastics material such as polypropylene.

It is preferable that milk does not contain residues from the device.

The following examples are provided in order that the invention may be fully understood. Such examples are not to be construed as being ^ 10 limitative of the invention. ^ EXAMPLE 1 COMPOSITION The active ingredient is mixed with the carrier in a jacketed agitated vessel with vacuum applied. It is important to remove all air 15 bubbles in the manufacturing process. The hot mixture is pumped to silicone rubber moulds to form the core. After cooling in a refrigerated apparatus, the core is removed from the mould and placed in the empty plastic body of the capsule which has previously been treated with silicone fluid. With the core in place a plastic piston is placed on top of the 20 cotton wool core. A metal spring and capsule cap with wings in place is added and used to compress the spring. The cap and body are snapped together and spin welded. After testing, the capsule is sealed in a polythene bag and packaged in a fibreboard container for sale. ^v Also supplied with each capsule is a cardboard ring which is used to ' 25 secure the wings to the body of the capsule for administration. This ring dissolves within minutes in the rumen allowing the wings to regain their "spread" configuration. This ring is very important from an animal safety viewpoint in assisting easy administration. It is also an efficient and ^ practical method of utilising the inherent memory of the polypropylene wings of the device in returning to the desired "spread" position rapidly to prevent regurgitation from the animal.

EXAMPLE 2 Twenty lactating cows (averaging 378 kg live weight) were challenged with bloat twice daily over an 8 day uniformity period then allocated to 35 one or two treatment groups: Without capsule - untreated, control With capsule - treated with one monensin capsule per cow.

TCW/723V r> 23 The capsules were administered orally to 6 of the cows and via a rumen fistula to the remaining 4 cows in the treatment group. Treated and untreated cows were challenged with bloat twice daily on 13 days over an 18 day period. There was a delay of 6 days between capsule administration and 5 the first bloat challenge.

After each milking (milked at 0800 h and 1530 h each day) the cows were grazed on bloat-potent feed for 1 to 2 h. At other times they were grazed on pasture which did not cause bloat. The bloat-potent feed included lucerne (Medicago sativa) and pasture containing red clover 10 (Trifolium pratense L.). The non-bloating pasture contained ryegrass (Lolium perenne L.), white clover (Trifolium repens) and paspalum (Paspalum dilatatum Poir).

The cows were scored for bloat during 1 to 2 h following the start of grazing on lucerne or red clover. The highest score observed over the 15 scoring period was recorded for each cow. The scoring was based on a visual assessment of bloat. (In 1954 Dr A J T Johns, devised a simple method of bloat scoring which is still being used. The method relies primarily on visual assessment. The observer stands end on to the animal so that the line of the animals' flanks can be seen. Any distension of the 20 flanks can be seen). Any distension of the flanks at the level of the pin bones indicates bloat. On a scale from 0 (no bloat) to 4 (severe bloat requiring treatment to prevent death) with half scores above 1 included.

Cows showing any distress due to bloat or showing no sign of deflation during the 1 h following the scoring period were drenched with 25 paraffin oil, in 20 ml doses. Repeated doses were given if required.

Moderate to severe bloat was experienced during the experiment. The average daily bloat score significantly lower for cows with capsules than for those without (Table 1).

TABLE 1 The number of occasions on which cows scored 0, 1-2 and 2.5-3.5 in each group expressed as a percent of the total number of scorings in the group during the uniformity and experimental periods.

Score Q 1-2 2.5 - 3.5 Period Unif. Exper. Unif. Exper. Unif. Exper.

Without capsules 43 46 43 30 14 24 With Capsules 41 83 51 15 8 1 TCW/723V o 23 1 7 58 O 5 0 10 O 15 Bloat scores for individual cows ranged from 0 to 3.5. Prior to administration of capsules, 41-437. of the scorings were cows that were not bloated (Table 1). After treatments were imposed the proportion of cows that were not bloated increased to 837. in the group with capsules. There were decreases in the proportion of cows showing mild bloat (scores 1-2) and moderate to severe bloat (scores 2.5-3.5) in cows with capsules compared to the control cows and compared to the uniformity scores. Two cows with capsules showed moderate to severe bloat, scoring 2.5 and 3.0. The latter of these required treatment to relieve bloat. Both occurred during the same scoring period.

EXAMPLE 3 The monensin capsule significantly reduced both the Incidence and severity of bloat. Deaths were reduced by 80%.

TABLE 2 Summary of Bloat Scores and Bloat Deaths of Fifteen Trials in Beef Cattle AVERAGE BLOAT SCORE No. OF BLOAT DEATHS Treatment (Scale 1 - 4 ) Control 2.89 17 ABC 1.21 3 Treatment Effect/ Difference 1.68 14 EXAMPLE 4 Milk yield and composition data for weeks 2, 3 and 4 following administration of capsules were analysed using data from the 2 weeks prior to capsule treatment as covariates.

Milk yield and protein yield averaged over weeks 2 to 4 following capsule administration were higher in cows with capsules than in those without (Table 3). The percentage of fat was lower in milk from cows with capsules than from those without. The two groups did not differ in fat yield.

TABLE 3 Milk composition and daily yields (kg/cow) of milk and its constituents for cows with and without capsules.

TCW/723V o 2317 58 With Capsule Without Capsule Standard Errors - Milk Yield 8.7 Fat Yield 0.37 Protein Yield 0.33 Fat% 4.32 Protein*/. 3.78 7.9 0.38 0.30 4.68 3.78 0.4+ 0.02ns 0.01 + 0.18+ 0.04ns ns - not significant + - P <0.10 EXAMPLE 5 INCREASED GROWTH Giving one device orally using the monensin capsule administration tool at any time of year. Data showing the effect of growth after administration of monensin.

TABLE 4 Summary - Liveweight Data (kg) LIVEWEIGHT kg OVERALL (93.7 DAYS) TREATMENT INITIAL FINAL GAIN A.D.G.

Control 294.4 Monensin 299.0 Treatment Effect Difference 402.7 415.8 108.3 116.8 +8.5kg 1.156 1.247 +0.091kg Use of the monensin capsule resulted in an increase in weight gain, on average, of 8.5kg per head. At $1.00 per kg liveweight, that more than 10 covers the cost of the capsule.

EXAMPLE 6 THE EFFECTS OF MONENSIN CONTROLLED RELEASE CAPSULES ON BLOAT INCIDENCE AND MILK PRODUCTION IN DAIRY COWS SIX TRIAL SUMMARY Six clinical trials including a total of 369 animals were conducted in Australia and New Zealand to confirm expected bloat control effectiveness of monensin Controlled Release Capsule (CRC) in dairy cows and to evaluate the effect of such treatment on milk production and TCW/723V n composition.

An appreciable bloat problem occurred in two trials while only minor problems were experienced in two others; bloat scores were reduced <P<0.05>. No visual signs of bloat were observed in the remaining two 5 trials.

Mean daily milk, production was increased in all six trials (P<0.025>. In trials with minor or no bloat, the increase was significant (P<0.05). The results are summarised as follows: TABLE 5 Control Monensin Treatment CRC Effect Mean Bloat Score: 1 0.84 0.29 -0.55 (P<0.05) 2 0.41 0.33 -0.08 Mean daily milk yield (L> (Six trials) 17.68 18.82 1.14 (P<0.025) (4 no or low bloat trials) 18.18 19.45 1.27 (P<0.05) Mean daily fat yield (kg) 0.762 0.768 0.006 ns Mean daily protein yield (kg) 0.550 0.580 0.03 (P<0.025) Mean milk fat content (%> 4.37 4.15 -0.22 (P<0.025) Mean milk protein content (%) 3.16 3.13 -0.03 ns 1 Appreciable bloat incidence 2 Minor bloat incidence ns non significant TCW/723V o 2317 EXAMPLE 7 Rumens in ABC Market Research Results Of The 1988 Sales (Use in Beef Producing Animals) Producer Sample Number was 104 Total Capsule Purchases: 22,132 Total Capsules Used: 19,245 There were 172 reported areas of use: 10 Steers 47% Heifers 21% Cows 20% Bulls 12% - Bloat season rating on a scale of 1 to 5: 1 = No Bloat, 2 = Mild, 3 = Average, 4 = Pretty Bad, 5 = Severe Average Score =4.1 Number of ABC Treated Animals lost to Bloat: 115 over 50 Producers Pasture at time of Death-Lush Clover, Lucerne, Sub-Clover or Medics Number of Untreated Animals lost to Bloat: 492 over 44 Producers Pasture - There was a tendency to put cattle on less potent legume paddocks or onto native pasture Perceived differences in bloating between Treated vs Untreated: 30 58% Believed there was a difference 42% Did not look for or see a difference Consecutive capsule use after the 100 days were up: 91 Producers did not redose TCW/723V 23 1 7 F 12 Producers did redose 806 Head of cattle Will You See The Capsule Again?? 98*/. Said, They Would (Depending On The Season) 21 Said, No (3 Were Undecided) EXAMPLE 8 Monensin Residue Analysis Of Milk From Cows Treated With Monensin Controlled Release Capsules 5 Milk samples from a total of twenty (10 treated/10 controls) cows involved in two clinical trials (1 Australia/1 New Zealand) to evaluate the effectiveness of monensin controlled release capsules (CRC) were periodically collected for analysis for the presence of monensin. The CRC is designed to release approximately 320 mg monensin into the rumen daily, 10 but may range from 278-355 mg/hd/day. Milk from the five treated cows in Australia was collected on days -1, 1, 3, 7, 21, 28, 56, 100 and 107 of CRC treatment. Five untreated samples were collected on days 1 and 107. In the New Zealand experiment, samples from five treated cows were collected on days 1, 3, 7, 21 and 84. Where possible, samples were also collected on 15 days 28, 56, and 107. Samples from five control cows were collected at regular intervals.

No monensin residues were detected by a thin layer chromatographic analytical method with near ultra-violet light readout. Some of the earlier samples were tested to a detection sensitivity of < 6 ng/ml milk, 20 while the majority were tested to a sensitivity of < 2.5 ng/ml.

INDUSTRIAL APPLICATION Monensin capsules reduced the incidence of bloat under moderate to severe bloating conditions by increasing the proportion of cows showing nil or mild bloat compared to severe bloat. The occurrence of severe bloat was 25 not eliminated but was substantially reduced in cows with capsules. This result is comparable to that of other bloat preventatives currently used to control bloat. There was a tendency for cows with capsules to produce more milk of a slightly higher protein percent and lower fat percent. These TCW/723V 2317 58 differences in milk yield and composition may be due to a lower food intake by cows without capsules as a result of their higher incidence of bloat, rather than as a direct result of capsules.

TCW/723V 231758 o

Claims (12)

WHAT WE CLAIM IS:

1. A method of treating bloat in pasture-fed cattle requiring said treatment which method comprises administering to the rumen of said cattle, crystalline monensin, in a sustained release capsule, in an amount effective to control bloat.

2. The method of claim 1 wherein the amount of monensin is from 170 mg/day.

3. The method of claim 1 wherein the amount of monensin is 300mg/day.

4. The method of any one of claims 1 to 3 wherein the monensin is released over a period of approximately 100 days.

5. The method of any one of claims 1 to 4, said capsule being substantially as hereinbefore described with reference to the accompanying drawing.

6. A method of treating bloat in pasture-fed cattle requiring said treatment substantially as herein described with reference to any one of Examples 2, 3, 6 or 7, but excluding any comparative examples.

7. A method of increasing milk yield in dairy cows which comprises administering to the rumen of said dairy cows a milk production enhancing amount Of crystalline monensin in a sustained release capsule.

8. The method of claim 7 wherein the amount of monensin is from 170 mg/day.

9. The method of claim 7 wherein the amount of monensin is 300mg/day.

10. The method of any one of claims 7 to 9 wherein the monensin is released over a period of approximately 100 days.

11. The method of any one of claims 7 to 10, said capsule being substantially as hereinbefore described with reference to the accompanying drawing.

12. A method of increasing milk yield in dairy cattle substantially as herein described with reference to any one of Examples 4, 6 or 8, but excluding any comparative examples. £L! LILLY AN)b COMPANY By Kfs/TTwir authorised Agent 23175 A J. PARK & SON Per