SE458009B - WANTED TO INCREASE MILK PRODUCTION OF ANIMAL, LACTATING ANIMALS BY ADMINISTRATION OF AVOPARCIN - Google Patents

Description

458 009 - Ho on Q I- d-avoparcin R ': R = hydrogen B-avoparcin R' = hydrogen, R = chlorine According to the present invention, avoparcin is administered orally to lactating ruminants in or with their food as an animal food premix or a concentrate. It can also be offered in fi prm of a "top dressing" for the animal's food or administered to it incorporated with a slow release bolus adapted to continuously supply the animal with the desired amount of antibiotic over the lactation period.

Said antibiotic may be used in its substantially pure crystalline form or may be used as a pharmaceutically acceptable salt, such as the hydrochloride salt of this antibiotic, or as an antibiotic complex, such as the alkylated sulphate, syn-tan or tru-tan. the complex of avoparcin. In the practice of the present invention, it has also been found that the antibiotic avoparcin is effective in increasing the milk production of lactating ruminants, when this antibiotic is administered orally in any of the above forms but in conjunction with the dried solids of the invention. the total harvest-fermentation mixture in which it is prepared.

Administration of from 0.04 mg to 0.33 mg avoparcin per kg animal body weight per day (ie 0.04 - 0.33 mg / kg body weight per day) corresponds to approximately 25 to 200 mg / kg per animal per day for lactating dairy cattle and 2.5 to 25 mg per kg per animal per day for lactating goats or sheep.

When this antibiotic is administered in the form of a salt or complex, the amount of salt or complex used should, of course, be adjusted in order to provide the previously stated dose level of avoparcin. Although ayoparcin has been a significant, commercially available antibiotic used for breeding meat-producing animals for the purpose of accelerating their growth rate, we have found that when said antibiotic is administered to lactating dairy cattle at the dose levels recommended for the benefit of growth in cattle, milk production and / or milk quality are measurably reduced.

Thus, the uptake is that all glycopeptides including: actoplanin¿ avoparcin A-35512, vancomycin, ristocein A ~ 477, I K-288 and? AM-374 are essentially equivalent as milk product = ¿^ u. lactation enhancers, as suggested by the applicant in G.B. patent application 2,096,895A, published October 27, 1982, erroneous and / or misleading, at least with respect to the incorporation of avoparcin among the listed glycopeptides. 458 ÛÛ9 As demonstrated below, avoparcin administered to lactating dairy cattle increases in dose levels from about 50 mg and 150 mg per animal per day to milk production and / or milk quality; At the same time, the administration of avoparcin to lactating dairy cattle at 300 mg per body weight per day reduces to 600 mg per body weight per day milk production and / or the quality of the milk from the treated animals.

The invention in the present application is further demonstrated by the examples given below.

Example 1 Evaluation of avoparcin to increase milk production and / or the quality of milk in lactating dairy cattle The experimental design used in this evaluation consisted of three periods. Peroid I was a pre-experimental 28-day period when all the cows in the dairy herd were registered, and selection of suitable objects for the experiment was made. Period II consisted of 28 days of avoparcin treatment, and period III was a 28-day period following avoparcin treatment. The total trial took place over a three-month period.

A total of 28 Frisian dairy cows were selected from a dairy herd of more than 60 animals. Each cow had calved for at least six and not more than 22 weeks and at the time showed a daily milk yield in the range of 17 - 32 liters. Four balanced treatment groups were carefully composed so that each group contained animals, which were paired with respect to milk exchange and lactation stage. Each balanced group was then randomly subjected to one of four experimental treatments. Group A received no avoparcin and served as an untreated control group.

Groups B, C and D received 50, 150 and 300 mg avoparcin per animal per day for a period of 28 consecutive days. Each of the test subjects received their allocation of avoparcin in a target during the afternoon milking. Carefully weighed 458,009 amounts of avoparcin (ie 1 g, 3 g and 6 g AVOT 50, avoparcin, the 5% active ingredient premix for treatments B, C and D respectively) were included in 250 g batches of a tasty maize-based concentrate.

At the beginning of the study, the cows grazed. During the first week of period II, they completely switched to the winter base ration consisting of 35 kg of fresh green fodder, which was calculated to provide only maintenance. A balanced milk concentrate (180 g CP / kg) was given for the whole milk produced in an amount of 0.4 kg per liter over the whole experiment.

Milk yields were recorded and milk samples were taken on four occasions during the pre-experimental period I and daily during the first three days of avoparcin administration. Thereafter, milk exchanges and samples were taken on alternating days until the end of the entire trial period. Milk exchanges and samples continued to be taken periodically during the 28 days immediately following the end of the avocarcin supply (period III).

When the milk samples were taken, they were collected at both the morning (5.30) and evening milkings (15.30) and combined for each day. Analyzes with respect to the composition of; - butterfat, protein and lactose were carried out according to automated standard techniques.

During the course of the trial, five cows required antibiotic therapy for mastitis. Two cows were severely affected and removed from the study. As a result, final data are reported for seven cows from groups A and D each, and six cows from groups B and C each.

Tables I and II give the details of the average daily yields and butterfats for the four treatment groups they registered during the trial. Table III gives in detail an obvious consideration of these data when presenting the mean values for the group's milk yields and butterfat contents' for the cows ti? 458 009 immediately before treatment, during the 28 days of avoparcin administration and, similarly, during the 28 days following the end of avoparcin treatment. The groups were closely matched during the pre-treatment phase; after ayoparcin treatment, however, it was clear that the untreated controls, group A, and the group receiving 300 mg avoparcin per animal and day, group D, showed a significantly greater decrease in milk production and some decrease in butterfat content, compared to groups B and C The declining milk yield continues in particular in these groups (A and D) during the 28 days following the end of the treatment. During the avoparcin supply period (II), yields of both groups B and C decrease at a slower daily rate than the untreated control group A. When the decrease in total yield is examined (by calculating the mean value of milk yields during both the avoparcin supply period (II) and the 28 days following the end of this period (III) to then compare these averages with the average value of milk yields obtained in period I) shows that the reduction of total milk yields obtained for groups B, 50 mg per animal and day; and C, 150 mg per animal and day, constituting only about 1/4 to 1/2 of the reduction obtained with the treated control animals, group A, and group D, treated with avoparcin at 300 mg per animal per day.

The largest reductions in both milk yield and butterfat were in fact observed in the group receiving 300 mg per animal per day. Table III gives averages for the group regarding milk yield and butterfat immediately before treatment, during the last two weeks of avoparcin treatment and during the last two weeks of the period following the end of avoparcin treatment.

Data from tables I and III are also graphically illustrated below. 458 009 TABLE I Milk production during period I 28 days pre-treatment The average value for milk yield (liters / day) from untreated cows drawn to group (A) untreated control animals, group (B) 50 mg avoparcin per animal and day, group (C) 150 mg avoparcin per animal per day or group (D) 300 mg avoparcin per animal per day. _: GROUP g Q 9 Q Untreated 50 mg / day 150.93 / day 300 mg / day Milk yield Milk yield Milk yield Milk yield Day liter / day liter / day liter / day liter / day -28 26.1 26.3 24.8 24 , 5 - 9 22.9 23.0 22.7 2310 ~ l 22.0 23.1 22.6 23.0 21.7 23.0 22.4 22.1 Average milk yield (L / D ) 23.18 23.85 23212 23.15 f I '; | l'-a TABLE I (continued) Period II milk production during 28 days of treatment The average value of milk cow hut (liters / day) from untreated cows group (A) and cows either given 50 mg avoparcin per animal and day group (B), 150 mg avoparcin per animal and day group (C) or given 300 mg avoparcin per animal and day group (D) over a 28-day treatment period. "ru" w.- 458 009 GROUP ABCD Untreated 50 mg / day 150 mg / day 300 mg / day Milk yield Milk yield Milk yield Milk yield 233 liters / day liter / day, liter / day liter / day 1 21.8 23.8 22, 1 22.2 2 21.8 23.9 23.1 21.5 3 21.9 24.9 21.9 22.3 5 21.3 25.3 22.7 20.1 7 - 23.1 25, 7 24.8 22.7 9 '“22.7 26.3 24.5 21.5 ll 22.6 26.6 24.4 23.7 13 22.6 25.8 24.3 23.1 15 21 .2 25.0 22.1 21.0 17 20.7 25.2 20.3 21.3 19 19.5 25.2 22.4 20.3 21 20.0 24.4 23.5 20.1 23 19.0 22.5 22.4 18.9 25 19.4 22.4 21.2 18.7 28 19.5 22.7 21.4 18.7 Average milk yield (L / D) ''21, 14 24,85 22,74 21.08, |) - a TABLE I (continued) Period III milk production during 28 days post-treatment The average value for milk yield (liters / day) from untreated cows group (A) and cows treated during period II of this evaluation with 50 mg avoparcin per animal and day group (B), 150 mg avoparcinëper animal and day group IC) or 300 mg avoparcin per animal and day group (D). 757 458 009 GROUP go ggg Untreated 50 mg / day 150 mg / dgg 300 mg / dgg Milk yield Milk yield Milk yield Milk yield 255 liters / day liter / day liter / day liter / day + 2 18.9 22.3 20.7 19.4 + 4 18.8 22.3 20.2 19.1 + 7 19.3 22.9 21.3 19.1 + 9 18.3 21.9 20.3 18.5 +11 _ 18.9 20, 4 19.7 17.4 +14 '“19.5 21.1: 20.4 17.6 +16 19.4 20.1 20.3 17.3 +18 18.5 20.1 18.6 17 , 1 +20 18.3 20.4 18.8 16.3 +22 18.5 19.9 20.4 15.5 +25 18.0 20.1 19.8 15.6 +28 18.2 - 20.0 19.9 15.7 Average milk yield (L / D) 18.72 20.95 20.03 17.38 Groups B and C were reduced to six cows during period III. g n- g fl zl TABLE II Period I percentage of butterfat content in milk samples from cows during 28 days pre-treatment Percentage average of butterfat 1 milk sample from untreated cows drawn into group (A) untreated control animals, group (B) 50 mg avoparcin per animal and day, gruPP (C) 150 mg avoparciniper animals and day and group (D) 300 mg avoparcin per .q- -. animals and day. 458 009 10 GROUP 5 gg Q Untreated 50 mg / day 150 mg daily 300 mg / day Day% Butterfat% Butterfat% Butterfat% Butterfat -28 4.01 3.84 3.82 4.11 - 9 3.89 3.78 3 , 71 3.97 - l 3.71 3.72 3.80 3.82 O 3.82 3.80 3.80- 3.71 Average process- ^ content butter- »fat 3.86 3 , 79 3.78 3.90 TABLE II (continued) Period II percent butterfat in milk samples from cows during 28 days of treatment The average value of percent butterfat in milk samples from cows either without treatment group (A) or given 50 mg avoparcin per animal and day (group (B), 150 mg avoparcin per animal and day group (C) and 300 mg avoparcin per animal and day over 28 days end group (D). wool || l'- | 458 009 ll GROUP 'ABCD Untreated 50 mg / day 150 mg / day 300 mg / day Qgg% Butterfat% Butterfat% Butterfat% Butterfat 1 3.79 3.78 3.78 3.87 2 3.75 3.65 3.21 3.70 3 3.71 3.83 3.54 3.21 5 3.54 3.80 3.37 3.57 7 3.30 3.84 3.40 3.40 9 _; 3.27 3.97 3.58 3.42 ll 3.37 3.84 3.63 3.85 13 3.25 3.79 3.44 3.25 15 3.47 3.72 3.80 3.53 17 3.40 3.54 3.59 3 , 50 19 3.45 3.60 3.30 3.38 21 3.57 3.71 3.41 3.35 23 3.58 3.47 3.58 3.38 25 4.05 3.70 3.78 3 , 66 28 4.06 3.76 3.67 3.66 Average percentage of butterfat 3.57 3.73 3.54 3.51,. , | l = 1 TABLE II (continued) Period III percent butterfat in milk samples from cows during 28 days post-treatment The mean value for percent butterfat in milk samples from untreated cows group (A) and cows treated during period II of this evaluation by 50 mg avoparcin per animal and day group (B) e 150 mg avoparcin per animal and day group (C) and _; 300 mg avoparcin per animal and day group (D). 458 009 12 .GÄLP è ä E 2 Untreated S0 mg / day 150 mg / day 300 mg / day 233% Butterfat% Butterfat% Butterfat% Butterfat + 2 3.94 3.50 3.86 3.91 + 4 3.52 3.80 3.64 3.75 + 7 3.57 3.72 3.55 3.61 + 9 3.71 3.74 3.66 3.76 +11 3.71 3.80 3.86 3, 72 +14 -Å 33.84 3.81 3.86 3.73 +16 3.91 3.77 3.79 3.71 +18 3.93 3.87 3.74 3.70 +20 3.84 3.43 3.52 3.65 +22 3.75 4.00 3.63 4.03 +25 3.99 3.96 3.78 3.82 +28 3.83 3.98 3.84 3, 77 Average percentage of butterfat 3.79 3.78 3.72 3.76 _ _ Table 111 || l = | Mean milk yield_ and percentage butterfat content in milk samples, for periods I, II and III, taken from untreated cows group (A), and cows treated with 50 mg avoparcin per animal and day group (B), 150 mg avoparcin per animal and day group (C) and 300 mg avoparcin per animal and day group (D). ._.- '~ _ 458 009 13 Average- Average milky percentage- yield content of butter- Period ggggg (liters / day) fat Pre-treatment) A 23.18 3.86 I) B 23.85 3 .79) C 23.13 3.78) D 23.15 3.90 Treatment) A 21.14 3.57 n. I "> B 24.85 3.73) C 22.74 3.54) D 21 .08 3.51 Post-treatment) A 18.72 3.79 III) B 20.95 3.78) C 20.03 3.72) D 17.38 3.76; | l '~ | __- TÉ > ~ _o mw.m om.m Qom Q mH \ o mw_m æ> _m omH U mo.o wß \ m mH.m om m wH_o æm.m ww_m om uuww HHH H HH m = uwwoHHwm H © oHHmm rnmëw> m mcHcxnmm uumm uuwwnnäm uHm: u: wooHm: knän uHmsu: mooum uHmnu: mooum mHHuuHnmEocwO mHHuuHcmEocmw mHHuvH: wEß: mu 4 H l; ~ m_m m ~ _mH mH mH m ~ m Qm m. .o om_- mw.mN om mm ~ _m ~ m ~ mH æH_m ~ om ^ mm @ w ~ w »HHV H Amwww fl mu fifi v ^ mßww ~ @« HH.. mu> Q # sxHß fi E HHH w HH mcnwø H woHuwm mmw \ ns fi U \ mE mmsnw »mHHu @ H = meo = @ m lo fi uwm @@> ß @ sxH @ He @»> n »ø« H @ Hs = H0 ~ m @ o> <> m mc fi cxcmm umHHuwHcmEo: mo uvHHwuH: mEo: mw mcHHwcmtmm HHH u0HummmmcHH fl cmswn | umuHm m: Hm HH @ oHummmäcHHw: øLmn .m> _ _ @ ^ m: fl H @ = m; wn | ~ wHv H wo fl .w MHNLUUUMHQEW H HNDHÉHUUONQ 200 .mäm fi vww Hmm Hwwcs mcmmu ummm5ummmcHHø: mswn mmHHvEmw: www um> oumxH © nE u> nw: xHmwE mmHHuuH: mEocmm cmHHwE wmHmunHEmh Avc fl muu hw qw nfl? 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\ UZH fi OZ 9 Julle H: Qoïëm ä »wzHqazšimTzHu ÉÉ f“ Emšzmzï fi mmxmïmom Û / _ S ccëä _ .. \ _ _. nu ßlfllullliå Qoëäli oo 5 4 / Y 9% n? 02 2: pvllrl1llo 33.? QS CV vflfii. i. _. i 1 i mmæ \ umu fi H I muænwm äfä Om š l. _ N _ _. in; .i _ .fl mcmnwn: mu: ^ z <ma íoom nøo fi: we QS _ 2: me om: wëëmmupoe. R: www Hmm zHummmoäN ® nm fifi w ^ fi w @ m2 HH MDUHM 458 009 16 Evaluation of the effects of 600 mg avoparcin given per animal and day on milk production in lactating Frisian dairy cows Ten Frisian dairy cows were selected in a herd of more than 60 animals so that each cow had calved for 18 to 23 weeks and at the time showed a daily milk yield in the range of 13 - 18 lilacs. The basic diet consisted of 35 kg of fresh green fodder which was calculated to add only the break. A balanced milk condensate feed was given for the total amount of milk produced in an amount of 0.4 kg per liter of milk.

Each of the test subjects received 600 mg avoparcin in one meal per day on each of three consecutive days (one, two and three). Weighted amounts of 600 mg avoparcin (i.e. 12gAvoT avoparcin 50.5% active ingredient premix) were included in 500 g batches of a tasty corn-based u: concentrate. 0.5 kg of avoparcin-containing concentrate replaced 0.5 kg of the normal concentrate at each feeding.

Milk yields were recorded and milk samples were taken during the avoparcin administration period (days one, two and three) and on days' four, five, seven and ten (ie one, two, four and seven days after the avoparcin administration had discontinued). The mean value for milk yields from 52 other cows in the herd was also taken during the trial period as a control.

The milk samples were analyzed for butterfat, protein, lactose and total solids according to standard methods. : n. ' Only one cow at one time refused part of the avoparcin-containing concentrate offered. In all other cases, the material content in 0.5 kg of the concentrate was consumed well.

At no time were any adverse effects noted in the cows examined. I "45s oo?« - 458 009 17 8 H 3. "The arrangement according to t_krav 1, k e nn e_ The average value for milk exchange ran the ten cows, vi that the distance between the Qalans arms 11 12 avoparcin, fell considerably from 15.1 kg fer ag pa, 39, 4) lb drawn by lka received,, 40) three joints- _ day -one points (10, ll ', l2'; 16 H ar ol_ka._ _ (ie two days before avoparcin supplementation on örjades ) to 4% Anogdning_enl1gt claim l, can e fl c knad of 12.7 kg per day on the tenth day of the experiment. became fairly constant at about 16.5 kg per day.

(See Table IV). ÜHH I 458 009 18 _.__; , »Ox la fl ohucox Nm ñmmm Hwm mxv wuwnßo w ~ w fi m ~ m fi m_wH æ.v fi .. w ~ ma ß_wH ß_wH m- fi m_mH« .w fl v.mH m.v fi o \ mH H_mH Hex xc fl onmmo> ® mmm mxv wpmnpa @ _ @ H ~. @ H mß_ ~ H w. ~ H OH ß mvm NHQH: www mpwxmmnnm: Huumao> m u fi mwuuoë wuc fl mxH «> .wuo fi s mšëßm \ uoxxHnnE Nm: www ë Howm uUE fi Amman wwåmw fl ww mu © cmHø> wm mn »> @_ cw: oo um> wm c fl uummo> m må cow mouuoê mxHH> .uox o fl u: www Ammwíhw fl mxv w @> n @ gxH @ fi s www w @ Hm> Hm @ wz> AANMÉB 458 009 19. i ... lm fl fl ßmdw _ »Han fi m» oa ¥ m @ _ «o>.« mw. «fl> _«> w_ «nw.« Hw_ ««> _ | .u. = woux fl q mm. ~ ° m_m m ~ .m mm_m m ~ .m mm_m mm_m mm.mw ~. ~ n fl wßoum @ m_ ~ ° Q_m> m_ ~ m ~ \ m H «_m mm_m« m_m mm.m mm_m ppwwumsm OH> m <m NHO Hmm mpwgmmnmm Hmm @ »wwcm fifl wm mnunmuwb mm WUE> m cm UG microns> wm a fl unmmoè al tra oem wunmmmuvoë uox O fl u: mmm hw> oumxAmmE> m WAE al møwtmx fl uo f n f VCM: www ßmua al mwnumwv S00 Aamßnwm al vv v fi Mn Xm al uwuxm fi Am al us. ^ fl muG0 fiflfl Ev amuüm flfi wo _HmHwumU: wummn mummu m fl muou ß fl muoum .unmuønmwouxm fi .v fi muoumc fl muoum .udmuonmuumwumëm Hmm cwwHw> amøw2> QQWNQB 2458 009 " However, the butterfat content clearly shows a marked decrease on days five, seven and ten. The observed decrease in total solids content (l2, l3% on day -1 falls to ll, 7% on day 10) thus constitutes a result of the reduced milk fat production and does not involve any change in protein or lactose production.

From the above data it is clear that the oral administration of 600 mg per animal per day of avoparcin to lactating cows caused a marked and remarkable effect on milk yield (l5% reduction) and butterfat (approximately l0% reduction) with a consequent effect on the total solids content of the milk. (The reduction to ll, 7% total solids from l2, l% would in fact be sufficient to incur a penalty of 0.3 p / l based on the Scottish Milk Marketing Board Compositional Quality Payments Scheme, 1981). '

Claims (6)

-m now. »W a _ .. 1. = ~ 4h ~ _ .. ,, .., ..- S. _ 458 009 PATENTKRÄV Methods for increasing the milk production of ruminants, lactating animals, comprising administering orally to them from 0.04 mg to 0.33 mg avoparcin per kg animal body weight and day. A method according to claim 1, wherein said avoparcin is administered orally to the ruminants in an amount from 0.08 mg to 0.25 mg of avoparcin per kg of animal body weight and day. A method according to claim 1, wherein the ruminants are selected from dairy cattle, sheep and goats. 4. Methods for increasing the milk production of lactating dairy cattle, comprising orally administering to this cattle from 25 to 200 mg of avoparcin per animal per day. 5. A method of increasing the milk production of lactating dairy cattle, comprising orally administering to this dairy cattle avoparcin in an amount of 50 mg to 150 mg of avoparcin per; p! animals and day. Methods for increasing the milk production of lactating sheep and goats, comprising orally administering to them from 2.5 mg to 25 mg of avoparcin per animal per day. -ç .. .. ._