PIRLIMYCIN GROWTH ENHANCERS FOR MEAT PRODUCING ANIMALS

Abstract: Animal growth promotant compositions and methods for increasing performance in meat-producing animals that utilize a compound having formula (I) or a pharmaceutically acceptable acid addition salt thereof in combination with animal feed useful for increasing the performance of said animals. The concentration of compound in the formulation is from about 0.5 mg to about 55 mg per kilogram. Also provided is a process wherein the compound is fed to poultry only during the first 21 days of the growth period.

Description: PIRLIMYCIN GROWTH ENHANCERS FOR MEAT PRODUCING ANIMALS BACKGROUND OF THE INVENTION The present invention relates to the use of antibiotics to promote increased performance in meat producing animals, and espe- cially in broiler chickens and swine. It is known that meat-producing animals will gain more weight and gain it faster when various classes of compounds such as vita¬ mins, minerals, estrogens, antibiotics, and tranquilizers are added to the diet. Although the presently available compounds are useful, new materials are still being sought that would produce weight gains more rapidly, to a greater extent more efficiently with respect to feed intake at a lower cost and without undesirable side effects or other deleterious effects such as the development of cross resistance with humans. It has now been found that the antibiotic Pirlimycin (I), when added to the diet of healthy meat producing animals, such as broiler chicks and swine, can improve both weight gain and feed efficiency. INFORMATION DISCLOSURE As indicated above the use of antibiotics, including lincomycin (III) and clindamycin (II), to promote animal growth productivity is known in the art. Pirlimycin is an analog of lincomycin and clinda¬ mycin. In United States patent 3,086,912 lincomycin, its microbio¬ logical production and its use as a feed supplement to promote the growth of mammals and birds, either alone or in combination with other antibiotics is disclosed. Animal feed compositions containing lincomycin are described in United States patent 3,155,580. Animal feed compositions and methods of treating animals having mycoplasma infections utilizing a combination of lincomycin and spectinomycin are described in United States patents 3,261,687 and 3,679,787 respectively. Clindamycin and its therapeutic use in animals is described in United States patent 3,496,163. Formulations of clindamycin, including animal feed compositions, are disclosed in United States patent 3,539,689. It also discloses that the formulations can be given prophylactically to animals raised for neat to increase weight gain. Pirlimycin,the A-Cis-ethyl-L-pipecolic acid amide of 7-C1- methylthiolincosaaide , formulations thereof (including animal feed compos itions) and methods of using it to treat bacterial infections are disclosed in United States patent 4 , 278 , 789 . However , to applicant' s knowledge , there is no disclosure or suggestion of feeding Pirlimycin to healthy animals in the prior art . It is well documented that antibiotics in feed are βore ef¬ fective in the early stages of the growing period of the chick than in the latter. Confining the length of tine only to the growing period during which an antibiotic can be fed without reducing its effectiveness on the market weight would be very important to the broiler producer . There are conflicting reports in the literature on the effects of the presence of antibiotics in the feed, and the degree of diminution in response when they are removed . Heuser and Norris , Poultry Sci. 31: 857-862 , 1952 , reported that when antibiotics were withdrawn from the diet at four weeks the average growth response at eight weeks of age was approximately the same whether the antibiotic was continued or discontinued during the four-week period. March et al, , Poultry Sci . 51 : 1409 -1414(1972) reported no significant differences in performance for floored- reared birds fed a combination of the antibiotics oleandomycin (11 mg/kg) and zinc bacitracin (27 . 5 mg/kg) . The periods of antibiotic supplementation were , 1-4 weeks , 4-8 and 1-8 of the eight- eek feeding trials . They concluded that the antibiotics were only effective in the feed during periods when they were present in the diets . Marusich et al . , Poultry Sci . 52: 1774-1779(1973) also described similar trials in which four antibiotics were fed to broilers raised in battery brooders . The antibiotics (penicillin, ooenomycin, zinc bacitracin, lincomycin) were fed either continuously or intermittent¬ ly in four trials. Feeding periods were 0-2, 0-4, 4-8 , 6-8 and 0-8 weeks. The combined data from the four trials showed significantly better growth and feed conversion for the continuous feed from 0-8 weeks and for intermittent feeding from 4-8 weeks . The 0-2 or 0-4 week periods showed the antibiotics to be effective during the periods when the antibiotics were present in the feed, but these differences were not sustained after the antibiotics were withdrawn. No effect was observed from the 6-8 week feed period, it appeared that this period was too short for the anti¬ biotics to exert any positive effects . The use of antibiotics in swine have been discussed by Lasely, J.F., L. F. Tribble and A. G. Hagan, 1954 "Value of Antibiotics in Swine Rations", Research Bulletin #543, University of Missouri, Columbia, Missouri, and Hays, V. W. , "Effectiveness of Feed Additive Usage of Antibacterial Agents in Swine and Poultry Production. The Hays Report. Publisher Rachelle Laboratories, Inc., 700 Henry Ford Avenue, Long Beach, California 90801. Other reports on antibiotic usage show that in some species the effects of short-term or long-term feeding depend on the composition of the basal diets Dubos et al., J. Exp. Med. 117:231-243, 1963, and Eyssen and deSomer, J. Exp. Med. 117:127-138, 1963a,. Still other reports have shown that the responses obtained with antibiotics depend on how long they are used in the same environment. Waibel et al., Poultry Sci. 33:1141-1146, 1954 and Libby and Schaible, Science 121:733-734, 1955 all reported that continuous feeding of antibiotics resulted in decreased responses. In contrast, Heth and Bird, Poultry Sci. 41:755-760, 1962, Hays, V. V. , Position Paper for Office of Technology Assessment 1976, Bird, World Poultry Sci. J. 24:309-312, 1968 and Bird Feedstuffs, 40:16-24, 1980 have all reported no diminution of responses after several years of continuous feeding in the same environment. SUMMARY OF THE INVENTION This invention relates to the use of Pirlimycin as a growth promotant in meat producing animals . The present invention particularly provides: A method for obtaining increased performance in a healthy meat producing animal during its growth period which comprises the feeding of said animal a formulation containing a compound having the Formula I or a pharmaceutically acceptable acid addition salt thereof in combination with animal feed, wherein the concentration of compound is about 0.5 to about 55 mg per kilogram of feed. For poultry the amount of compound to be used is about 0.5 to about 11 mg per kilogram of feed and for swine about 10 mg to about 55 mg per kilogram of feed. This results in an average daily dose of about 0.0358 to about 0.879 mg of compound per bird and about 8.7 to about 47.6 mg of compound per animal for swine . The invention further provides compositions comprising a compound of Formula I or one a pharmaceutically acceptable acid addition salt thereof in combination with an animal feed, wherein the concentration of the compound of Formula I or its pharmaceutically acceptable acid addition salt is about 0.5 to about 55 mg . per kilogram of feed. Formulations prepared from Pirlimycin hydrochlo- ride are particularly effective as growth promotants for broiler chickens and swine . The invention further provides a method wherein the formulations are fed to broiler chickens for only the first 21 days of the growth period. The term "increased performance" means increased weight gain, increased feed efficiency or both . DESCRIPTION OF PREFERRED EMBODIMENT Pirlimycin, its preparation and methods of preparing animal feed compositions containing it are described in United States patent 4 , 278 , 789. These preparations and methods are hereby incorporated by reference . POULTRY Two trials were run concurrently and all trials lasted for 49 days . Experimental animals . Day-old broiler chicks obtained from a commercial hatchery were used for each trial. Breed/strain. A different broiler strain was obtained for each trial. Lighting program. A continuous lighting program was used for all trials . The light period was continuous for 23 hours and 1 hour of darkness . The hour of darkness helped to condition the birds against piling up or suffocation in the event there was a power f ilure . Litter. Wood shavings were used as litter. At the start of each trial fresh litter was mixed with approximately one bushel of old litter per pen. The old litter was free of antibiotic residue. Health program. All chicks were vaccinated against Marek's disease. They were also vaccinated for Newcastle-Bronchitis at 14 days of age by the air-mist method. Diets. All basal diets were formulated to meet or exceed the National Research Council (NRC) suggested nutrient guidelines. A coccidiostat, monensin (Coban) , was used in all diets. To prepare the experimental diets the test compounds were premixed into a carrier (soybean mill feed) and remixed into the appropriate amounts of the basal diets. All diets were in mash form and were fed ad libitum. Treatment. The treatments utilized in these trials are shown in Table 1. * allocations. 1. The sexes were assigned randomly to pens so that two blocks of males and two blocks of females existed at each location (room) . 2. Chicks of the same sex were distributed randomly to the pens of each block. The randomization was such that chicks of the same sex from a single shipping box were equally distributed among all pens of a given block. 3. Treatments were allocated randomly to pens within blocks of six pens. An outline of the dietary treatments and experimental design are shown in Table 1. STATISTICAL ANALYSIS Pen was the experimental unit for these trials. Treatments were individually compared to the negative control by first calculating improvements over control in average daily gain and in feed per unit of gain for each block. A treatment index was computed for each block as a weighted combination of percent improvements over control in growth (gain) and feed conversion (FC) . The index used the following formula: TGN - (TGN-CGN)CGN x 100 TFC - (CFC-TFC)/CFC x 100 TI - TGN/3 x TFC where TGN - improvement in treatment gain over controls TFC - improvement in feed conversion over controls TI - treatment index An analysis of variance was run on the calculated parameters to obtain estimates of the trial and random error variance. Trial means squares were used as an estimate of error variance in a t-test of the hypothesis that these parameter means are not greater than zero. Comparison of 21 day treatment with 49 day treatment was done by running an analysis of variance on the TGN, TFC and TI parameters comparing the treatment utilizing pirlimycin with controls. RESULTS AND DISCUSSION Results are shown in Tables 2 to 4. In these results the feeding of formulations containing drug are compared to the non- medicated control . At 21 days all the comparison parameters of growth, feed conversion and growth index for all treatments were significantly greater (P<0.05) than the negative control (Table 2) . These same comparison parameters were also significantly greater (P<0.05) than zero for pirlimycin at 49 days (Table 3) . The data from these experiments clearly demonstrate that compounds of Formula I , in particular the Pirlimycin hydrochloride salt, will improve the growth rate and feed conversion of the healthy broiler chick whether fed from 1-21 days or 1-49 days . Table 1 Outline of dietary treatments and experiment design Sex Distribution Treatment Chicks/ Total Chicks/ Treatment Group Pens /Treatment Pen Treatment Males Females 1 Pirlimycin (11.0 mg/kg) 50 200 100 100 2 Pirlimycin (11.0 mgAg) 4 50 200 100 100 4 Control (Negative) 4 50 200 100 100 Note: Treatment 1: no antibiotics in feed after 21 days Table 2 Summary of weight gain, feed conversion and treatment indexes responses of Pirlimycin compared to its non-medicated controls when fed short term or long term (21 day data) . (1) (2) Pirlimvcin Pirlimvcin Feeding Period (Days) 21 49 Improved Gain (%) 4.84 5.49 Improved Feed/Gain (%) 1.94 1.90 Growth Index 3.55 3.73 All values significantly (P<0.05) greater than negative control. Treatments 1 1-21 days - basal control -22-49 days 2 1 -49 days T?bl? 3 Summary of weight gain, feed conversion and treatment indexes responses of Pirlimycin compared to its non-medicated controls when fed short term or long term (49 day data) . (1) (2) Pirlimvcin Pirlimvcin Feed Period (days) 21 49 Improved Gain (%) 2.84* 3.24* Improved Feed/gain (%) 1.63* 1.91* Growth Index 2.58* 3.00* * All values significantly (P<0.05) greater than negative control. Treatments 1 1-21 days - basal control - 22-49 days 2 1-49 days Table 5 Summary of weight gain, feed conversion and treatment indexes for the evaluation of treatment responses. Improved Gain Improved Feed/ Treatment (%~) Gain (%) Index (2) Pirlimycin (1) 2.953 2.310 3.294(P0.01) All values significant by )P >0.05) greater than negative control (1) 11 g.Ag (2) Index Formula: TGN - (TGN-CGN)/CGN x 100 TFC - (CFC-TFC)/CFX x 100 TI - TGN/3 + TFC Where: TGN - improvement in treatment gain over controls TFC - improvement in feed conversion over controls TI - treatment index SWINE Facilities: Each trial was conducted in a facility where heating and ventilation equipment were adequate to maintain a desirable nursery environment. Each pen is equipped with a self- feeder and a nipple type drinker. The floor of each pen is solid concrete except for .74 m^ of expanded metal slats over a flush gutter at one end of the pens for manure removal. Animals: Equal numbers of healthy female and castrate male Hampshire X Yorkshire crossbred, weaned pigs five to six weeks of age were used for each trial. The experimental unit consisted of a pen of four pigs, two females and two males. Within each trial, pigs were assigned to blocks of pens by weight group and randomly allotted to individual pens within the blocks (same procedure followed for both sexes) . Blocks of pens were randomly assigned to positions within the nursery and treatments were randomly assigned to pens of pigs within the block. Diets and Treatments: A corn soybean meal based diet with approximately 18% crude protein, was based as the basal diet to which the drugs were added to provide the treatments. Appropriate quantities of pirlimycin and clindamycin were premixed into soybean mill feed to a concentration of 44 grams per kilogram of premix. The premixes were then mixed singly with the diet to attain a finished feed level of 55 mg of drug activity per kilogram of diet. Analysis of Data: Variables of interest are gain, expressed as average daily gain (ADG) , feed efficiency, expressed as feed consumed divided by gain (F/G) , and growth index (GI) which is calculated by slimming the within block improvements in ADG and F/G with each weighted equally. The responses from each drug for each variable was calculated within each weight block relative to controls, e.g.: Improvements in ADG - 100 (ADG of treated - ADG of Control) ADG of Control A t-test was vised to evaluate the probability of chance differences. Estimates of variance were obtained from analysis of variance using a model with trials and blocks within trials. Following the swine performance screen procedures, 384 Yorkshire X Hampshire crossbred pigs were fed diets which contained either no drug or pirlimycin 55 eg/kg for 21 days. Each treatment was repre¬ sented in eight blocks (four pigs per pen) per trial in four trials conducted over 13 months. A growth index (GI) was calculated from the within block comparisons to measure improvements in gain and feed efficiency for each compound. To pass this screen a compound must have a GI of at least 7.5 and be significantly different from zero at P <.10. Pirlimycin was acceptable with a GI equal to 8.16 with P - .08. From Table 5, it can be seen that the growth index for Pirli¬ mycin on the average is positive and exceeds the minimum criteria of 7.5. From Table 6, it can be seen that the probability that this response is due to chance is less than p <.10. Table 5 Mean Improvement in Gain and Feed Conversions and Mean Growth Indexes by Trials Mean Improvement In Trial Treatment ADG F/G Growth Index 1 Pirlimycin 11.70 1.59 13.29 2 Pirlimycin -3.49 -2.43 -5.92 3 Pirlimycin 4.65 0.82 5.46 4 Pirlimycin 15.08 4.74 19.81 OVERALL Pirlimycin 6.98 1.18 8.16 Table 6 Statistical Parameters and t-Test 0-21 Days Pirlimycin Mean Growth Index 8 .16 t 1 .47 Prob. Mean is < - 0.0 0 .08 Variance Components: Trials 69. .5634 Blocks (trial) 423. .4849 Total 493. .0483 Tft p7.ff. OF FORMULAS

Claims: 1. A method for obtaining increased performance in a healthy meat producing animal during its growth period which comprises the feeding of said animal a formulation containing a compound having the Formula I: or a pharmaceutically acceptable acid addition salt thereof in combi- nation with animal feed, wherein the concentration of the compound or pharmaceutically acceptable salt thereof is about 0.5 mg to about 55 mg per kilogram of feed. 2. A method according to claim 1 wherein the meat producing animal is poultry. 3. A method according to claim 2 wherein the poultry is a broiler chicken and the compound is Pirlimycin hydrochloride. 4. A method of claim 3 wherein the concentration of Pirlimycin hydrochloride is about 2 to about 11 mg per kilogram of feed. 5. A method according to claim 2 wherein the compound is fed only during the first 21 days (for broilers only) of the growth period. 6. A method according to claim 5 wherein the poultry are broiler chickens and the compound is Pirlimycin hydrochloride. 7. A method of claim 6 wherein the concentration of Pirlimycin hydrochloride is about 0.5 to about 11 mg. per kilogram of feed. 8. A method according to claim 1 wherein the meat-producing animal is swine and the compound is pirlimycin hydrochloride. 9. A method according to claim 8 wherein the concentration of Pirlimycin hydrochloride is about 10 to 55 mg per kilogram of feed. 10. A composition comprising a compound having the formula OH or a pharmaceutically acceptable acid addition salt thereof in combination with animal feed wherein the concentration of compound is from about 0.5 mg to about 55 mg per kilogram of feed. 11. A composition according to claim 10 wherein the compound is Pirlimycin hydrochloride. 12. A composition according to claim 11 wherein the concentration of Pirlimycin hydrochloride is about 1.0 to about 20 mg per kilogram of feed.

Inventors: EVANS ROGER, MARRETT LOUIS E, EVANS, ROGER, MARRETT, LOUIS, E.
Applicants: UPJOHN CO, THE UPJOHN COMPANY
Application year: 1988
Main classification: A23K1
IPC codes: A23K1