CA1296636C - 2-pyridinol compounds useful as anabolic agents - Google Patents
2-pyridinol compounds useful as anabolic agentsInfo
- Publication number
- CA1296636C CA1296636C CA000525020A CA525020A CA1296636C CA 1296636 C CA1296636 C CA 1296636C CA 000525020 A CA000525020 A CA 000525020A CA 525020 A CA525020 A CA 525020A CA 1296636 C CA1296636 C CA 1296636C
- Authority
- CA
- Canada
- Prior art keywords
- feed
- animal
- animals
- swine
- weight
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Fodder In General (AREA)
- Feed For Specific Animals (AREA)
Abstract
ABSTRACT
A method of producing an anabolic response in animals selected from the group of swine, cattle, sheep or poultry comprising administering to the animal an anabolically effective amount of one or a mixture of two or more compounds of the following formula (I) wherein X1, X2 and X3 independently represent halogen, preferably chloro;
A represents hydrogen, alkali metal, alkaline earth metal, zinc, iron, manganese or -?Z; and Z represents C1-C11 alkyl, C1-C11 haloalkyl or C1-C11 hydroxyalkyl is disclosed. The anabolic response is exhibited by one or more of the following: an increased growth rate, increased milk production, increased protein content/ increased fiber production, improved reproductive performance, and increased feed conversion efficiency. Also claimed are feed composi-tions containing the active compounds.
A method of producing an anabolic response in animals selected from the group of swine, cattle, sheep or poultry comprising administering to the animal an anabolically effective amount of one or a mixture of two or more compounds of the following formula (I) wherein X1, X2 and X3 independently represent halogen, preferably chloro;
A represents hydrogen, alkali metal, alkaline earth metal, zinc, iron, manganese or -?Z; and Z represents C1-C11 alkyl, C1-C11 haloalkyl or C1-C11 hydroxyalkyl is disclosed. The anabolic response is exhibited by one or more of the following: an increased growth rate, increased milk production, increased protein content/ increased fiber production, improved reproductive performance, and increased feed conversion efficiency. Also claimed are feed composi-tions containing the active compounds.
Description
2-PYRIDINOL CO~IPOSITIONS AND MET~IODS
.
This invention relates to a method o~ pro-duciny an anabolic response in animals by administering to the animals an anabolic agent whereby s~ch response is exhibited in one or more of the fo-lowing ways:
(a) an increased growth rate, (b~ increased milk production, (c) increased fibeL production, (d) increased protei.n content, (e) improved reproductive performance and ( f j increased feed conversion efficiency in animals.
More particularly, the present inv~ntion xelates to a method of obtaining the above anabolic responses by administering to an animal an anabolically effective amount o a substituted-2 pyridinol or a physiolGyi.c~
ally acceptable salt or ester thereo.
Briefly, in accordance with the present invention,~ the anabolic response in animals, for ; : example, the feed conversion efficiency, milk and fiber 30,249A F -1- f ~
. -2-production, protein content, reproductive performance, and growth rate of meat-bearing animals, can be increased by administering to said animals an anabolic~
ally effective amount of a compound corresponding to the following formula X3 ~ X
wherein X1, x2 and X3 independently represent halogen, preferably chloro;
A represen-ts hydrogen, alkali metal, alkaline earth metal, zinc, iron, manganese or -CZ ; and Z represents Cl-C11 alkyl, Cl C11 h y Cl-C11 hydroxyalkyl.
Preerably, X1, x2 and X3 are chlorine. Also preerred is that A is an alkali metal, more preferably sodium.
For convenience, the compounds of Formula I
will be hereinafter referxed -to as the "pyridinol compounds".
When used herein, the term "alkyl" is mean-t to encompass straight and branched chain alkyl groups and cycloalkyl groups of from 3 carbon at3ms up to the 30,249A-F -2
.
This invention relates to a method o~ pro-duciny an anabolic response in animals by administering to the animals an anabolic agent whereby s~ch response is exhibited in one or more of the fo-lowing ways:
(a) an increased growth rate, (b~ increased milk production, (c) increased fibeL production, (d) increased protei.n content, (e) improved reproductive performance and ( f j increased feed conversion efficiency in animals.
More particularly, the present inv~ntion xelates to a method of obtaining the above anabolic responses by administering to an animal an anabolically effective amount o a substituted-2 pyridinol or a physiolGyi.c~
ally acceptable salt or ester thereo.
Briefly, in accordance with the present invention,~ the anabolic response in animals, for ; : example, the feed conversion efficiency, milk and fiber 30,249A F -1- f ~
. -2-production, protein content, reproductive performance, and growth rate of meat-bearing animals, can be increased by administering to said animals an anabolic~
ally effective amount of a compound corresponding to the following formula X3 ~ X
wherein X1, x2 and X3 independently represent halogen, preferably chloro;
A represen-ts hydrogen, alkali metal, alkaline earth metal, zinc, iron, manganese or -CZ ; and Z represents Cl-C11 alkyl, Cl C11 h y Cl-C11 hydroxyalkyl.
Preerably, X1, x2 and X3 are chlorine. Also preerred is that A is an alkali metal, more preferably sodium.
For convenience, the compounds of Formula I
will be hereinafter referxed -to as the "pyridinol compounds".
When used herein, the term "alkyl" is mean-t to encompass straight and branched chain alkyl groups and cycloalkyl groups of from 3 carbon at3ms up to the 30,249A-F -2
3~i upper carbon atom limits as specifically set forth.
The term "Cl Cll" indicates that from one -to 11 carbon atoms may be present in a group.
.
It is well known that pyridinols exist in the S pyridinol and tautomeric pyridone form. When any reference is made to present pyridinol compounds o~
Formula I where A is hydrogen, it is understood to encompass both tautomeric forms.
The term "anabolic response" refers to the effects eghibited by an animal in response to an anabolic agent. ~len an anabolic agent is administered to an animal the anabolic response is exhibi~ed by, for example, an increase in weight gain, increase in fiber production, increase in milk production in lactating animals, increase in feed conversion efficiency, increase in protein content or improved reproductive performance when compared to animals not receiving the anabolic agent.
An important objec-tive of this invention is to produce an anabolic response in animals which is maniested by, for example, one or more of the following:
increased weight gain, incxeased protein content, increased wool production, improved reproductive per-formance, increased milk production in lactating animals, and increased feed conversion e~ficiency. Examples of animals which exhibit increased grow-th rate when admin~
istered an anabolically e~fec-tive amount of one or more of the present pyridinol compounds are commercial meat-bearing animals such as cattle, sheep, swine, and poultry.
30,249A-F -3-~,...
~ ~3~3~:~
In commercial prac-tice, imma-ture sheep, cattle and swine are commonly fed for maximum growkh rate in feed lots and poultry, such as chickens and turkeys, are raised in broiler pens, until -they reach a marketable weight. When the desirecl weight of the animals is achieved, they are then sold for slaughter.
It is important economically, that the animals achieve market weight in as short a time as possible, while consuming the least amount of food necessary to achieve such gain. It has been unexpectedly found that when anabolically effective levels of one or more of the present pyridinol compounds are administered -to animals of the classes described hereinabove, they gain weight at a faster rate while consuming less feed per pound of gain resulting in better overall economic efficiency, and reflecting the fact that administration of the present pyridinol compounds results in an anabolic response.
The present pyridinol compounds can be admin-istered to animals orally by dosage forms, such as, inadmixture with food, and additionally in the form of boluses, capsules, tablets, susp~nsions or solutions containing the present pyridinol compounds. The com~
pounds can also be adminis~ered paxenterally, such as, for example, intramuscularly or inkrav~nous]y, or by way of an implant which slowly releases the pyridinol compound into the tissue or blood stream of the animal.
The anabolically effective amount of the present pyridinol compounds exists as a range of from 0.01 to 20 milligrams per kilogram (kg) of body weight of the animal per day. This effective range can vary dep~nding on the size of the animal, the species of the 30,249A-F -4-animal, the age of the animal, -the type of feed used, the active compound used, or the rouke of administra--tion of the active compound. The optlmum range of an effective amount, based on -the above-mentioned vari-ables, can be found using conventionally knowntechniques, i.e., dose titration determinations.
An anabolically effec-tive amount of the present pyridinols can be conveniently administered substantially daily for at leas-t 7 days, preferably at least 28, more preferably at least 90 days and even more preferably throughout the life of the animal.
Lactating animals exhibit an increase in milk production when administered an anabolically effectlve am~unt of the present pyridinols. Lactating animals seem to be more sensitive to the effects o the present pyridinol compounds and thus may require a lower dose of the present pyridinol compounds to produce an increase in milk production when compared to an anabolically effective dose in other animals to produce an increase in body weight gain.
Animals raised for their fiber production, such as sheep, exhibit an increase in fiber production when administered an anabolically effective amount of the present pyridinol compounds.
The present pyridinol compounds are conveni-ently incorporated in a feed composition in an appropri-ate amount to achieve the desired daily d.osage in the amount of ration or supplement consumed regularly. For example J one or more of the present pyridinol compounds 30,249A-F -5-are conveniently incorporated in a feed composi-tion from generally 0.5 to 1600 grams per ton [metric] o - complete ration dependiny on the age and type of animal. The term "ton", "tonne" or "ton [me-tric]" is intended to mean, in khis speciEication, a metric ton of 1000 kilograms. The "ton" in parenthesis associated with "lb" or "pounds" uni-ts is intended to mean the short ton of 907 kilograms. The present pyridinol compounds may also be incorporated in a mineral, protein or energy~type feed additive supplement in an appropri-ate amount to provide anabolically effective daily dosages.
For commercial use, it is convenient to provide a feed additive premix or concentrate con-taining one or more of the present pyridinol compoundsin a proportion such that a predetermined quantity of the premix is to be added per ton [metric] of complete ration, for example, from 0.2 to 454 kg (0.5 to 1,000 pounds) contains rom ~.5 to 16~0 grams of the present pyridinol compounds. The feed additive premix or concentrate comprises one or more of khe present pyridinol compounds and a~carrier such as soybean meal or ground corn or okher edible feed grade material or innocuous diluent, such as, allohols, glycols or molasses, suitable or the animal at han~. A concen-trate may contain from 2 to 98 percent by weight of one or more of the present pyridinol compounds in inkimate admixture with an adjuvant there~or.
The present pyridinol compounds, when admin-istered parenterally, are pref~rably dissolved insterile distilled water or other physiologically accept able liquid media and compounded in accordance with the known pharmaceutical art.
30,249A-F -6 ~ i3~.~
The term "feed conversion efficiency" refers to the total amount of feed consumed over a period of time divided by the amount of body weight gain over that period as seen in -the following formula:
feed consumed over time period gain in body weight over time period The term "increased feed conversion efficiency"
refers to a more efficient means of bringing animals to market weight. An increase in feed conversion effici-ency will be reflected by a lower numerical value of the feed conversion efficiency number when compared to a lower feed conversion efficiency.
The term "increa~ed protein content", when referred to as being an anabolic response, means car-15 cass alteration of an animal exhibited by a relativeincrease in body protein content and a relative decrease in body fat con-tent.
One of the practical effects of this inven-tion is to bring animals such as sheep, cattle, swine, and poultry promptly to market weight with minimal feed consumption. The present pyridinol compounds are most conveniently dispersed uniformly throughout the normal feed or feed additive supplement of the subject animal in anabolically effective dosage levels. For example, an anabolically effective amount of the present pyridinol compounds is supplied in an animal feed comprising from 0.0005 to 16 percent by weight of one or more of the present pyridinol compounds and more preferably from 0.005 to 0.10 percent by weight cor~
responding to 50 and 100 parts per million (ppm). Such 30,249A-F -7~
~3~
animal feeds should, when fed to an animal, provide ko the animal from 0.01 to 20 milligrams per kilogram of body weight per day of one or more of the present pyxidinol compounds.
In further embodiments of the method o the present invention, compositions containing -the present pyridinol compounds can he advantageously employed in combination with one or more additional feed additives such as coccidiostats, antibiotics, minerals, vitamins or the like.
The animal feeds most generally used in con-junction with this invention are composed of various grains and/or grain mixtures and/or roughage feeds such as hay, cotton seed hulls, rice hulls, silage, or other high fiber feedstuffs commonly fed to meat-, milk-, and/or wool-producing animals, especially in cattle or sheep feeds. The feeds for swine and poultry will consist primarily of various grain mixtures plus the usual additaments such as bran meal, soybean meal, cotton seed meal, tankage or alfalfa meals suitable for monogastric animals.
Examples oE carriers for premix or concentrate composi.tions are soybean meal, corn oil, ground corn, ground corn cobs, barlsy, wheat, mineral m:Lxtures con-taining, e.g., vermiculite or diatomaceous earth, corngluten meal, corn distillers' solubles, soy flour or other modestly priced edible ingredients. The active ingredient will be in amounts to satisfy the criteria set forth above for balanced feed rations. This premix or concentrate is then in turn mixed uniformly with the normal diet for the animal as desired by the grower or 30,249A-F -8-,;
3~
g the feed mixer. The above mentioned grains, grain mix-tures, roughage feeds, usual additaments, carriers and innocuous diluents constitute acceptabl~ adjuvants for purposes of this invention.
-5 As indicated hereinabove, the amount of the present pyridinol compounds added to such feeds will be in the range of from 0.5 to ~600 grams per ton [metric]
of feed (dry matter basis), depending on the age and type of animal. More prefercibly the amount added to such feeds will be in the range of from 5 to 700 grams per ton [metric]. Very young animals that have been weaned or young poultry one or a few days old, will have a lower feed consumption compared to an older animal. However, as the animal goes through a growth period to a fattening period, sometimes called finish-ing, the feed consumption gradually increases, but generally falls in proportion to body weight.
The daily dosage o a preferred compound, 3,5,6-trichloro-2~pyridinol or a physiologically accept-able salt thereof, in swine falls in the range of from0.01 to 20 milligrams per kilogram of body weight. More preferably, in the range of from 0.1 to 10 milligrams per kilogram of body weight, and even more preerably from 2.5 to 5 milligrams per kilogram of body weight.
Exarnples oP physiologically acceptable salts of 3,5,6-trichloro-2-pyridinol are the Na, K, Ca, Mg, Mn, Zn and iron salts thereof.
Based on known inormation concerning the average feed intake for various sizes and types of animals, the followin~ amounts of one or a mixture of two or more of the present pyridinol compounds are 30,249A-F -9~
, 3~
incorporated into each ton of animal feed in order to provide an anabolically effective dose described herein.
For example, cattle on a growing diet will ordinarily be fed a diet containing from 3 to ~00 grams of one or a mixture of the present~pyridinol compounds per ton of feed on a dry matter basis (DM), while cattle on a fattening diet will be fed a feed containing ~rom 3 to 1000 grams of one or a mixture of the present pyridinol .
compounds per ton [metric] 5DM) (0.007 to 2.0 lb/ton).
Maintenance diets fed lactating dairy cattle should contain from 5 to 1600 grams of one or a mixture of the present pyridinol compounds per ton [me-tric] of feed (DM) (.01 to 3.60 lbs/ton), depending on the size and feed intake of the animal. Non-lactating dairy cattle should receive a feed containing 5 to 1000 grams of one or a mixture of the present pyridinol compounds per ton of feed ~DM) (0.01 to 2.70 lbs/ton). Lambs on dry feed will generally be fed a ration containing 2 to 600 grams of one or a mixture of the present pyridinol compounds per ton of feed (DM) (0.004 to 1.4`1bs/ton).
Grower pigs may be fed a ration containing 1 to 400 grams of one or a mixture o the present pyridinol - compounds per ton of feed (DM) while swine in the fat-tçniny stage will generally be supplied a ration con-taining 2 to 500 grams per ton (DM~ (0.002 to 1.20lbs/ton). Poultry such ~s very ~mall day-old or older birds up through starter or grower s-taye will generally be fed a complete ration of mash containing 0~5 to 400 grams of one or a mixture of the present pyridinol comr-pounds per ton of feed (DM) while poultry on a fat-tening diet will feed on a ration containing 1 to 400 grams per ton (DM) (0.001 to 0.8 lb/ton~.
30,249A-F -10-36~
--11~
- The following examples further illustrate -the practice of the present invention, but, as such, are not intended to be limitations upon the overall scope of the same.
Example 1: A typical growing ration for ruminants is as follows:
Weight Percent I d ents (D.M Ba6is) 10 Ground Yellow Corn 45.0 Soybean Oil Meal 7.0 Can Molasses 7.0 Dicalcium Phosphate 0.5 Trace Mineral Salt 0.5 100 . O
In addition to the above the following supplements are added.
Vitami~ A 300 I~
Vitamin D 150 IU/lb 3,5,6-Trichloro-2~pyridinol 3.5 to 450 or a physiologically acceptable grams/ton of salt thereof eed Such a feed typically contains 8 to 15 percent by weight moisture.
30,249A-F -11-~26~3~
-Example_2: A typlcal finishing ration for ruminants is as follows:
Weight Percent IncJredients (D.M. Basis) 5 Ground Shelled Corn 65.85 Mixed Ground EIay 20.00 Dried Molasses 6.00 Soybean Meal 6.00 Trace Mineral Salt 0.50 10 Dicalcium Phosphate 0.40 Ground Limestone 0.70 9g.45 In addition to the above the following supplements are added.
Vitamin A (300,000 units/gms)66.7 grams/-ton Vitamin D2 (16,000,000 um ts/lb)7.1 grams/ton 3,5,6-Trichloro-2-pyridinol 3.5 to 450 or a physiologically acceptablegrams/kon of salt thereof feed Such a feed typically contalns 8 to 15 percent by weight moisture.
30,249A F~12-~6 Example 3 An example of a suitable feed addi~tive premix is as follows:
3,5,6-Trichloro-2-pyridinol or 64 grams 5 a physiologically acceptable salt thereof Ground Yellow Corn (5-10% moisture) 390 grams Example_4 For use in the field for animals on range, the present pyridinol compounds may be administered by means of salt or molasses blocks. A typical block is prepared using the following compositions:
Weight Percent Ingredients (D.M. Basis) 15 Dried Cane Molasses 35.00 Ground Soyhean Hulls 29.60 3,5,6-Trichloro-2 pyridinol or a physiologically acceptable salt thereof* 5.36 20 Granulated Salt 25.90 Trace Minerals and ~itamins 0.2g Stabilized Animal Fat 1.30 Moisture 2.60 100 . 00 *Provided that the field animal ingests enough of the block per day to provide an effective dose of active ingredient hereinbefore mentioned.
30,249A-F -13-p Exam~le 5 If desired, the present pyridinol compounds may be administered as a part of a liquid animal ~eed supplement such as a supplement containing a non-protein nitrogen source such as urea or ammonium sulfate in : admixture with molasses and other feed ingredients. .
Such a liquid supplement is prepared using the fol-lowing formula:
Weight Percent 10 In~edients (D.M. Basis) Molasses 80.00 Water 16.25 Urea or Ammonium Sulfate 2.00 Trace Minerals .50 15 Vitamin A, D & E .05 Salt 1.00 : 3,5,6-Trichloro-2-pyridinol or j a physiologically acceptable : salt thereof* .20 *Provided the animal drinks enough o~ the li~uid per day to provide an effective dose o~ active ingredien-t hereinbefore mentioned.
The following examples demonstrate the ana~olic ef~ects of the present pyridinols as seen by an incxease in the average daily gain in weight, increased feed conversion ef~iciency, or increased milk production in feeding trials conducted in Europe and in the United States.
30,249A-F -14-~15-I. Protocol and Results for European Trials The process of the present invention was tested in pig feed trials in 4 European countries as a pig growth and as a feed eficiency promoting agent on a total of 520 pigs, including controls. The cowntries included Denmark, England, Germany and ~Iolland (Netherlands~.
The use 2,3,5-trichloropyridinol (TriCP) in feed was from weaning to the end of th~ fa-ttening period. A s-tarter diet was fed to the pigs from the beginning of the weaning period, which was 25 kg (in Germany, 30 kg~ to a weight of 50 kg (in Germany, 65 kg~. ~ finisher diet was fed to the pigs from a weight of 50 kg (in Germany, 65 kg) to the end of the fa-tten-ing period which was 100 kg (in Germany, 105 kg).
Dosage rates of zero "0" (the control), 50, 75 and 100 ppm of TriCP in the feed were tes-ted. Protein supply and energy content of the starter and finisher diets was adapted to represent the most common nutri-tional balance in each country, as represented in Table 1.
30,249A-F 15-6~i3~b Table 1 Nutritional Data of Feed Used in European Trials Energy In Feed ~ Lysine Number % Protein (KCal/Kg in Feed Country of Pi~s Diet By Weight Feed) b Denmark128 Starter 21.4 2098 0.81 Finisher 16.6 2105 0.55 England64 Starter 17.0 2108 0.89 Finisher 15.7 2150 0.77 . _ Germany168 Starter 16.5 2210 0.90 Finisher 15.0 2225 0.70 . . . _ . .
Holland160 Starter 17.0 2190 0.96 Finisher 13.6 2185 0.70 :
30,249A-F -16-.:
3~
- Individual protocols for each European country are provided hereinafter.
IA. Denmark Trial The ~enmark trialplan is shown below.
Feeding Trial Plan in Denmark _ Group Number Number of Pigs 3232 32 32 TriCP concentration 050 75 100 in feed in ppm In each of the four groups there were 32 pigs, divided into 4 pens with 4 males and 4 pens with
The term "Cl Cll" indicates that from one -to 11 carbon atoms may be present in a group.
.
It is well known that pyridinols exist in the S pyridinol and tautomeric pyridone form. When any reference is made to present pyridinol compounds o~
Formula I where A is hydrogen, it is understood to encompass both tautomeric forms.
The term "anabolic response" refers to the effects eghibited by an animal in response to an anabolic agent. ~len an anabolic agent is administered to an animal the anabolic response is exhibi~ed by, for example, an increase in weight gain, increase in fiber production, increase in milk production in lactating animals, increase in feed conversion efficiency, increase in protein content or improved reproductive performance when compared to animals not receiving the anabolic agent.
An important objec-tive of this invention is to produce an anabolic response in animals which is maniested by, for example, one or more of the following:
increased weight gain, incxeased protein content, increased wool production, improved reproductive per-formance, increased milk production in lactating animals, and increased feed conversion e~ficiency. Examples of animals which exhibit increased grow-th rate when admin~
istered an anabolically e~fec-tive amount of one or more of the present pyridinol compounds are commercial meat-bearing animals such as cattle, sheep, swine, and poultry.
30,249A-F -3-~,...
~ ~3~3~:~
In commercial prac-tice, imma-ture sheep, cattle and swine are commonly fed for maximum growkh rate in feed lots and poultry, such as chickens and turkeys, are raised in broiler pens, until -they reach a marketable weight. When the desirecl weight of the animals is achieved, they are then sold for slaughter.
It is important economically, that the animals achieve market weight in as short a time as possible, while consuming the least amount of food necessary to achieve such gain. It has been unexpectedly found that when anabolically effective levels of one or more of the present pyridinol compounds are administered -to animals of the classes described hereinabove, they gain weight at a faster rate while consuming less feed per pound of gain resulting in better overall economic efficiency, and reflecting the fact that administration of the present pyridinol compounds results in an anabolic response.
The present pyridinol compounds can be admin-istered to animals orally by dosage forms, such as, inadmixture with food, and additionally in the form of boluses, capsules, tablets, susp~nsions or solutions containing the present pyridinol compounds. The com~
pounds can also be adminis~ered paxenterally, such as, for example, intramuscularly or inkrav~nous]y, or by way of an implant which slowly releases the pyridinol compound into the tissue or blood stream of the animal.
The anabolically effective amount of the present pyridinol compounds exists as a range of from 0.01 to 20 milligrams per kilogram (kg) of body weight of the animal per day. This effective range can vary dep~nding on the size of the animal, the species of the 30,249A-F -4-animal, the age of the animal, -the type of feed used, the active compound used, or the rouke of administra--tion of the active compound. The optlmum range of an effective amount, based on -the above-mentioned vari-ables, can be found using conventionally knowntechniques, i.e., dose titration determinations.
An anabolically effec-tive amount of the present pyridinols can be conveniently administered substantially daily for at leas-t 7 days, preferably at least 28, more preferably at least 90 days and even more preferably throughout the life of the animal.
Lactating animals exhibit an increase in milk production when administered an anabolically effectlve am~unt of the present pyridinols. Lactating animals seem to be more sensitive to the effects o the present pyridinol compounds and thus may require a lower dose of the present pyridinol compounds to produce an increase in milk production when compared to an anabolically effective dose in other animals to produce an increase in body weight gain.
Animals raised for their fiber production, such as sheep, exhibit an increase in fiber production when administered an anabolically effective amount of the present pyridinol compounds.
The present pyridinol compounds are conveni-ently incorporated in a feed composition in an appropri-ate amount to achieve the desired daily d.osage in the amount of ration or supplement consumed regularly. For example J one or more of the present pyridinol compounds 30,249A-F -5-are conveniently incorporated in a feed composi-tion from generally 0.5 to 1600 grams per ton [metric] o - complete ration dependiny on the age and type of animal. The term "ton", "tonne" or "ton [me-tric]" is intended to mean, in khis speciEication, a metric ton of 1000 kilograms. The "ton" in parenthesis associated with "lb" or "pounds" uni-ts is intended to mean the short ton of 907 kilograms. The present pyridinol compounds may also be incorporated in a mineral, protein or energy~type feed additive supplement in an appropri-ate amount to provide anabolically effective daily dosages.
For commercial use, it is convenient to provide a feed additive premix or concentrate con-taining one or more of the present pyridinol compoundsin a proportion such that a predetermined quantity of the premix is to be added per ton [metric] of complete ration, for example, from 0.2 to 454 kg (0.5 to 1,000 pounds) contains rom ~.5 to 16~0 grams of the present pyridinol compounds. The feed additive premix or concentrate comprises one or more of khe present pyridinol compounds and a~carrier such as soybean meal or ground corn or okher edible feed grade material or innocuous diluent, such as, allohols, glycols or molasses, suitable or the animal at han~. A concen-trate may contain from 2 to 98 percent by weight of one or more of the present pyridinol compounds in inkimate admixture with an adjuvant there~or.
The present pyridinol compounds, when admin-istered parenterally, are pref~rably dissolved insterile distilled water or other physiologically accept able liquid media and compounded in accordance with the known pharmaceutical art.
30,249A-F -6 ~ i3~.~
The term "feed conversion efficiency" refers to the total amount of feed consumed over a period of time divided by the amount of body weight gain over that period as seen in -the following formula:
feed consumed over time period gain in body weight over time period The term "increased feed conversion efficiency"
refers to a more efficient means of bringing animals to market weight. An increase in feed conversion effici-ency will be reflected by a lower numerical value of the feed conversion efficiency number when compared to a lower feed conversion efficiency.
The term "increa~ed protein content", when referred to as being an anabolic response, means car-15 cass alteration of an animal exhibited by a relativeincrease in body protein content and a relative decrease in body fat con-tent.
One of the practical effects of this inven-tion is to bring animals such as sheep, cattle, swine, and poultry promptly to market weight with minimal feed consumption. The present pyridinol compounds are most conveniently dispersed uniformly throughout the normal feed or feed additive supplement of the subject animal in anabolically effective dosage levels. For example, an anabolically effective amount of the present pyridinol compounds is supplied in an animal feed comprising from 0.0005 to 16 percent by weight of one or more of the present pyridinol compounds and more preferably from 0.005 to 0.10 percent by weight cor~
responding to 50 and 100 parts per million (ppm). Such 30,249A-F -7~
~3~
animal feeds should, when fed to an animal, provide ko the animal from 0.01 to 20 milligrams per kilogram of body weight per day of one or more of the present pyxidinol compounds.
In further embodiments of the method o the present invention, compositions containing -the present pyridinol compounds can he advantageously employed in combination with one or more additional feed additives such as coccidiostats, antibiotics, minerals, vitamins or the like.
The animal feeds most generally used in con-junction with this invention are composed of various grains and/or grain mixtures and/or roughage feeds such as hay, cotton seed hulls, rice hulls, silage, or other high fiber feedstuffs commonly fed to meat-, milk-, and/or wool-producing animals, especially in cattle or sheep feeds. The feeds for swine and poultry will consist primarily of various grain mixtures plus the usual additaments such as bran meal, soybean meal, cotton seed meal, tankage or alfalfa meals suitable for monogastric animals.
Examples oE carriers for premix or concentrate composi.tions are soybean meal, corn oil, ground corn, ground corn cobs, barlsy, wheat, mineral m:Lxtures con-taining, e.g., vermiculite or diatomaceous earth, corngluten meal, corn distillers' solubles, soy flour or other modestly priced edible ingredients. The active ingredient will be in amounts to satisfy the criteria set forth above for balanced feed rations. This premix or concentrate is then in turn mixed uniformly with the normal diet for the animal as desired by the grower or 30,249A-F -8-,;
3~
g the feed mixer. The above mentioned grains, grain mix-tures, roughage feeds, usual additaments, carriers and innocuous diluents constitute acceptabl~ adjuvants for purposes of this invention.
-5 As indicated hereinabove, the amount of the present pyridinol compounds added to such feeds will be in the range of from 0.5 to ~600 grams per ton [metric]
of feed (dry matter basis), depending on the age and type of animal. More prefercibly the amount added to such feeds will be in the range of from 5 to 700 grams per ton [metric]. Very young animals that have been weaned or young poultry one or a few days old, will have a lower feed consumption compared to an older animal. However, as the animal goes through a growth period to a fattening period, sometimes called finish-ing, the feed consumption gradually increases, but generally falls in proportion to body weight.
The daily dosage o a preferred compound, 3,5,6-trichloro-2~pyridinol or a physiologically accept-able salt thereof, in swine falls in the range of from0.01 to 20 milligrams per kilogram of body weight. More preferably, in the range of from 0.1 to 10 milligrams per kilogram of body weight, and even more preerably from 2.5 to 5 milligrams per kilogram of body weight.
Exarnples oP physiologically acceptable salts of 3,5,6-trichloro-2-pyridinol are the Na, K, Ca, Mg, Mn, Zn and iron salts thereof.
Based on known inormation concerning the average feed intake for various sizes and types of animals, the followin~ amounts of one or a mixture of two or more of the present pyridinol compounds are 30,249A-F -9~
, 3~
incorporated into each ton of animal feed in order to provide an anabolically effective dose described herein.
For example, cattle on a growing diet will ordinarily be fed a diet containing from 3 to ~00 grams of one or a mixture of the present~pyridinol compounds per ton of feed on a dry matter basis (DM), while cattle on a fattening diet will be fed a feed containing ~rom 3 to 1000 grams of one or a mixture of the present pyridinol .
compounds per ton [metric] 5DM) (0.007 to 2.0 lb/ton).
Maintenance diets fed lactating dairy cattle should contain from 5 to 1600 grams of one or a mixture of the present pyridinol compounds per ton [me-tric] of feed (DM) (.01 to 3.60 lbs/ton), depending on the size and feed intake of the animal. Non-lactating dairy cattle should receive a feed containing 5 to 1000 grams of one or a mixture of the present pyridinol compounds per ton of feed ~DM) (0.01 to 2.70 lbs/ton). Lambs on dry feed will generally be fed a ration containing 2 to 600 grams of one or a mixture of the present pyridinol compounds per ton of feed (DM) (0.004 to 1.4`1bs/ton).
Grower pigs may be fed a ration containing 1 to 400 grams of one or a mixture o the present pyridinol - compounds per ton of feed (DM) while swine in the fat-tçniny stage will generally be supplied a ration con-taining 2 to 500 grams per ton (DM~ (0.002 to 1.20lbs/ton). Poultry such ~s very ~mall day-old or older birds up through starter or grower s-taye will generally be fed a complete ration of mash containing 0~5 to 400 grams of one or a mixture of the present pyridinol comr-pounds per ton of feed (DM) while poultry on a fat-tening diet will feed on a ration containing 1 to 400 grams per ton (DM) (0.001 to 0.8 lb/ton~.
30,249A-F -10-36~
--11~
- The following examples further illustrate -the practice of the present invention, but, as such, are not intended to be limitations upon the overall scope of the same.
Example 1: A typical growing ration for ruminants is as follows:
Weight Percent I d ents (D.M Ba6is) 10 Ground Yellow Corn 45.0 Soybean Oil Meal 7.0 Can Molasses 7.0 Dicalcium Phosphate 0.5 Trace Mineral Salt 0.5 100 . O
In addition to the above the following supplements are added.
Vitami~ A 300 I~
Vitamin D 150 IU/lb 3,5,6-Trichloro-2~pyridinol 3.5 to 450 or a physiologically acceptable grams/ton of salt thereof eed Such a feed typically contains 8 to 15 percent by weight moisture.
30,249A-F -11-~26~3~
-Example_2: A typlcal finishing ration for ruminants is as follows:
Weight Percent IncJredients (D.M. Basis) 5 Ground Shelled Corn 65.85 Mixed Ground EIay 20.00 Dried Molasses 6.00 Soybean Meal 6.00 Trace Mineral Salt 0.50 10 Dicalcium Phosphate 0.40 Ground Limestone 0.70 9g.45 In addition to the above the following supplements are added.
Vitamin A (300,000 units/gms)66.7 grams/-ton Vitamin D2 (16,000,000 um ts/lb)7.1 grams/ton 3,5,6-Trichloro-2-pyridinol 3.5 to 450 or a physiologically acceptablegrams/kon of salt thereof feed Such a feed typically contalns 8 to 15 percent by weight moisture.
30,249A F~12-~6 Example 3 An example of a suitable feed addi~tive premix is as follows:
3,5,6-Trichloro-2-pyridinol or 64 grams 5 a physiologically acceptable salt thereof Ground Yellow Corn (5-10% moisture) 390 grams Example_4 For use in the field for animals on range, the present pyridinol compounds may be administered by means of salt or molasses blocks. A typical block is prepared using the following compositions:
Weight Percent Ingredients (D.M. Basis) 15 Dried Cane Molasses 35.00 Ground Soyhean Hulls 29.60 3,5,6-Trichloro-2 pyridinol or a physiologically acceptable salt thereof* 5.36 20 Granulated Salt 25.90 Trace Minerals and ~itamins 0.2g Stabilized Animal Fat 1.30 Moisture 2.60 100 . 00 *Provided that the field animal ingests enough of the block per day to provide an effective dose of active ingredient hereinbefore mentioned.
30,249A-F -13-p Exam~le 5 If desired, the present pyridinol compounds may be administered as a part of a liquid animal ~eed supplement such as a supplement containing a non-protein nitrogen source such as urea or ammonium sulfate in : admixture with molasses and other feed ingredients. .
Such a liquid supplement is prepared using the fol-lowing formula:
Weight Percent 10 In~edients (D.M. Basis) Molasses 80.00 Water 16.25 Urea or Ammonium Sulfate 2.00 Trace Minerals .50 15 Vitamin A, D & E .05 Salt 1.00 : 3,5,6-Trichloro-2-pyridinol or j a physiologically acceptable : salt thereof* .20 *Provided the animal drinks enough o~ the li~uid per day to provide an effective dose o~ active ingredien-t hereinbefore mentioned.
The following examples demonstrate the ana~olic ef~ects of the present pyridinols as seen by an incxease in the average daily gain in weight, increased feed conversion ef~iciency, or increased milk production in feeding trials conducted in Europe and in the United States.
30,249A-F -14-~15-I. Protocol and Results for European Trials The process of the present invention was tested in pig feed trials in 4 European countries as a pig growth and as a feed eficiency promoting agent on a total of 520 pigs, including controls. The cowntries included Denmark, England, Germany and ~Iolland (Netherlands~.
The use 2,3,5-trichloropyridinol (TriCP) in feed was from weaning to the end of th~ fa-ttening period. A s-tarter diet was fed to the pigs from the beginning of the weaning period, which was 25 kg (in Germany, 30 kg~ to a weight of 50 kg (in Germany, 65 kg~. ~ finisher diet was fed to the pigs from a weight of 50 kg (in Germany, 65 kg) to the end of the fa-tten-ing period which was 100 kg (in Germany, 105 kg).
Dosage rates of zero "0" (the control), 50, 75 and 100 ppm of TriCP in the feed were tes-ted. Protein supply and energy content of the starter and finisher diets was adapted to represent the most common nutri-tional balance in each country, as represented in Table 1.
30,249A-F 15-6~i3~b Table 1 Nutritional Data of Feed Used in European Trials Energy In Feed ~ Lysine Number % Protein (KCal/Kg in Feed Country of Pi~s Diet By Weight Feed) b Denmark128 Starter 21.4 2098 0.81 Finisher 16.6 2105 0.55 England64 Starter 17.0 2108 0.89 Finisher 15.7 2150 0.77 . _ Germany168 Starter 16.5 2210 0.90 Finisher 15.0 2225 0.70 . . . _ . .
Holland160 Starter 17.0 2190 0.96 Finisher 13.6 2185 0.70 :
30,249A-F -16-.:
3~
- Individual protocols for each European country are provided hereinafter.
IA. Denmark Trial The ~enmark trialplan is shown below.
Feeding Trial Plan in Denmark _ Group Number Number of Pigs 3232 32 32 TriCP concentration 050 75 100 in feed in ppm In each of the four groups there were 32 pigs, divided into 4 pens with 4 males and 4 pens with
4 female pigs. The trial was repeated 4 times. One repetition consisted of 10 pens, with the pigs derived mainly from the same livestock and the weight of the individual pigs differed as little as possible. A11 4 groups were fed the same feed mixture; except that, groups 2, 3 and 4 received 50, 75 and 100 ppm l~riCP, respectively.
As agreed with the Ministry of Agriculture and the Vetexinary Directorate, a withdrawal per:Lod of 10 days a~ter the latest supply of TriCP was follQwed.
To do this all pigs in every repetition received the same feed mixture without additive as soon as -the first pig had reached the time of 10 days before slaughter.
30,249A-F -17-The following quantity of feed was given daily :
Weight, kg 20 30 40 50 60 70 80 Feed units* per pig daily 0.9 1.5 1.9 2.2 2.5 2.7 2.8 * Feed units are calculated according to the Danish Standard. In the feed composition used here it is equal to 1.010 kg.
Table 2 shows the composition and contents of the feed mixture used. The feed was in the forrn of meal and a new lot was produced every month~ To the basic feed the TriCP additives were added. The table shows that up to 50 kg there was a percentage of 24 I5 percent soya in the mixture and after 50 kg this was 12 percent.
30,249A F 18-.~.,;~t~ 6;~P
--lg--Table 2 Feed Mixture Composition and Contents in Denmark Trial Period, kg _ Up to 50 kg After 50 k~
Barley % 73.4 ~5.4 Soya % 24.0 12.0 Chalk % 0.8 0.8 Dicalciumphosphate % 1.2 1.2 Salt % * 0.4 0-4 Vitamine and microelemen~s % 0.2 0.2 Dry stuff % 86.8 87.2 In ~O of Dr~ Stuff Raw protein 21.4 16.6 Raw fat 2.2 2.1 Fiber 5.8 5.5 NFE (Nitrogen Free Extract) 64.~ 70.6 Ash 5.8 5.2 Feed units per kg dry stuff ~ 1.16 Digestible protein, g/unit 154.0 118.0 Digestible lysin, g/unik 8.1 5.5 20 Diyestible Threonine, g/unit 5.~, 4.2 Cvntent per g: 1500 i.e., A-vitamin,~500, i.e., D3-vitamin, 0.01 mg B12-vitamin, 10 mg alpha--tocoferolacetat, 2.5 mg B2-vitamin, 7.S mg pantothenic acid, 0.66 mg natriumse~enit, 50 mg zincoxyde, 62.5 mg copper sulphate, 62.5 mg manganese sulphate, 2.5 mg cobalt sulpha-te, 62.5 mg iron sulphate and 0.5 mg kaliumiodid.
:
30,249A-F -19-IB. England Trial The study was designed to evaluate the growth promotion potential of TriCP as assessed in pigs reared for bacon production. I'he test diets were off~red continuously until the animals reached 100 kg. The pigs were then slaughtered after a 2-week withdrawal period. Weight gain, food consumption and feed utili-zation were measured and at termina-tion carcass data were obtained under commercial conditions.
Thirty-two ~32) castrated males and thirty-two (32) female pigs (Sus scrofa) of the Large White type, approximately 11 weeks old at the start of treatment, were used in the study. They were obtained from R. Beedles, Shadymoor, Dorrington, Shropshire.
The animals were housed throughout the study in a building designed for hacon pig production in ~loor pens of concrete construction. Each floor pen incorporated individual metal feeding cxates, a communal lying area and a dung passage. The pens also contairled automatic dxinkers and wheat straw was provided as bedding material. The building was ventilated by mearls of baffled inlets along the side walls and 2 extract fans in the central roof ridge.
Four feed premixes were used to produce Eour experimental diets, three containing TriCP at difexing inclusion levels and one control diet without TriCP.
The feed premixes were not identified until after termination of the study.
30,249A-F ~20-3~
The animals were delivered -to Huntingdon Research Çenter (HRC) at approxima-tely 8 weeks o age and were maintained on basal diet for 3 weeks prior to -the start of -the experimental period. All pigs were inspected by a veterinary surgeon and were routinely treated with an anthelmintic ('Thiprazole', ~erck, Sharp and Dohme) and a swine erysipelas vaccine (Wel-lcome Foundation Limited).
Immediately before the start of the study, all pigs were allotted a temporary identification number and were weighed and re-examined to assess general health and condition. After discarding spare animals, the pigs selected for use in the study were allocated to treatment according to body weigh-t. In practice this was achieved by stratification by weigh-t (males and females separately) followed by systematic allocation to feeder posi-tions in order star-ting in the irst pen. This procedure minimized the variation in size and weight within pens (blocks). The animals were then tagged with permanent identifica-tion numbers to keep track of each Animal's identity.
The pigs were offered one o 2 pelleted concentrate rations throughout the study. The irs~
ration was a grower or starter ration with a higher nutrien,t density. The grower ration was used initially and up to 50 kg body weight, and was xeplaced by a pig ~inisher diet from 50 kg to termina-tion. The composi-tion and specification of these 2 basal diets is given in Table 3.
30,249A-F ~21-Table 3 Feed Mixture Composition and_Contents in England Trial Pig grower Pig finisher ration ration ~< 50 kg ~> 50 kg body weight) body welght) Composition Barley 40.51 40.51 (% w/w) Wheat 10.00 10.00 Maize 15.00 15.00 Extracted soya bean meal 14.50 11.50 Provimi 66 fish meal 3.50 2.50 Weatings 10.00 15.00 Dicalcium phosphate 0.44 0.44 Limestone flour 1.05 1.05 Salt 0.25 0.25 Molasses 2.50 2.50 Fat premix (50%) 2.00 1.00 Beta 114* 0.25 0.25 Pellet size (mm diameter) 4 10 Theoretical Oil 3.25 2.85 25 analysis (%) Crude Protein16.95 15.66 Fiber 4.48 4.61 Total digestible - nutrienks 71.81 70.93 Digestible energy 30 MJ/kg (approx.) 13.00 12.75 Lysine 0.89 0.77 Methionine and cystine 0.56 0.51 Calcium 0.87 0.81 Phosphorus 0.60 0.5 Salt 0.47 ~ 0.46 * Mineral/vitamin premix ~B.P. Nutrition~ - formulated without the standard inclusion of copper at 180 ppm 30,249A-F -22~
A restricted feedin~ regime was used in accordance with normal commercial practice. The pigs were given 2 e~ual feeds per da~, the feed allowance based on body weight as follows:
5Body weight (kg)Feed allowance (g ~er feed~
< 25.0 500 25.5 to 30.0 600 30.5 to 35.0 700 35.5 to 40.0 800 1040.5 to 45.0 900 45.5 to 50.0 1000 50.5 to 55.0 1100 55.5 to 60.0 1200 60.5 to 65.0 1300 > 65.0 1400 Animals were weighed and feed allowances adjusted at`
weekly intervals.
All feed reusals were measured and recorded and the total weekl~ food consumption for each pig was derived.
Test diets wPre mixed and pelleted in batches of 0.5 ox 1.0 tonne as follows: 1 tonne batches of basal diet (2 or 4 as appropriate) were first mixed and retained in meal form in 25 kg bags. These were then divided into 4 lots of 0.5 or 1.0 tonne such -that each lot consisted of an equal num~er of bags selected at random from each basal 1 tonne mix. Test die-ts were then prepared by returning each 0.5 or 1.0 tonne of 30,249A~F -23-meal to the mixer together with the appropriate tes-t premix (pre-weighed and supplied by HRC). The mix was then pelleted to produce the finished diet.
Before the start of the study, 4 x 0.5 tonnes of test diets were prepared using the test premixes at the intended inclusion level of 500 g/tonne and samples of the diets taken both be~ore and after pelleking were submitted for assay. All samples were assayed at 40 percent below nominal levels and further test diets were prepared using 750 g of premix/tonne. Analysis of this second batch of diets showed recovery of target levels of TriCP. This was the required premix inclu-sion level throughout the -trial.
In all test diets used throughout the study, premixes were included a-t a level of 750 g per tonne of finished feed. The levels of test compound in each diet (ppm) after termination of the study, are as shown in Table 1.
On completion o~ its 2 week withdraw~l period (basal diet only) each pig was sent for slaughter at an approved commercial abatkoir. The eviscerated carcasses were weighed a~d graded and this in~ormation was re-turned to HRC.
All pigs were maintained on test diet from the start of the test period until they reached 100 kg live weight. They were then fed with basal diet only for a period of 2 weeks before slaughter. All piy5 were observed daily and any clinically abnormal signs were noted.
30,249A-F -24-IC. Germany Trial In a test on growing pigs, the effect of the additive 3,5,6-trichloro-2-pyridinol (TriCP~ on the body weight gain, feed consumption and feed conversion was investigated. The aim of the investigations was to determine the effectiveness of the additive from the nutrition physiology point of view.
A total of 168 pigs consisting of ec~ual numbers of castrated males and females were available for the tests. The pigs were largely of uniform ~enetic origin. The animals were numbered individually. At the start of the test each pig had a body weight of about 30kg. Fattening was continued until a final weight of about 105 kg was achieved.
The 168 test pigs were divided into our treatment groups at the start of the test, so th~t 42 animals were subjected to treatment in each case. Each test group was subdivided into seven sub-groups with six animals in each sub-group. These six pigs were kept together in a pen.
The our test groups were trea-ted as follows.
One group was kept as a control group without addition of the additive. Three further groups were used as test groups, in which TriCP was administered in a dosage of 5Q ppm, 75 ppm or 100 ppm in the feed.
. The composition of the test feed met the requirements of the "Feed Regulations in the Federal Republic of Germany". Table 4 gives details of the nutrient content of the test feed.
30,249A F -25--2~
Table 4 Contents of the Test Mixtures in Percent in German~ Trial Preparatory Feeding Raw Protein 16.50 Lysine 0.90 Raw Fat 4.25 Starch 39.00 Sugar 4,50 Crude Fiber 3.~/5 Calcium 0.90 Phosphorus 0.60 Sodium 0.20 Final Fattenin~
Raw Protein 15.00 Lysine 0.70 Raw Fat 4.75 Starch 38.25 Sugar 4.70 - Crude Fiber 4.40 Calcium 0O85 Phosphorus 0.55 'I Sodium 0.18 . . ", . . .
I
30,249A-F -26-$~
The test animals were kept in a closed house on the experimental farm at Gottingen University. The environmental condi-tions were largely standardized.
The feed was distributed twice daily a-t fixed times (8 a.m. and 3 p.m.~. Water consumption ~as ensured by automatic drinking bowls.
The following criteria were checked during the test. The body weights of -the individual animals were weighed every 28 days. This interval was reduced to 21 days for some sub groups at the end of the test.
This was necessary, if the body weight trend with a 28 day interval between the last two weighings would have resulted in excessive final weights.
The feed consumption of the o~uantity of feed consumed daily was recorded. The feed conversisn per kg gain was calculated from the feed consump~ion and the gain in body weight.
.
ID. ~olland Trial In this trial the effect of oral adminis-tration of khree doshges of TriCP on we:Lyht gain and eed conversion efficiency is described. The effect of TriCP on the~e criteria is compared with that of a control group without a growth promotor.
. The study was carried out with 160 pigs distributed arnony four groups of 40 animals each. Each group contained five repetitions of eight animals, (2 pens with 8 castrated males, 3 pens with 8 females~.
The trial was comprised of two periods. A first period of 0 to 6 weeks, wherein the live weight of the pigs 30,249A-F 27-~ ~9~i~3~
-28~
was 22 to 45 kg, in which pigs receiving 50, 75 or 100 ppm TriCP were compared with a control group without supplementation. The second period was 6 to 16/18 weeks, wherein the live weight of the pigs was 45 to 100 kg, in which pigs receiving 50, 75 or 100 ppm TriCP were compared-with a control group withou-t supplemen-tation.
The pigs were of the cross Dutch Landrace x Large White. For this experiment 64 castrated males and 96 females of a known offspring were purchased.
The animals were selected in such a way that the varia-tion in age and live weight was as small as possible.
At the beginning of the feed trial the aye of the piglets was eight weeks; the average live weight of the females was 21.5 kg and of the castrated males 21.9 kg.
Before the feed -trial commenced the pigs were fed a commercial ration containing an antibiotic. Six weeks after arrival of the animals at the Institute they were treated with 0.25 g piperazine adipas per kg body weight~
One day after arrival of the animals ak the Institute they were distributed among the four treat-ment groups in such a way, that the groups were com-parable with respect to sex, parentage, age and live weight. For both sexes ~h~ avexage initial live weight and their standard deviation was equalized as well as possible for each group. In general each group com-prised no more than one animal of the same litter.
.
The pigs were housed in a piggery of the Danish -type with partly slatted floors withou-t straw.
30,249A F ~28-3~
~9 The piggery holds 24 pens. Eight animals wexe housed in each pen. Ten pens held cas-tra-ted males and 14 pens females. The piggery is lighted, heated and ventilated ar-tificially.
The minimal and maximal temperature in the piggery varied during the whole experimental period - between 15 and 22C.
The experiment consisted of two treatment periods of 6 and 10 weeks, respectively, during which the experimental rations were fed.
The composition of the diets is given in Table 5. The diets for the animals of groups 1 to 4 contai~ed no extra copper.
30,249A-F -29-.30~3 Table 5 Feed Mixtu.re, Composition and Conten-ts in Holland Trial Ingredient 0 - 6 week~ 6 - 16/18 weeks Wheat 10.0 11.0
As agreed with the Ministry of Agriculture and the Vetexinary Directorate, a withdrawal per:Lod of 10 days a~ter the latest supply of TriCP was follQwed.
To do this all pigs in every repetition received the same feed mixture without additive as soon as -the first pig had reached the time of 10 days before slaughter.
30,249A-F -17-The following quantity of feed was given daily :
Weight, kg 20 30 40 50 60 70 80 Feed units* per pig daily 0.9 1.5 1.9 2.2 2.5 2.7 2.8 * Feed units are calculated according to the Danish Standard. In the feed composition used here it is equal to 1.010 kg.
Table 2 shows the composition and contents of the feed mixture used. The feed was in the forrn of meal and a new lot was produced every month~ To the basic feed the TriCP additives were added. The table shows that up to 50 kg there was a percentage of 24 I5 percent soya in the mixture and after 50 kg this was 12 percent.
30,249A F 18-.~.,;~t~ 6;~P
--lg--Table 2 Feed Mixture Composition and Contents in Denmark Trial Period, kg _ Up to 50 kg After 50 k~
Barley % 73.4 ~5.4 Soya % 24.0 12.0 Chalk % 0.8 0.8 Dicalciumphosphate % 1.2 1.2 Salt % * 0.4 0-4 Vitamine and microelemen~s % 0.2 0.2 Dry stuff % 86.8 87.2 In ~O of Dr~ Stuff Raw protein 21.4 16.6 Raw fat 2.2 2.1 Fiber 5.8 5.5 NFE (Nitrogen Free Extract) 64.~ 70.6 Ash 5.8 5.2 Feed units per kg dry stuff ~ 1.16 Digestible protein, g/unit 154.0 118.0 Digestible lysin, g/unik 8.1 5.5 20 Diyestible Threonine, g/unit 5.~, 4.2 Cvntent per g: 1500 i.e., A-vitamin,~500, i.e., D3-vitamin, 0.01 mg B12-vitamin, 10 mg alpha--tocoferolacetat, 2.5 mg B2-vitamin, 7.S mg pantothenic acid, 0.66 mg natriumse~enit, 50 mg zincoxyde, 62.5 mg copper sulphate, 62.5 mg manganese sulphate, 2.5 mg cobalt sulpha-te, 62.5 mg iron sulphate and 0.5 mg kaliumiodid.
:
30,249A-F -19-IB. England Trial The study was designed to evaluate the growth promotion potential of TriCP as assessed in pigs reared for bacon production. I'he test diets were off~red continuously until the animals reached 100 kg. The pigs were then slaughtered after a 2-week withdrawal period. Weight gain, food consumption and feed utili-zation were measured and at termina-tion carcass data were obtained under commercial conditions.
Thirty-two ~32) castrated males and thirty-two (32) female pigs (Sus scrofa) of the Large White type, approximately 11 weeks old at the start of treatment, were used in the study. They were obtained from R. Beedles, Shadymoor, Dorrington, Shropshire.
The animals were housed throughout the study in a building designed for hacon pig production in ~loor pens of concrete construction. Each floor pen incorporated individual metal feeding cxates, a communal lying area and a dung passage. The pens also contairled automatic dxinkers and wheat straw was provided as bedding material. The building was ventilated by mearls of baffled inlets along the side walls and 2 extract fans in the central roof ridge.
Four feed premixes were used to produce Eour experimental diets, three containing TriCP at difexing inclusion levels and one control diet without TriCP.
The feed premixes were not identified until after termination of the study.
30,249A-F ~20-3~
The animals were delivered -to Huntingdon Research Çenter (HRC) at approxima-tely 8 weeks o age and were maintained on basal diet for 3 weeks prior to -the start of -the experimental period. All pigs were inspected by a veterinary surgeon and were routinely treated with an anthelmintic ('Thiprazole', ~erck, Sharp and Dohme) and a swine erysipelas vaccine (Wel-lcome Foundation Limited).
Immediately before the start of the study, all pigs were allotted a temporary identification number and were weighed and re-examined to assess general health and condition. After discarding spare animals, the pigs selected for use in the study were allocated to treatment according to body weigh-t. In practice this was achieved by stratification by weigh-t (males and females separately) followed by systematic allocation to feeder posi-tions in order star-ting in the irst pen. This procedure minimized the variation in size and weight within pens (blocks). The animals were then tagged with permanent identifica-tion numbers to keep track of each Animal's identity.
The pigs were offered one o 2 pelleted concentrate rations throughout the study. The irs~
ration was a grower or starter ration with a higher nutrien,t density. The grower ration was used initially and up to 50 kg body weight, and was xeplaced by a pig ~inisher diet from 50 kg to termina-tion. The composi-tion and specification of these 2 basal diets is given in Table 3.
30,249A-F ~21-Table 3 Feed Mixture Composition and_Contents in England Trial Pig grower Pig finisher ration ration ~< 50 kg ~> 50 kg body weight) body welght) Composition Barley 40.51 40.51 (% w/w) Wheat 10.00 10.00 Maize 15.00 15.00 Extracted soya bean meal 14.50 11.50 Provimi 66 fish meal 3.50 2.50 Weatings 10.00 15.00 Dicalcium phosphate 0.44 0.44 Limestone flour 1.05 1.05 Salt 0.25 0.25 Molasses 2.50 2.50 Fat premix (50%) 2.00 1.00 Beta 114* 0.25 0.25 Pellet size (mm diameter) 4 10 Theoretical Oil 3.25 2.85 25 analysis (%) Crude Protein16.95 15.66 Fiber 4.48 4.61 Total digestible - nutrienks 71.81 70.93 Digestible energy 30 MJ/kg (approx.) 13.00 12.75 Lysine 0.89 0.77 Methionine and cystine 0.56 0.51 Calcium 0.87 0.81 Phosphorus 0.60 0.5 Salt 0.47 ~ 0.46 * Mineral/vitamin premix ~B.P. Nutrition~ - formulated without the standard inclusion of copper at 180 ppm 30,249A-F -22~
A restricted feedin~ regime was used in accordance with normal commercial practice. The pigs were given 2 e~ual feeds per da~, the feed allowance based on body weight as follows:
5Body weight (kg)Feed allowance (g ~er feed~
< 25.0 500 25.5 to 30.0 600 30.5 to 35.0 700 35.5 to 40.0 800 1040.5 to 45.0 900 45.5 to 50.0 1000 50.5 to 55.0 1100 55.5 to 60.0 1200 60.5 to 65.0 1300 > 65.0 1400 Animals were weighed and feed allowances adjusted at`
weekly intervals.
All feed reusals were measured and recorded and the total weekl~ food consumption for each pig was derived.
Test diets wPre mixed and pelleted in batches of 0.5 ox 1.0 tonne as follows: 1 tonne batches of basal diet (2 or 4 as appropriate) were first mixed and retained in meal form in 25 kg bags. These were then divided into 4 lots of 0.5 or 1.0 tonne such -that each lot consisted of an equal num~er of bags selected at random from each basal 1 tonne mix. Test die-ts were then prepared by returning each 0.5 or 1.0 tonne of 30,249A~F -23-meal to the mixer together with the appropriate tes-t premix (pre-weighed and supplied by HRC). The mix was then pelleted to produce the finished diet.
Before the start of the study, 4 x 0.5 tonnes of test diets were prepared using the test premixes at the intended inclusion level of 500 g/tonne and samples of the diets taken both be~ore and after pelleking were submitted for assay. All samples were assayed at 40 percent below nominal levels and further test diets were prepared using 750 g of premix/tonne. Analysis of this second batch of diets showed recovery of target levels of TriCP. This was the required premix inclu-sion level throughout the -trial.
In all test diets used throughout the study, premixes were included a-t a level of 750 g per tonne of finished feed. The levels of test compound in each diet (ppm) after termination of the study, are as shown in Table 1.
On completion o~ its 2 week withdraw~l period (basal diet only) each pig was sent for slaughter at an approved commercial abatkoir. The eviscerated carcasses were weighed a~d graded and this in~ormation was re-turned to HRC.
All pigs were maintained on test diet from the start of the test period until they reached 100 kg live weight. They were then fed with basal diet only for a period of 2 weeks before slaughter. All piy5 were observed daily and any clinically abnormal signs were noted.
30,249A-F -24-IC. Germany Trial In a test on growing pigs, the effect of the additive 3,5,6-trichloro-2-pyridinol (TriCP~ on the body weight gain, feed consumption and feed conversion was investigated. The aim of the investigations was to determine the effectiveness of the additive from the nutrition physiology point of view.
A total of 168 pigs consisting of ec~ual numbers of castrated males and females were available for the tests. The pigs were largely of uniform ~enetic origin. The animals were numbered individually. At the start of the test each pig had a body weight of about 30kg. Fattening was continued until a final weight of about 105 kg was achieved.
The 168 test pigs were divided into our treatment groups at the start of the test, so th~t 42 animals were subjected to treatment in each case. Each test group was subdivided into seven sub-groups with six animals in each sub-group. These six pigs were kept together in a pen.
The our test groups were trea-ted as follows.
One group was kept as a control group without addition of the additive. Three further groups were used as test groups, in which TriCP was administered in a dosage of 5Q ppm, 75 ppm or 100 ppm in the feed.
. The composition of the test feed met the requirements of the "Feed Regulations in the Federal Republic of Germany". Table 4 gives details of the nutrient content of the test feed.
30,249A F -25--2~
Table 4 Contents of the Test Mixtures in Percent in German~ Trial Preparatory Feeding Raw Protein 16.50 Lysine 0.90 Raw Fat 4.25 Starch 39.00 Sugar 4,50 Crude Fiber 3.~/5 Calcium 0.90 Phosphorus 0.60 Sodium 0.20 Final Fattenin~
Raw Protein 15.00 Lysine 0.70 Raw Fat 4.75 Starch 38.25 Sugar 4.70 - Crude Fiber 4.40 Calcium 0O85 Phosphorus 0.55 'I Sodium 0.18 . . ", . . .
I
30,249A-F -26-$~
The test animals were kept in a closed house on the experimental farm at Gottingen University. The environmental condi-tions were largely standardized.
The feed was distributed twice daily a-t fixed times (8 a.m. and 3 p.m.~. Water consumption ~as ensured by automatic drinking bowls.
The following criteria were checked during the test. The body weights of -the individual animals were weighed every 28 days. This interval was reduced to 21 days for some sub groups at the end of the test.
This was necessary, if the body weight trend with a 28 day interval between the last two weighings would have resulted in excessive final weights.
The feed consumption of the o~uantity of feed consumed daily was recorded. The feed conversisn per kg gain was calculated from the feed consump~ion and the gain in body weight.
.
ID. ~olland Trial In this trial the effect of oral adminis-tration of khree doshges of TriCP on we:Lyht gain and eed conversion efficiency is described. The effect of TriCP on the~e criteria is compared with that of a control group without a growth promotor.
. The study was carried out with 160 pigs distributed arnony four groups of 40 animals each. Each group contained five repetitions of eight animals, (2 pens with 8 castrated males, 3 pens with 8 females~.
The trial was comprised of two periods. A first period of 0 to 6 weeks, wherein the live weight of the pigs 30,249A-F 27-~ ~9~i~3~
-28~
was 22 to 45 kg, in which pigs receiving 50, 75 or 100 ppm TriCP were compared with a control group without supplementation. The second period was 6 to 16/18 weeks, wherein the live weight of the pigs was 45 to 100 kg, in which pigs receiving 50, 75 or 100 ppm TriCP were compared-with a control group withou-t supplemen-tation.
The pigs were of the cross Dutch Landrace x Large White. For this experiment 64 castrated males and 96 females of a known offspring were purchased.
The animals were selected in such a way that the varia-tion in age and live weight was as small as possible.
At the beginning of the feed trial the aye of the piglets was eight weeks; the average live weight of the females was 21.5 kg and of the castrated males 21.9 kg.
Before the feed -trial commenced the pigs were fed a commercial ration containing an antibiotic. Six weeks after arrival of the animals at the Institute they were treated with 0.25 g piperazine adipas per kg body weight~
One day after arrival of the animals ak the Institute they were distributed among the four treat-ment groups in such a way, that the groups were com-parable with respect to sex, parentage, age and live weight. For both sexes ~h~ avexage initial live weight and their standard deviation was equalized as well as possible for each group. In general each group com-prised no more than one animal of the same litter.
.
The pigs were housed in a piggery of the Danish -type with partly slatted floors withou-t straw.
30,249A F ~28-3~
~9 The piggery holds 24 pens. Eight animals wexe housed in each pen. Ten pens held cas-tra-ted males and 14 pens females. The piggery is lighted, heated and ventilated ar-tificially.
The minimal and maximal temperature in the piggery varied during the whole experimental period - between 15 and 22C.
The experiment consisted of two treatment periods of 6 and 10 weeks, respectively, during which the experimental rations were fed.
The composition of the diets is given in Table 5. The diets for the animals of groups 1 to 4 contai~ed no extra copper.
30,249A-F -29-.30~3 Table 5 Feed Mixtu.re, Composition and Conten-ts in Holland Trial Ingredient 0 - 6 week~ 6 - 16/18 weeks Wheat 10.0 11.0
5 Barley 27.0 Corn germmeal feed ~ 15.0 Wheat middlings 5.0 20.0 Tapioca 23.2 32.7 Soya oil 1.5 2.5 10 Whey powder (delactosed) 2.0 Whey powder 5.0 Soybean oilmeal 23.0 15.6 Vitamins, minerals ** 3.3 3.2 Calculated contents ~in %) Crude protein 17.0(16.6*) 13.6(14.4*) Lysine 0.96 0.70 Methionine ~ cystine 0.55 0.45 Net energy (kcal/kg) (2190) (2185~
Calcium 0.95(0.96*) 0.80(0.89*) Phosphorous 0.75(0.70*) 0.65(0.65*) * Analyzed ** The vitamin premix supplied per 1 kg die-t: 6,000 I.U. Vitamin A, 1,200 I.U. Vitamin D3, 25 mg Vitamin E, 2 mg Vitamin K, 4 mg Riboflavin, 20 mg Niacin, 10 mg d-Pantothenic acid, 80 mg Choline chloride, 0.030 mg Vitamin B12, 0.54 mg Kl and 4.65 mg COSOg-7H2O.
30,249A-F -30 After mixing ~he basal ra-tion, it was divided into five sub-charges and then supplemented respectively with carrier and 50, 75 and 100 ppm TriCP. The mixing was done in several batches. Sampling of batches followed by analysis of crude protein, calcium and phosphorus were carried out.
The animals were fed in groups of eight, twice a day, according to a fixed scheme based on the mean body weight of the animals of each pen. If the pigs of one or more pens grow faster than khose in other pens, they were offered more feed. After each feeding, the meal for the next feeding was mixed with water in a 1:1 ra~io. The pigs had free access to fresh water via automatic drinkers.
State of health of the pigs was observed daily. Live w~ight of the pigs was determined every three weeks. Feed conversion efficiency (kg feed/kg live weight gain) was calculated per pen of eight animal~ at the time oE each weighing. The animals were slaughtered 16, 17 or 18 weeks after the start of the experiment. The experimental rations were Eed -till 24 hours before slaughter, except for some castrated male animals of group 4 (75 ppm): for one animal of this group the withdrawal time was 0 days, for three animals three days and for three animals seven days.
30,249A-F -31-' ;
~3~
Summary of Results for European Trials - After the end of the finisher diets, individual pig weights and amount of feed consumed were ob-tained in order to determine weight gains and efficiency o~
feed use. The results for swine average daily weighk gain for pigs receiving TriCP are presented in Table 6.
The results for the feed conversion efficiency by the pigs receiving TriCP are presen-ted in Table 7.
Table 6 SWINE AVERAGE DAILY WEIGHT GAIN (ADG~ IN GRAMS/DAY
DURING FINISHING PERIOD (50 TO 100 KG) Number Concentration of Country of Pi~s TrlCP in Feed in ppm Denmark 12~696(0)~730(+34)1 712(+16) 729(+33) ~ngland 64777(0) 765(-12) 759(-la) 8~0(-~43) Germany 168705(0)792(-~7) i732(~27) 697(~8) Holland 160710~0)747(+37) 738(+2a) 738(~28) ~ Numbers in parenthesis ( ) represent ~he diffexence in weight gain between those animals recei~ing TriCP
in their diets and those receiving "0" or n~ TriCP.
As can be seen in Table 6, TriCP was effective in increasing the daily weight gain in swine receiving ~eed containing from 50 to 100 ppm TriCP.
30,249A-F -32-Table 7 FEED CONVERSION EFFICIENCY BY PIGS RECEIVING TRICP
Concen-tration Feed Effici-of TriCP ency of pigs in feed 50-l00 kg Country (ppm~ (%) England Q l00.0 l0l.8 l0~.0 l00 93.3 Germany 0 l00.0 89.4 94.7 1 5 100 101 .
1 Measurements taken at pig weights 65 to 1.00 kg As can be seen in Table 7, pigs receiving TriCP achieved a feed conversion efficiency of 6 percent or more over the pigs not receiving TriCP, where average daily weight gains were also increased as in Table 6.
30,249A-F -33-.3~ d~
-~4--II. Protocol for United States Trials Example 6: The anabolic effect of sodium 3,5,6--tri.-chloro-2-pyridinate as exhibited by an increase in average daily gain and an increase in feed conversion efficiency for swine.
T~ree-hundred-forty (340) swine averaging 20 kg each, were allotted into 5 treat.ments of 6 replicates of 8 animals and 2 replicates of 10 animals. The animals were fed a two part basal diet consisting of:
~ of Diet ~ ient Grower Diet _ _ ?i n~ ~her DiY ~
Ground Corn79.60 (722 kg/ton)84.64 (767 kg/ton) Soybean Oil Meal 17.85 ~162 kg/ton) 12.91 (117 kg/ton) 15 Defluorinated Rock Rhosphate 1.80 (16 kg/ton) 1.80 (16 kg/ton) Salt 0.50 (4.5 kg/ton)0.50 ~4.5 kg/ton) Trace Mineral &
Vitamin Premix 0.25 (2.2 kg/kon) 0.25 (2.~ kg/ton) whereby the grower diet was fed to animals until they xeached a weight of 55 kg and the finisher diet was fed to animals thereafter.
To these dlets, sodium 3,5,6-trichloro-2 pyridinate, hereinafter referred to as Na-TriCP, was added at a rate so that the different trea~ment groups received 1 mg/kg/day, 2 mg~kg/day, 3 mg/kg/day and 4 mg/kg/day of Na-TriCP in accordance with the invention.
30,249A-F 34~
3.~
The control group was fed the basal diet alone wi-th no addition of Na-TriCP. After a 112 day total feeding period, weight gains and feed consump-tion of -the animals were determined. The results obtained are -tabulated as follows:
Average Dose of Sodium 3,5,6--Trichloro-2-~yridinate, mg/kg/da~*
Treatment 0 1 2 3 4 Avg. Daily Feed Consumption, lb. 5~32 5.32 5.43 5.68 5.59 Avg. Daily Gain, lb. 1.54 1.61 1.63 1.72 1.72 Feed Conversion Efficiency 3.46 3.32 3.34 3.31 3.26 *The average daily dose of sodium 3,5,6~tri-chloropyridinate in mg/kg was achieved by incorporatingNa-TriCP into the feed in 25 ppm, 50 ppm, 75 ppm and 100 ppm which correspond to an average dose of 1 mg/kg/day, 2 mg/kg/day, 3 mg/kg/day and 4 mg/kg/day respectively.
This is based on the average daily feed intake and the average weight of the animals. The actual dose of Na-TriCP may have varied from day to day.
The anabolic efec~ of 3,5,6-trichloro-2--pyridinol as e~hibiked by an increase in milk production of lactating cows.
Six ~6) lactating Holstein-Friesian cows, in their 4th to 10th week of lactation, were allotted into 2 treatments consisting of 3 cows each. All animals were fed the same ration except the second group which was fed the ration plus 3,5,6-trichloro-2-pyridinol, hereinafter referred to as TriCP, at levels that were increased at 14 day intervals for 6 feeding periods.
30,249A-F -35-.; .
~36-At the end of these feeding pexiods, a 14 day withdrawal period was insti-tuted. The concentrations of TriCP
added to the ration were as follows:
Concentration of 5 Feeding Period TriCP in ppm (14 days)Group 1 ~Control~ Group 2 1 (prefeeding) O O
Calcium 0.95(0.96*) 0.80(0.89*) Phosphorous 0.75(0.70*) 0.65(0.65*) * Analyzed ** The vitamin premix supplied per 1 kg die-t: 6,000 I.U. Vitamin A, 1,200 I.U. Vitamin D3, 25 mg Vitamin E, 2 mg Vitamin K, 4 mg Riboflavin, 20 mg Niacin, 10 mg d-Pantothenic acid, 80 mg Choline chloride, 0.030 mg Vitamin B12, 0.54 mg Kl and 4.65 mg COSOg-7H2O.
30,249A-F -30 After mixing ~he basal ra-tion, it was divided into five sub-charges and then supplemented respectively with carrier and 50, 75 and 100 ppm TriCP. The mixing was done in several batches. Sampling of batches followed by analysis of crude protein, calcium and phosphorus were carried out.
The animals were fed in groups of eight, twice a day, according to a fixed scheme based on the mean body weight of the animals of each pen. If the pigs of one or more pens grow faster than khose in other pens, they were offered more feed. After each feeding, the meal for the next feeding was mixed with water in a 1:1 ra~io. The pigs had free access to fresh water via automatic drinkers.
State of health of the pigs was observed daily. Live w~ight of the pigs was determined every three weeks. Feed conversion efficiency (kg feed/kg live weight gain) was calculated per pen of eight animal~ at the time oE each weighing. The animals were slaughtered 16, 17 or 18 weeks after the start of the experiment. The experimental rations were Eed -till 24 hours before slaughter, except for some castrated male animals of group 4 (75 ppm): for one animal of this group the withdrawal time was 0 days, for three animals three days and for three animals seven days.
30,249A-F -31-' ;
~3~
Summary of Results for European Trials - After the end of the finisher diets, individual pig weights and amount of feed consumed were ob-tained in order to determine weight gains and efficiency o~
feed use. The results for swine average daily weighk gain for pigs receiving TriCP are presented in Table 6.
The results for the feed conversion efficiency by the pigs receiving TriCP are presen-ted in Table 7.
Table 6 SWINE AVERAGE DAILY WEIGHT GAIN (ADG~ IN GRAMS/DAY
DURING FINISHING PERIOD (50 TO 100 KG) Number Concentration of Country of Pi~s TrlCP in Feed in ppm Denmark 12~696(0)~730(+34)1 712(+16) 729(+33) ~ngland 64777(0) 765(-12) 759(-la) 8~0(-~43) Germany 168705(0)792(-~7) i732(~27) 697(~8) Holland 160710~0)747(+37) 738(+2a) 738(~28) ~ Numbers in parenthesis ( ) represent ~he diffexence in weight gain between those animals recei~ing TriCP
in their diets and those receiving "0" or n~ TriCP.
As can be seen in Table 6, TriCP was effective in increasing the daily weight gain in swine receiving ~eed containing from 50 to 100 ppm TriCP.
30,249A-F -32-Table 7 FEED CONVERSION EFFICIENCY BY PIGS RECEIVING TRICP
Concen-tration Feed Effici-of TriCP ency of pigs in feed 50-l00 kg Country (ppm~ (%) England Q l00.0 l0l.8 l0~.0 l00 93.3 Germany 0 l00.0 89.4 94.7 1 5 100 101 .
1 Measurements taken at pig weights 65 to 1.00 kg As can be seen in Table 7, pigs receiving TriCP achieved a feed conversion efficiency of 6 percent or more over the pigs not receiving TriCP, where average daily weight gains were also increased as in Table 6.
30,249A-F -33-.3~ d~
-~4--II. Protocol for United States Trials Example 6: The anabolic effect of sodium 3,5,6--tri.-chloro-2-pyridinate as exhibited by an increase in average daily gain and an increase in feed conversion efficiency for swine.
T~ree-hundred-forty (340) swine averaging 20 kg each, were allotted into 5 treat.ments of 6 replicates of 8 animals and 2 replicates of 10 animals. The animals were fed a two part basal diet consisting of:
~ of Diet ~ ient Grower Diet _ _ ?i n~ ~her DiY ~
Ground Corn79.60 (722 kg/ton)84.64 (767 kg/ton) Soybean Oil Meal 17.85 ~162 kg/ton) 12.91 (117 kg/ton) 15 Defluorinated Rock Rhosphate 1.80 (16 kg/ton) 1.80 (16 kg/ton) Salt 0.50 (4.5 kg/ton)0.50 ~4.5 kg/ton) Trace Mineral &
Vitamin Premix 0.25 (2.2 kg/kon) 0.25 (2.~ kg/ton) whereby the grower diet was fed to animals until they xeached a weight of 55 kg and the finisher diet was fed to animals thereafter.
To these dlets, sodium 3,5,6-trichloro-2 pyridinate, hereinafter referred to as Na-TriCP, was added at a rate so that the different trea~ment groups received 1 mg/kg/day, 2 mg~kg/day, 3 mg/kg/day and 4 mg/kg/day of Na-TriCP in accordance with the invention.
30,249A-F 34~
3.~
The control group was fed the basal diet alone wi-th no addition of Na-TriCP. After a 112 day total feeding period, weight gains and feed consump-tion of -the animals were determined. The results obtained are -tabulated as follows:
Average Dose of Sodium 3,5,6--Trichloro-2-~yridinate, mg/kg/da~*
Treatment 0 1 2 3 4 Avg. Daily Feed Consumption, lb. 5~32 5.32 5.43 5.68 5.59 Avg. Daily Gain, lb. 1.54 1.61 1.63 1.72 1.72 Feed Conversion Efficiency 3.46 3.32 3.34 3.31 3.26 *The average daily dose of sodium 3,5,6~tri-chloropyridinate in mg/kg was achieved by incorporatingNa-TriCP into the feed in 25 ppm, 50 ppm, 75 ppm and 100 ppm which correspond to an average dose of 1 mg/kg/day, 2 mg/kg/day, 3 mg/kg/day and 4 mg/kg/day respectively.
This is based on the average daily feed intake and the average weight of the animals. The actual dose of Na-TriCP may have varied from day to day.
The anabolic efec~ of 3,5,6-trichloro-2--pyridinol as e~hibiked by an increase in milk production of lactating cows.
Six ~6) lactating Holstein-Friesian cows, in their 4th to 10th week of lactation, were allotted into 2 treatments consisting of 3 cows each. All animals were fed the same ration except the second group which was fed the ration plus 3,5,6-trichloro-2-pyridinol, hereinafter referred to as TriCP, at levels that were increased at 14 day intervals for 6 feeding periods.
30,249A-F -35-.; .
~36-At the end of these feeding pexiods, a 14 day withdrawal period was insti-tuted. The concentrations of TriCP
added to the ration were as follows:
Concentration of 5 Feeding Period TriCP in ppm (14 days)Group 1 ~Control~ Group 2 1 (prefeeding) O O
6 0 100
7 0 O (withdrawal) Milking and feeding were done on a morning and evening schedule for each cow. The feeding was done after the milking.
The average daily feed consumption in kg; the average daily d.ry matter milk production in kg; and the milk production efficiency are as follows:
G:roup 1 ~Control~ Gro~
Avg. Daily Feed Conswmption in kg 18.52 18.1 Avg. Daily ~ry Matter Milk Production per day in kg* 2.15 2.41 Milk Production Effic.iency 8.51 7.54 *the dry matter milk production is equal to 12% of the actual milk production.
30,249A-F -36-' :' -37~
Example ~: The anabolic effect of sodium 3,5,6-tri-chloro-2-pyridinate as exhibited by an increase in average daily ga.in and an increase in ~eed conversion efficiency for beef cat-tle.
Two hundred fifty-six (256) steer calves averaging 283 kg (625 lbs~ were allotted into four (4) treatments of 8 replicates of 8 animals, i.e., 64 animals per treatment. The animals were assigned to replicates in a randomized complete block design. The animals were fed a two part basal diet consisting of:
% of Diet (by Weigh~
Intermedlate Finlshlng _ In~redient _ Ration Ration .
Dehydrated Alfalfa Meal 10.0 5.0 Cottonseed Hulls 15.0 10.0 Steam Rolled Corn 58.0 74.8 Soybean Meal (44%) 10.0 3.0 Calcium Carbonate 1.0 0.7 20 Na Tripolypho~phate 0.5 0.3 Cane Molasses 5.0 5.0 Trace Min0rali.zed Salt 0.5 0.5 Urea None 0.7 whereby the int~rmediate ration was fed to animals the first 28 days o~ the e~periment and -the finishing ration was ~ed to animals thereafter. All dieks and water were available to the animals on an ad libitum basis.
30,249A~F -37-,,, ~38-To the above diets, sodium 3,5,6~trichloro-2-pyridirlate ~Na-TriCP) was added in amounts sufficient to satisfy the dose requirements of Na~TriCP each treatment was to receive, namely:
Concentration o~
TreatmentNa-TriCP in Diet (wt. percent) 1 0 tControl) 2 0.005 (50 ppm) 3 0.0075 (75 ppm) 4 0.01 (100 ppm) The control diet contained no Na-TriCP while -the other three treatments were fed diets containing ~a-TriCP in concentrations listed above. After a 112 day total eeding period, weight gains and feed conversion effici ency improvements were determined. The average inikial weight, average 112-day weight, average daily gain, average feed intake per day and, average feed conver-sion efficiency (feed consumed/body weight gain) are tabulated as follows:
_ Treatment ~ 3 _ _ 4 Average initial weight (kg) 285 285 284 285 Average 112 day weight (kg) 424 433 432 429 Average daily gain (kg) 1.24 1.32 1.30 1.28 Average ~eed intake/da~ 9.40 9.50 9.40 9.40 Average feed conversion efficien~y 7.52 7.23 7.14 7.39 All animal weights were calculated after a 16 hour shrink off f~eed and water. The incorporation of Na-TriCP
into the feed in 50 ppm, 75 ppm and 100 ppm corresponds approximately to an average daily dose of 1.55 mg/kg of body weight/day, 2.33 mg/kg of body weight/day and 3.1 30,249A-F -38-,i ~39 mg/kg of body weight/day respectively. This is based on the average daily feed intake and the average weight of the animals. The actual individual doses of Na-TriCP
may have varied from day to day.
~, , i .
. 30,249A-F -39-.,
The average daily feed consumption in kg; the average daily d.ry matter milk production in kg; and the milk production efficiency are as follows:
G:roup 1 ~Control~ Gro~
Avg. Daily Feed Conswmption in kg 18.52 18.1 Avg. Daily ~ry Matter Milk Production per day in kg* 2.15 2.41 Milk Production Effic.iency 8.51 7.54 *the dry matter milk production is equal to 12% of the actual milk production.
30,249A-F -36-' :' -37~
Example ~: The anabolic effect of sodium 3,5,6-tri-chloro-2-pyridinate as exhibited by an increase in average daily ga.in and an increase in ~eed conversion efficiency for beef cat-tle.
Two hundred fifty-six (256) steer calves averaging 283 kg (625 lbs~ were allotted into four (4) treatments of 8 replicates of 8 animals, i.e., 64 animals per treatment. The animals were assigned to replicates in a randomized complete block design. The animals were fed a two part basal diet consisting of:
% of Diet (by Weigh~
Intermedlate Finlshlng _ In~redient _ Ration Ration .
Dehydrated Alfalfa Meal 10.0 5.0 Cottonseed Hulls 15.0 10.0 Steam Rolled Corn 58.0 74.8 Soybean Meal (44%) 10.0 3.0 Calcium Carbonate 1.0 0.7 20 Na Tripolypho~phate 0.5 0.3 Cane Molasses 5.0 5.0 Trace Min0rali.zed Salt 0.5 0.5 Urea None 0.7 whereby the int~rmediate ration was fed to animals the first 28 days o~ the e~periment and -the finishing ration was ~ed to animals thereafter. All dieks and water were available to the animals on an ad libitum basis.
30,249A~F -37-,,, ~38-To the above diets, sodium 3,5,6~trichloro-2-pyridirlate ~Na-TriCP) was added in amounts sufficient to satisfy the dose requirements of Na~TriCP each treatment was to receive, namely:
Concentration o~
TreatmentNa-TriCP in Diet (wt. percent) 1 0 tControl) 2 0.005 (50 ppm) 3 0.0075 (75 ppm) 4 0.01 (100 ppm) The control diet contained no Na-TriCP while -the other three treatments were fed diets containing ~a-TriCP in concentrations listed above. After a 112 day total eeding period, weight gains and feed conversion effici ency improvements were determined. The average inikial weight, average 112-day weight, average daily gain, average feed intake per day and, average feed conver-sion efficiency (feed consumed/body weight gain) are tabulated as follows:
_ Treatment ~ 3 _ _ 4 Average initial weight (kg) 285 285 284 285 Average 112 day weight (kg) 424 433 432 429 Average daily gain (kg) 1.24 1.32 1.30 1.28 Average ~eed intake/da~ 9.40 9.50 9.40 9.40 Average feed conversion efficien~y 7.52 7.23 7.14 7.39 All animal weights were calculated after a 16 hour shrink off f~eed and water. The incorporation of Na-TriCP
into the feed in 50 ppm, 75 ppm and 100 ppm corresponds approximately to an average daily dose of 1.55 mg/kg of body weight/day, 2.33 mg/kg of body weight/day and 3.1 30,249A-F -38-,i ~39 mg/kg of body weight/day respectively. This is based on the average daily feed intake and the average weight of the animals. The actual individual doses of Na-TriCP
may have varied from day to day.
~, , i .
. 30,249A-F -39-.,
Claims (12)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. The use for producing an anabolic response in animals selected from the group of swine, cattle, sheep or poultry of an anabolically effective amount of one or a mixture of two or more active compounds of the following formula (I) wherein X1, X2 and X3 independently represent halogen, optionally chloro;
A represents hydrogen, alkali metal, alkaline earth metal, zinc, iron, manganese or -?Z; and Z represents C1-C11 alkyl, C1-C11 haloalkyl or C1-C11 hydroxyalkyl.
A represents hydrogen, alkali metal, alkaline earth metal, zinc, iron, manganese or -?Z; and Z represents C1-C11 alkyl, C1-C11 haloalkyl or C1-C11 hydroxyalkyl.
2. A use according to Claim 1 wherein said compound is 3,5,6- trichloro -2- pyridinol, or the sodium salt thereof.
3. A use according to Claim 1 wherein said anabolic response is exhibited by an increase in average daily weight gain, feed conversion efficiency or by an increase in milk production in a lactating animal.
4. A use according to Claim 1 wherein said active compound is administered to swine at a rate of from 0.01 to 20 milligrams per kilogram of body weight per day.
5. A use according to Claim 1 wherein the active ingredient is administered to swine at a rate of 50 to 100 grams/ton in animal feed.
6. An animal feed for swine, cattle, sheep or poultry comprising from 0.0005 to 15 percent by weight of one or a mixture of two or more anabolically active compounds of the formula (I) wherein X1, X2 and X3 independently represent halogen;
A represents hydrogen, alkali metal, alkaline earth metal, zinc, iron, manganese or -?Z; and Z represents C1-C11 alkyl, C1-C11 haloalkyl or C1-C11 hydroxyalkyl.
A represents hydrogen, alkali metal, alkaline earth metal, zinc, iron, manganese or -?Z; and Z represents C1-C11 alkyl, C1-C11 haloalkyl or C1-C11 hydroxyalkyl.
7. The animal feed of Claim 6 which when fed to an animal provides to the animal from 0.01 to 20 milligrams per kilogram of body weight per day of one or more of said active compounds.
8. The animal feed of Claim 6 which is a swine feed wherein the active compound is present in an amount of from 0.5 to 1600 grams per ton of finished feed (Dry Matker Basis).
9. The animal feed of Claims 6, 7 or 8 wherein said active compound is 3,5,6-trichloro-2-pyridinol or the sodium salt thereof.
10. The animal feed of Claim 6 wherein said active compound is present in an amount of from 0.0004 to 0.18 percent by weight.
11. The animal feed of Claim 6 which is a swine feed wherein the active compound is present in an amount of from 50 to 100 grams per ton of finished feed (Dry Matter Basis).
12. The animal feed of any one of claims 6 to 8 and 10 to 11 wherein X1, X2 and X3 are chloro.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000525020A CA1296636C (en) | 1986-12-11 | 1986-12-11 | 2-pyridinol compounds useful as anabolic agents |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000525020A CA1296636C (en) | 1986-12-11 | 1986-12-11 | 2-pyridinol compounds useful as anabolic agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1296636C true CA1296636C (en) | 1992-03-03 |
Family
ID=4134529
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000525020A Expired - Fee Related CA1296636C (en) | 1986-12-11 | 1986-12-11 | 2-pyridinol compounds useful as anabolic agents |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1296636C (en) |
-
1986
- 1986-12-11 CA CA000525020A patent/CA1296636C/en not_active Expired - Fee Related
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5028440A (en) | Method of raising meat producing animals to increase lean tissue development | |
| EP0620981B1 (en) | Method of increasing the hatchability of eggs by feeding hens carnitine | |
| US8808728B2 (en) | Feed additive for laying hen and feed containing the same | |
| US3812259A (en) | Animal feed and process | |
| De Goey et al. | Energy values of corn and oats for young swine | |
| US5006558A (en) | Method for reducing stress in piglets pigs and poultry | |
| US3261687A (en) | Animal feed containing lincomycin and spectinomycin | |
| Lillie et al. | Feather meal in chick nutrition | |
| Bird et al. | Addition of DL-methionine to starting and growing mashes | |
| US4835185A (en) | Immunomodulator for improving commercial performance of domestic animals | |
| KR102472661B1 (en) | Method of raising cattle that can improve meat quantity grade and meat quality grade | |
| EP0271607B1 (en) | 2-pyridinol compositions and methods of use as anabolic agents | |
| CA1296636C (en) | 2-pyridinol compounds useful as anabolic agents | |
| Plegge et al. | Performance of growing and finishing steers fed roasted soybean meal | |
| US4454137A (en) | Feed compositions containing copper salts of 2-hydroxypyridine-N-oxides | |
| US4353902A (en) | Livestock feed and method for improving food utilization | |
| US4666891A (en) | Method of stimulating animal growth by administering feed and inosine complex | |
| US4211775A (en) | Ronnel composition and use to promote nutritional response | |
| RU2159558C1 (en) | Method of feeding animals and birds | |
| US4414206A (en) | Animal feeds | |
| Lambert et al. | Crambe meal protein and hulls in beef cattle rations | |
| KR100213829B1 (en) | Feed for infant swine | |
| GB1564187A (en) | Composition and method for promoting animal nutrition | |
| US3870793A (en) | Animal feed and process | |
| JPH10165109A (en) | Feed composition and feed |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |