Patented Aug. 19, 1952 2,607,716 UNITED STATES PATENT OFFICE PROPHYLACTIC coMPOSITION FOR scours Karl Paul Link, Middleton, Wis, assignor to Wis consin Alumni Research Foundation, Madison Wis., a corporation of Wisconsin No Drawing. Application August 2, 1949, Serial No. 108,233 5 Claims. (C. 167-53) 2 s The present invention relates to a new con sion. It is also applicable to rabbits and the like position of matter, and more specifically to a which fall between man and the ruminant of composition having particular utility in the pro the calf type. phylaxis of Scours. The new-born mammal is for all practical pur Scours is a disease of the new-born that suck, 5 poses born in a state of physiologic shock. i. e. Mammalia. It can be fatal. Indeed it is Hemorrhagic petechiae are present in the in held that it is one of the commonest causes of testinal tract which is essentially a delicate death of young farm animals. According to “raw' membrane. Within 7-10 days, a very Spielman, A. A., in the article, “Do calves need noticeable morphological change sets in and the vitamin supplements?,’ Feedstuffs, vol. 18, No. 1 10 hemorrhagic petechiae largely disappear from (1946), the mortality of calves on many dairy the tract. Adjustment must be made from a farms in the United States during the first Week wet (physiologically balanced) to a dry, unball- . or weeks of life primarily ascribed to scours is . anced environment. Adjustment must also be estimated at 15-20 per cent. Also, according to made to two new conditions (d) fluid-balance the U. S. D. A. Yearbook, Keeping Live Stock 15 and (b) nourishment by mouth as opposed to Healthy, U. S. Gov. Printing Office (1942), 20-40 nourishment via the placenta. Imposed on per cent of lambs may die in Severe outbreaks of these is the urgent necessity of developing re dysentery sometimes called “white scours,' sistance to the new bacterial flora encountered. whilst 50 per cent of new-born pigs may die of 20 The change may be stated as: enteritis (or three day pig disease) and scours. Aseptic environment, Septic environment The chief symptoms preceding death are diar (In the uterus) as (Outside the uterus) rhea (hence the name scours), inflammation of Immunity via the Immunity must be the...umbilical stump, and a general exudative mother developed arthritis. W - - - The primary cause of scours is strains of bac * The problem presented by scours has been teria of the colon group (Bacillus coli or coli recognized for many years and many specific aerogenes) encountered by the new-born for the preventative measures and recipes for treatment, first time and against whom a resistance must particularly for calf scours have been proposed. be developed for survival. Colon group bacteria, The preventive measures for calf Scours in of this type are non-pathogenic under normal 30 clude assurance that the calf receives an ample Conditions, B. coli being the first organism to Supply of colostrum, isolation of mother and calf establish itself in the large intestine after birth. to clean quarters, use of a muzzle to prevent the So long as it is confined to the intestine it lives calf from eating contaminated litter and over as a saprophyte, but if the integrity of the ali eating, injection of antibacterial serum-bovine, mentary mucous membrane is impaired in any 35 the feeding of milk diluted with lime water, way, it may invade the tissues. Smith, T. and feeding acidophilus milk, administration of Vita Little, R. B., Jour. Exp. Med. 30, 181 (1922); min A and certain members of the B complex Gaiger and Davies, Weterinary Pathology and and use of sulfa drugs. Udall, D. H., The Prac Bacteriology, 3rd ed. (1947). Associated factors tice of Veterinary Medicine, Utica, N.Y., 5th ed., that predispose or aggravate the disease are con 40 1947. x taminated or infected quarters, improper feeding The feeding of milk diluted with Water has also of the mother or young, and exposure to cold been proposed, Sheehy, E. J., The Scientific Pro and dampness. Specific preventatives are clean ceedings of the Royal Dublin Society, 21, (N.S.) quarters, proper feeding and particularly of the No. 9,73 (1934). new-born with the first milk (colostrum), free 45. The treatment of choice for the prophylaxis of dom from cold and dampness, and where infec scours is an ample supply of bovine colostrum tion is present the isolation of infected animals. (the first milk) since it has been demonstrated In highly virulent epizootics of Scours, however, that it contains in addition to the essential food all or nearly all of the young may become in elements, immune proteins or antibodies which fected and survival varies depending on the de 50 pass through the "raw" digestive tract to the gree of resistance and Vigor that has been de blood stream during the first days after birth veloped shortly after birth. This is particularly and passively immunize the new-born. Smith, T. the situation with the calf, lamb and pig which and Little, R. B., Jour. Exp. Med. 30, 181 (1922): unlike the ape and man, get little or no immune Smith, E. L. and Holm, A., Jour. Biol, Chem. bodies by... intrauterine or placental transnis 55 175, 39 (1948).

2,607,716 3 4. The use of colostrum while recognized to be tained from miammalian blood and preferably highly effective when good quality colostrum is from non-citrated pooled blood of dairy cattle available is frequently impractical since Colos or blood from sheep, pigs, etc. The blood may trum with a sufficient antibody or immune pro be secured by the bleeding of the animals includ tein content is not always available in adequate ing animals which have been specially treated to - amounts. Furthermore, there appears to be a provide hyper-immune blood, although a readily marked difference in the immunizing capacity available and Satisfactory Source of blood is that of the colostrum of different bovine breeds re available in the processing of animals at an abat sulting in a greater susceptibility to scours in toir. The immune proteins carried in plasma, the new born of some breeds, Wise., G. H., and 0 serum, Howes Na2SO4 globulin fraction or the Anderson, G. W., Jour. Dairy Science, 27, 965 like, may be produced from the blood by proc (1944). essing the blood in accordance with standard The use of calf scour serum (antibacterial practices in the art. The desired plasma, serum serum-bovine) Smith, T., Jour. Exp. Med. 51, or globulin fraction may be spray dried or be 473; 483; 519 (1930) has also been employed as 15 subjected to freeze-drying. Satisfactory proce a prophylactic (and cure). This proposal though dures are described in the Medical Research Scientifically sound has not been widely adopted Council Report No. 258, The Preservation of Pro in all probability because the serum needs to be teins by Drying, by R. I. N. Greaves, H. M. S. injected intravenously and this requires the Serv Stationary Office (1946). ices of skilled personnel such as a veterinarian. 20 Vitamin A-the vitamin K or vitamin K In place of commercially prepared serum, the compound used in the present invention may : use of the dam's blood (defibrinated and cit be natural Vitamin K, such as K1 or K2, or war rated) has also been proposed, the administra ious natural or synthetic compounds which pro tion being intravenous or subcutaneous. This note the formation or activation of prothron practice has not met wide adoption, even though bin. Some of the effective compounds are 2 recognized to be effective, since it requires the methyl-1,4-naphthoquinone (Menadione); 2 use of skilled technicians, see Udall, supra. methyl-1,4-naphthohydroquinone-3-sodium sul Next to colostrum, the sulfa drugs are prob fonate ("Hykinone'); 4 -amino - 2 - methyl-1- ably the most widely used for the prevention of naphtholhydrochloride ("Synkamin'); 2-methyl calf scours. The use of the sulfa drugs, however, 30 3-hydroxy-1,4-naphthoguinone (Phthiocol); 2 is not without risk due to their toxic effects. methyl - 14 - naphthohydroquinone - diphos Wise and Anderson, supra. The other preventive phoric acid ester tetrasodium salt ("Synkay measures listed above have been used to a limited vite') ; 2-methyl-1,4 naphthohydroquinone; 2 extent, but each has its shortcomings. Udall, methyl-1,4-naphthohydroquinone diacetate and supra. . . . ': 35 2 - methyl-1,4-dihydroxy - 3 - naphtholalde The art has long desired an effective, non hyde. When a water insoluble vitamin K com toxic, commercially practical prophylactic for position Such as natural K1 or K2 is employed, Scours that can be given orally. In particular, the addition of bile salts to facilitate absorption the art has desired a relatively inexpensive com is recommended. position readily adaptable for use on farms, 40 The following examples will serve to illustrate ranches and the like that does not require for the invention. administration the services of medically skilled Eacamples - - - personnel...... Grams The principal object of the present invention A. Bovine plasma------2500 : is to provide an effective, non-toxic composi 45 Menadione (2-methyl-1,4-naph tion for preventing or inhibiting scours in calves, thoquinone or its equivalent) -- 1-2 lambs,Another goats, object pigs, ofrabbits the present and the invention like. is to B. Bovine plasma-...------2500 provide an effective composition for preventing Menadione (2-methyl-1,4-naph Scours that can be given orally. - - - 50 thoquinone or its equivalent) -- 1-2 A further object of the present invention is to provide an inexpensive, commercially practical Ringer Tyrode salts------9.65 composition for preventing scours that is readily C. Partially digested milk solids----- 7500 adaptable for administration by personnel avail Bovine plasma------2500 able Cn farms, ranches and the like. 55 Other objects of the present invention will be Menadione (2-methyl-1,4-naph apparent as the detailed description proceeds thoquinone or its equivalent).----, 1-2 hereinafter. Ringer Tyrode salts'------9.65

I have discovered a combination of commer o w o cially available ingredients that actively co 60 NE 338E.; Si386BSS' 39-36 operate to produce an effective composition for grana; glucose, 1.0 gram. preventing or inhibiting scours. The composi The plasma is prepared from pooled dairy cow tion which is administered per os contains as blood in accordance with standard practices in essential ingredients immune bodies from blood, the art, and then spray dried or freeze dried. together with a small but effective amount of 65 The vitamin K (commercially available under the vitamin K or a compound characterized by vita name "Menadione') is a crystalline solid. The min K anti-hemmorrhagic activity. This com partially (or enzyme) digested milk solids are bination may be used with a Ringer-Tyrode salt prepared by treating cows milk with pancreatin. mixture, or with suitable food for the new-born for about one hour at 40° C., the digested mixture. animal such as colostrum, milk solids and the 70 pasteurized at 75 for thirty minutes, and then like, and for oral feeding can be incorporated into spray dried...... water or in water containing the Ringer-Tyrode In each example the ingredients are intimately physiological salt mixture...... mixed in the dry state, and then stored in a Immune bodies-The immune proteins or suitable stoppered container in- which form the antibodies used in the present invention are ob 5 mixtures are stable when kept refrigerated.

2,607,716 5 6 When ready for administration sufficient Water The Vitamin K used in the composition of the is added for every 50 grams of plasma to provide present invention reduces the extent and dura One liter of composition. It is ordinarily pre tion of hypoprothrombinemia, and the persistence ferred to administer the composition from a of hemorrhagic petechiae, i. e. minute hemor drench bottle or it can be fed from a pail. In irhages in the digestive tract. The action on the practice it is preferred to offer an equal volume digestive tract is of utmost importance as it of water immediately after administration-or blocksportals for entry of scour producing organ the composition containing 50 grams of plasma, isms into the blood stream. Also, at the same With Or without the digested milk solids and With time the administration of vitamin K changes the or Without the Ringer-Tyrode salt mixture, can normally hemorrhagic condition of the digestive be made up to 2 liters directly and administered tract of the new-born to a nonhemorrhagic con in that dilution. dition more suitable for rapid absorption of the For a calf two feedings of a composition con immune bodies into the blood. The operation of taining 50 grams of plasma, in one or tWO liter the basic (immune body-Vitamin K) ingredients volumes each per day for tWO to four dayS is gen of the present invention thus involves cooperative erally satisfactory. For Smaller animals. Such as action of the type long desired for preventing the rabbit, oral administration (via, a wide tipped SCO.S. dropper) of about 2-4 cc. of the composition of It will be understood that the present invention Example C (from a suspension containing 200 is not limited to the above illustrative examples grams per liter) daily increasing up to about : and that the use of equivalent materials fall with 10-12 cc. by the seventh day has proven Satis in the Scope of the invention. Examples are the factory. For example, in a colony of rabbitS par use of serum (defibrinated blood) and immune ticularly susceptible to scours (mucoid enteritis) fractions such as Howe's Na2SO4 globulin fraction where the Survival was approximately 52%, the and the like, in place of the plasma, described administration of the composition of Example C above. It Will also be understood that the corn of the present invention increased the Survival to position of the present invention may be used about 85%. to combat Scours in Warious animals including The proportions of ingredients employed above the rabbit, pig, goat and lamb as well as the calf. are merely illustrative, and they may be varied I claim: to meet particular needs. When using plasma 1. A non-toxic coimposition for Oral adminis and milk solids it is ordinarily preferred to use tration having utility in the prophylaxis of scours, at least about one part of partially digested milk Comprising as essential ingredients immune pro solids to one part of plasma, and in most in teins derived from mammalian blood and a vita stances it is preferred to use compositions con min K compound. taining a major proportion (60-90 per cent) of 3 2. A non-toxic composition for oral adminis milk Solids and a minor proportion (10-40 per tration having utility in the prophylaxis of Scours, cent) of plasma. The three to one ratio (75 per comprising bovine plasma, containing immune cent milk solids to 25 per cent plasma) employed proteins derived from the blood of dairy cattle in Example C has been found to give excellent and a vitamin K compound. results in practice. The amount of vitamin K 40 3. A non-toxic composition for oral adminis compound used may also be varied within Wide tration having utility in the prophylaxis of scours, limits depending, for example, upon the activity comprising bovine serum containing immune or anti-hemorrhagic characteristics of the Vita proteins derived from the blood of dairy cattle min K compound selected, etc. Preferably the and a vitamin K compound. vitamin K compound is used in excess and in all 45 4. A non-toxic composition for oral adminis cases is present in Sufficient amounts to Substan tration having utility in the prophylaxis of scours, tially reduce the extent and duration of hypo comprising as essential ingredients immune pro prothrombinemia (a condition found in new teins derived from the blood of cattle and a born) and the persistence of the hemorrhagic Vitamin K compound. petechiae in the intestinal tract. A composition 50 5. A non-toxic composition for oral adminis providing a daily dosage of around 40 to 80 mg. tration having utility in the prophylaxis of scours, of Menadione is indicated for relatively large comprising bovine plasma, containing immune animals. proteins derived from the blood of cattle and Investigations have demonstrated that the in menadione in a ratio of 1-2 grams per 2500 grams mune proteins (antibodies) used in the present 55 of plaSma. invention when absorbed unaltered from the ali EARL PAUT INK, mentary canal and into the blood in active con dition passively immunize new-born animals REFERENCES CEO against B. coli and related Organisms causing The following references are of record in the scours. See Smith, T. and Little, R. B., Jour. 60 file of this patent: Exp. Med. 30, 181, (1922); Smith, E. and Holm, A., Jour. Biol. Chem. 175, 349 (1948). Investiga Gutman: Modern Drug Encyclopedia, 3d tions have also demonstrated that Such immune edition (1946), page 58. bodies are readily absorbed unaltered and in a C Wise: Journal of Dairy Science, vol. 27, pages tive condition from the digestive tract of new 65 965 to 979. born up to about 7 to 10 days after birth when administered with vitamin K.