Method of treating scours

Scours in animals, particularly new-born calves, lambs, piglets and foals are treated with a compound containing an effective amount of an antidiarrheal amidinourea.

BACKGROUND 
Scours, particularly in new-born calves, lambs, piglets, and foals, is a 
major cause of death, especially under intensified commercial animal 
husbandry practices where the disease accounts for large economic losses. 
The disease occurs commonly in calves, pigs, lambs and foals under 10 days 
of age and is characterized by varying degrees of diarrhea and 
dehydration. 
The disease known as adult bovine scours is also prevalent among wintering 
adult cattle, frequently leading to death losses. The etiology and 
pathology of the disease are not well understood, but the disease is 
generally attributed to factors which cause ordinarily harmless intestinal 
bacteria to proliferate. Regardless of the cause, the result is a net loss 
of electrolytes and fluids into the intestinal lumen. The loss of 
electrolytes and fluids results in acidosis and dehydration leading to 
other acute toxic effects. Generally, treatment for this condition 
involves correction of the acid base imbalance and rehydration and 
treatment of intestinal infections, if present. Such treatments may 
include administration of antibacterial agents and electrolyte solutions 
orally. The usual antibacterial agents are antibiotics and sulfonamides. 
In recent years, a variety of amidinoureas have been shown to be effective 
antidiarrheal agents in laboratory test animals and in humans. 
Pharmaceutically effective antidiarrheal agents such as the amidinoureas 
are not known for use in the treatment of scours, particularly in calves, 
lambs and piglets, where annual losses to this disease are high. These 
compounds have demonstrated their activity in laboratory animals under 
test conditions designed to mimic gastrointestinal disorders in humans by 
inducing symptomatic diarrhea in the test animals. Such amidinoureas and 
their pharmaceutical activity are described in Arzneimittel Forschung, 
Drug Research 28 (II), 1433-1480, (1978). It has now been found that these 
amidinoureas are particularly effective in reducing morbidity and 
mortality rate in calves, lambs, piglets and foals suffering from scours, 
and in adult cattle suffering from bovine winter scours, when orally 
administered to such animals in effective amounts. 
SUMMARY OF THE INVENTION 
This invention pertains to novel veterinary compositions containing an 
effective amount of an antidiarrheal amidinourea and for the use of such 
compositions in the treatment of animal scours, particularly for the 
treatment of calves, lambs, piglets, foals, and cattle, and more 
particularly, for the treatment of new-born calves, piglets and lambs for 
the prevention and treatment of scours thereby reducing the mortality rate 
especially for new-born calves, lambs, piglets and foals afflicted with 
scours. The effective amidinourea is administered in the form of 
veterinary compositions formulated as tablets, capsules or liquids 
suitable for oral administration or the amidinourea may be formulated as a 
dietary supplement suitable for incorporating into the solid or liquid 
dietary intake of the afflicted animals. The amidinourea can, if desired, 
be combined with other therapeutic agents or with other suitable 
excipients. 
Losses from calf scours are perhaps the single most serious economic loss 
of any disease or condition in cattle. It affects about 10% of the 
50,000,000 calves born in the United States each year. 
The causes of calf scours are varied and not completely understood. 
Infectious agents include E. coli, salmonella, IBR virus (infectious 
bovine rhinotracheitis) and "Nebraska virus". Ancillary causes such as 
failure of the calf to obtain sufficient colustrum, stress, contaminated 
environment and physiologic immaturity all contribute to the problem. 
The economic loss due to baby pig scours is nearly as great. Generally 
caused by E. coli, it is the largest source of mortality in the swine 
industry. 
E. coli is generally the cause of outbreaks of neoatal diarrhea in lambs. 
While the economic losses do not approach either of the above, it is still 
significant to the industry. Young food-producing animals are not the only 
ones affected by diarrhea BVD (bovine virus diarrhea), caused by a 
myxovirus and bovine winter dysentary, caused by vibrio jejuni are 
important factors in the cattle industry. Neither disease condition can be 
treated very effectively with drugs presently available, though there are 
many antidiarrheal agents on the market which are used in the treatment of 
animal scours. Electrolyte solutions, antibiotics, sulfonamides and 
nitrofurans make up the great majority. Many contain various binding, 
coating, absorbing and adsorbing agents and astringents. A few have 
scopolamine, the only common drug being used to slow peristalsis. It is, 
therefore, an object of this invention to provide an effective treatment 
for animal scours, particularly in new-born calves, lambs and piglets, 
i.e. less than ten days old. 
It is a further object of this invention to reduce the mortality and 
morbidity rate of calves, lambs, piglets and foals by including an 
effective antiscouring amidinourea in the diet of new-born calves, lambs, 
piglets and foals. 
It is still a further object of this invention to provide an effective 
composition for the prevention and treatment of scours in animals 
comprising an antiscouring amidinourea in a suitable dosage form or as a 
feed supplement in combination with suitable excipients and adjuvants of 
the type noted above. 
DETAILED DESCRIPTION OF THE INVENTION 
Food-producing animals can suffer from scours, usually during the first ten 
days of life (neonatal diarrhea). It is a particular problem of serious 
economic concern in cattle, swine and sheep and methods for control of the 
disease in these species is especially important. 
The amidinoureas which are suitable for use in the method of this invention 
and which comprise the principal active ingredient in the veterinary 
compositions of this invention are the compounds of the formula: 
##STR1## 
wherein one of R.sub.1 or R.sub.5 is phenyl, phenyl in which one or more 
of the hydrogens is substituted by halo, lower alkyl, halo lower alkyl, 
nitro, lower alkoxy, hydroxy, aryl lower alkoxy, acyloxy, cyano, halo 
lower alkoxy, or lower alkyl sulfonyl; aralkyl, pyridyl, or pyridyl having 
one or more of the hydrogens replaced by lower alkyl, lower alkoxy, halo, 
halo lower alkyl, amino, nitro, hydroxy, cyano, carboxyl or lower alkyl 
sulfonyl; and the other of R.sub.1 and R.sub.5 is hydrogen, lower alkyl, 
lower alkoxy, lower alkenyl, cyclo lower alkenyl, cyclo lower alkyl, 
aralkyl, lower alkynyl, halo alkyl, hydroxy lower alkyl, lower alkoxy 
lower alkyl, cyano lower alkyl, amino lower alkyl, mono or di-lower alkyl 
amino lower alkyl, carbamoyl lower alkyl, mono or di-carbamoyl lower 
alkyl, lower alkoxy carbamoyl lower alkyl, aralkoxy carbamoyl lower alkyl, 
acyl lower alkyl, alkyl sulfonyl or aralkyl sulfonyl; R.sub.2 and R.sub.6 
are each independently selected from the group consisting of hydrogen, 
lower alkyl, lower alkoxy, lower alkenyl, cyclo lower alkenyl, cyclo lower 
alkyl, aralkyl, lower alkynyl, halo alkyl, hydroxy lower alkyl, lower 
alkoxy lower alkyl, cyano lower alkyl, amino lower alkyl, mono or di-lower 
alkyl amino lower alkyl, carbamoyl lower alkyl, mono or di-carbamoyl lower 
alkyl, lower alkoxy carbamoyl lower alkyl, aralkoxy carbamoyl lower alkyl, 
acyl lower alkyl, alkyl sulfonyl or aralkyl sulfonyl; and when R.sub.1 is 
phenyl, phenyl substituted as above, aralkyl, pyridyl or pyridyl 
substituted as above R.sub.5 together with R.sub.6 and the nitrogen to 
which R.sub.5 and R.sub.6 are attached may form a 5 or 6 membered 
heterocyclic ring which may include 0 to 2 additional hetero atoms which 
may be either oxygen, nitrogen or sulfur; and when R.sub.5 is phenyl, 
phenyl substituted as above, aralkyl, pyridyl, or pyridyl substituted as 
above, R.sub.1 and R.sub.2 together with the nitrogen to which they are 
attached may be a 5 or 6 membered heterocyclic ring which may include 0 to 
2 additional hetero atoms which may be either oxygen, nitrogen or sulfur; 
and R.sub.3 and R.sub.4 are each independently hydrogen, lower alkyl, 
lower alkoxy, lower alkenyl, lower alkynyl, cyclo lower alkyl or aralkyl; 
and their pharmaceutically acceptable acid addition salts. 
As employed above and throughout the disclosure, the following terms, 
unless otherwise indicated, shall be understood to have the following 
meanings: 
"alkyl" means a saturated aliphatic hydrocarbon which may be either 
straight or branched chain, lower alkyl being preferred; also included are 
the cycloalkyl groups such as cyclohexyl, cyclopropyl, etc. and the 
cycloalkyl lower alkyl groups such as cyclopropylmethyl and the like. 
"lower alkyl" means an alkyl group as above, having 1 to 6 carbon atoms. 
Suitable lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, 
sec-butyl, tertbutyl, pentyl and isopentyl. 
"cycloalkyl" means an aliphatic monocyclic saturated carbocyclic group 
having 3 to 6 carbon atoms, preferably cyclopropyl, cyclopentyl and 
cyclohexyl. 
"alkenyl" means an unsaturated aliphatic hydrocarbon which contains one or 
more double bonds and which may be straight or branched chain with lower 
alkenyl, i.e., alkenyl of 2 to 6 carbons being preferred. 
"lower alkenyl" means alkenyl of 2 to 6 carbon atoms such as ethylene, 
propylene, butylene, isobutylene, etc. 
"alkynyl" means an unsaturated aliphatic hydrocarbon containing one or more 
triple bonds with lower alkynyl, i.e. alkynyl of 2 to 6 carbons being 
preferred. 
"lower alkynyl" means alkynyl of 2 to 6 carbon atoms such as propargyl, 
butynyl, pentynyl, etc. 
"aryl" means phenyl and substituted phenyl. 
"substituted phenyl" means a phenyl group in which one or more of the 
hydrogens has been replaced by the same or different substituents 
including halo, lower alkyl, halo lower alkyl, nitro, amino, acylamino, 
hydroxy, lower alkoxy, aryl-lower alkoxy, acyloxy, cyano, halo-lower 
alkoxy or lower alkyl sulfonyl. 
"aralkyl" means an alkyl (preferably a lower alkyl) in which one or more 
hydrogens is substituted by an aryl moiety (preferably phenyl or 
substituted phenyl), e.g. benzyl, phenethyl, etc. 
"5 and 6 membered heterocyclic group" means a 5 or 6 membered ring having 1 
to 3 hetero atoms which may be nitrogen, oxygen or sulfur including 
pyridyl, 2-pyridyl or 3-pyridyl; pyrimidyl, pyrazolyl, imidazolyl, furyl, 
thienyl, oxazolyl, thiazolyl, piperidyl, piperazenyl, morpholinyl, 
thiomorpholinyl, etc. with the pyridyl groups being preferred. 
"substituted pyridyl" means a pyridyl in which one or more of the hydrogens 
on the ring carbons have been replaced by substituents as given above with 
respect to substituted phenyl. The pyridyl substituents may be either 2-, 
3-, or 4-pyridyls; preferred substituted pyridyls are those having 
substituents on the carbon or carbon atoms vicinal to the carbon attached 
to the amidino or urea nitrogen. 
The terms "halo" and "halogen" include all four halogens; namely, fluorine, 
chlorine, bromine and iodine. 
Halo alkyl and halophenyl include alkyl or phenyl groups having more than 
one halo substituent which may be the same or different such as 
trifluoremethyl, 1-chloro-2-bromo ethyl, chlorophenyl, 
2-chloro-6-bromophenyl, etc. 
The term "acyl" means an organic acid radical, preferably a lower alkanoyl 
or aroyl, e.g. acetyl, propionyl, benzoyl, benzenesulfonyl, etc. 
The term "acyloxy" is intended to mean an organic acid radical such as 
acetoxy, propionoxy, benzoyloxy, and the like. 
The term "acylamino" is intended to mean an organic amido group of the 
RCONH type where R is an organic radical preferably lower alkyl or aryl 
lower alkyl. 
The term "lower alkanoyl" is intended to include the acid radical of a 
lower alkanoic acid such as acetyl, propionyl and the like. 
It should be understood that whereas the structure of the starting 
materials are shown here in a particular configuration for purposes of 
illustration, the compounds may exist in various enolized or tautomeric 
forms, particularly where one of R.sub.3 and R.sub.4 is hydrogen, shown 
for example, by the following formula: 
##STR2## 
Certain of the compounds can also be obtained as hydrates or in different 
polymorphic forms. The structures used herein to designate novel compounds 
are intended to include the compound shown along with its alternative or 
transient states. 
Among the amidinoureas of Formula I, a particularly preferred group of 
amidinoureas suitable for use in the composition and method of this 
invention are those in which the R.sub.5 substituent is a phenyl or 
substituted phenyl and particularly a phenyl having substituents in the 2 
and 6 positions (i.e. ortho to the carbon attached to the urea nitrogen). 
Such preferred compounds can be represented by the formula: 
##STR3## 
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.6 all have the same 
meanings as above, and R.sub.n represents one, two or three substituents 
in any one or more of the para and meta positions which substituents may 
be hydrogen, halo, lower alkyl, halo lower alkyl, nitro, lower alkoxy, 
hydroxy, aryl lower alkoxy, acyloxy, halo lower alkoxy, or lower alkyl 
sulfonyl; R' and R" are hydrogen, halo, lower alkyl, halo lower alkyl, 
nitro, lower alkoxy, hydroxy, aryl lower alkoxy, acyloxy, halo lower 
alkoxy, or lower alkyl sulfonyl; and R.sub.n represents one, two or three 
substituents in any one or more of the para and meta positions which 
substituents may be hydrogen, halo, lower alkyl, halo lower alkyl, nitro, 
lower alkoxy, hydroxy, aryl lower alkoxy, acyloxy, halo lower alkoxy, or 
lower alkyl sulfonyl. 
Particularly preferred compounds of Formula I-a are those wherein the 
phenyl substituents are lower alkyl, lower alkoxy, or halo; and one of 
R.sub.1, R.sub.2, R.sub.3 and R.sub.4 is hydrogen, and the others are 
lower alkyl, halo lower alkyl, or lower alkoxy lower alkyl. The preferred 
lower alkyl substituents are methyl, ethyl, propyl, and isopropyl. The 
preferred halo substituents are chlorine and bromine. The preferred halo 
lower alkyl substituents are chloromethyl and trifluoromethyl. 
A most preferred group of amidinoureas suitable for use in the practice of 
this invention are the compounds of the formula: 
##STR4## 
wherein R.sub.1 and R.sub.2 are each hydrogen, lower alkyl, lower alkoxy 
or hydroxy; and R' and R" are each hydrogen, halo, or lower alkyl. 
The compounds of Formula I, I-a, II or III can be used in the practice of 
this invention in the form of the base or as salts prepared by reacting 
the compounds of Formula I with pharmaceutically acceptable acids. 
Suitable acid addition salts are for example, the salts derived from the 
following organic and inorganic acids: hydrochloric acid, nitric acid, 
sulfuric acid, phosphorous acid, ortho-phosphoric acid, etc.; aliphatic 
mono-and dicarboxylic acids such as acetic acid, propionic acid, succinic 
acid, formic acid, caprylic acid, maleic acid, oxalic acid, malonic acid, 
etc.; phenyl-substituted alkanoic acids, hydroxy alkanoic acid, aromatic 
carboxylic acids, and aliphatic and aromatic sulfonic acids such as 
methylbenzoic acid, phthalic acid, benzenesulfonic acid, phenylpropionate, 
tartaric acid, citric acid, lactic acid, glycollic acid, phenylacetic 
acid, phenylbutyric acid, methanesulfonic acid, etc. 
Suitable amidinoureas for use in the veterinary treatment method of this 
invention are those disclosed in the Arzneimittel Forschung monograph 
identified above and in U.S. Pat. Nos. 4,115,647; 4,088,785; 4,025,652; 
4,115,564; 4,060,635; and 4,058,557 and in co-pending application Ser. No. 
671,762, the disclosures of which are incorporated herein by reference. 
The amidinoureas employed as the principal active ingredient in the 
composition and method are prepared by methods known in the art. 
Exemplary compounds prepared in accordance with such teachings for 
utilization in this invention are named below wherein the urea nitrogens 
are designated as positions 1 and 3 respectively: 
1-(2,6-dimethylphenyl)-3-methylamidinourea 
0-chlorophenylamidinourea 
(2,3-dichlorophenylamidino)urea 
(2,4-dichlorophenylamidino)urea 
(2,5-dichlorophenylamidino)urea 
(3,4-dichlorophenylamidino)urea 
(3,5-dichlorophenylamidino)urea 
(2,6-dichlorophenylamidino)urea 
m-chlorophenylamidinourea 
p-chlorophenylamidinourea 
3,4-diflourophenylamidinourea 
m-bromophenylamidinourea 
p-bromophenylamidinourea 
3,4-dibromophenylamidinourea 
3-chloro-4-bromophenylamidinourea 
3-bromo-4-chlorophenylamidinourea 
3-chloro-4-fluorophenylamidinourea 
3-bromo-4-fluorophenylamidinourea 
3-fluoro-4-chlorophenylamidinourea 
2,6-dimethylphenylamidinourea 
2,6-diethylphenylamidinourea 
2-methyl-6-ethylphenylamidinourea 
2-methyl-6-methoxyphenylamidinourea 
2-methyl-6-ethoxyphenylamidinourea 
2-ethyl-6-ethoxyphenylamidinourea 
3,4-dimethoxyphenylamidinourea 
3,4-dihydroxyphenylamidinourea 
3,4,5-trimethoxyphenylamidinourea 
3,4,5-trihydroxyphenylamidinourea 
1-(2,6-dimethylphenylamidino-3,3-(N-methyl-3'-azapentamethylene (urea) 
1(2,6-dimethylphenylamidino)-3,3-(N-methyl-3'-azahexamethylene (urea) 
1-(2,6-dimethylphenylamidino)-3,3-(3'-oxapentame-thylene)urea 
1-(2,6-dimethylphenylamidino)-3,3-(2'-thiatetramethylene)urea 
1-(2,6-dimethylphenylamidino)-3,3-tetramethyleneurea 
1-(p-fluorophenylamidino)-3,3-(a,a'-dimethylpentamethylene)urea 
1-(p-chlorophenylamidino)-3,3-(pentamethylene)urea 
1-(2,6- 
dimethylphenylamidino)-3,3-(.alpha..alpha.'-dimethylpentamethylene)urea 
1-(2,6-dimethylphenylamidino)-3,3-pentamethyleneurea 
1-(2,6-dimethylphenylamidino)-3,3-(y-methylpentamethylene)urea 
1-(N-methylamidino)-3-(2,6-dimethylphenyl)urea 
1-(N-methylamidino)-3-(2,6-diethylphenyl)urea 
1-amidino-3-(2-methyl-6-chlorophenyl)urea 
1-amidino-3-(2-methyl-6-bromophenyl)urea 
1-amidino-3-(2-methyl-6-methoxyphenyl)urea 
1-amidino-3-(2,6-dimethylphenyl)urea 
1-amidino-3-(2-methyl-6-ethylphenyl)urea 
1-amidino-3-(2-ethyl-6-chlorophenyl)urea 
1-amidino-3-(2-ethyl-6-bromophenyl)urea 
1-amidino-3-(2,6-diethylphenyl)urea 
1-amidino-3-methyl-3-(2-methyl-6-chlorophenyl)urea 
1-amidino-3-methyl-3-(2-methyl-6-bromophenyl)urea 
1-amidino-3-methyl-3-(2-methyl-6-methoxyphenyl)urea 
1-amidino-3-methyl-3-(2,6-dimethylphenyl)urea 
1-amidino-3-methyl-3-(2-methyl-6-ethylphenyl)urea 
1-amidino-3-methyl-3-(2-ethyl-6-chlorophenyl)urea 
1-amidino-3-methyl-3-(2-ethyl-6-bromophenyl)urea 
1-amidino-3-methyl-3-(2-ethyl-6-methoxyphenyl)urea 
1-amidino-3-methyl-3-(2,6-diethylphenyl)urea 
1-amidino-3-(2-methyl-6-chlorophenyl)urea 
1-amidino-3-(2-methyl-6-bromophenyl)urea 
1-amidino-3-(2-methyl-6-methylphenyl)urea 
1-amidino-3-(2,6-dimethylphenyl)urea 
1-amidino-3-(2-methyl-6-ethylphenyl)urea 
1-amidino-3-(2-ethyl-6-chlorophenyl)urea 
1-amidino-3-(2-ethyl-6-bromophenyl)urea 
1-amidino-3-(2-ethyl-6-methoxyphenyl)urea 
1-amidino-3-(2,6-diethylphenyl)urea 
1-amidino-3-methyl-3-(2-methyl-6-chlorophenyl)urea 
1-amidino-3-methyl-3-(2-methyl-6-bromophenyl)urea 
1-amidino-3-methyl-3-(2-methyl-6-methoxyphenyl)urea 
1-amidino-3-methyl-3-(2,6-dimethylphenyl)urea 
1-amidino-3-methyl-3-(2-methyl-6-ethylphenyl)urea 
1-amidino-3-methyl-3-(2-ethyl-6-chlorophenyl)urea 
1-amidino-3-methyl-3-(2-ethyl-6-bromophenyl)urea 
1-amidino-3-methyl-3-(2-ethyl-6-methoxyphenyl)urea 
1-amidino-3-methyl-3-(2,6-diethylphenyl)urea 
The amidinoureas of Formula I and their pharmaceutically acceptable salts 
are useful as veterinary medicines. In particular, these compounds are 
useful in preventing or treating scours in food-producing animals. The 
compounds are useful in the treatment of neonatal diarrhea in animals, 
particularly lambs, calves, and baby pigs. Scours in calves, lambs, baby 
pigs and foals can be prevented or improved by administering an effective 
amount of a compound of Formula I, preferably as a food additive, though 
other forms of administration can be used. As a food additive, the active 
amidinourea can be dispersed or dissolved in the normal diet or formulated 
as part of the animal feed or dissolved in the drinking water. 
The compounds of Formula I, and especially those of Formula II and the 
specific compounds identified above, when formulated into therapeutic 
dosage forms, provide a beneficial means for the treatment of animal 
scours. The activity and recommended dosage amounts are shown by the 
following tests. 
SWINE SCOURS STUDY 
Doses of 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride that are 
well tolerated in piglets were determined as follows: 
9 piglets, 5 to 6 days old, were treated. Three piglets received 1 mg. 
each, three received 5 mgs. each and three received 10 mgs. each. Each 
dose was dissolved in 1.1 ml. dH.sub.2 O and administered orally with a 
plunger applicator bottle to which was attached 6 cm. of polyethylene 
tubing. No clinical adverse effects were noted during the two-hour 
post-treatment observation period. 
On the following day, the procedure was repeated on the same nine piglets 
using 30, 100 and 300 mg./each/3 pigs. Because of solubility difficulties 
each dose was administered in 2.2 ml. dH.sub.2 O. No adverse effects were 
noted in the three pigs receiving 30 mg. Their weights were 3.5, 4.0 and 
5.25 lbs. 
The results at 100 mg./pig, administered at 10:30 a.m. were as follows: 
1.75 lbs.: convulsions, vomiting, died 1:20 p.m. 
2.50 lbs: slight convulsions, convulsions, vomiting, died 1:00 p.m. 
4.50 lbs: vomited at 11:20 p.m. 
The results at 300 mg./pig, administered at 10:30 a.m. were as follows: 
2.25 lbs: convulsions, died 11:15 a.m. 
5.25 lbs: vomited at 11:40 a.m. 
5.50 lbs: vomited at 1:15 p.m. 
The three pigs that died were "posted" to determine cause of death. While 
the two that vomited had inhaled some of the material, death was caused by 
the drug. 
FOLLOW-UP 
Seven days later, a 30 mg. piglet died. Autopsy revealed thoracic cavity 
reddish and lungs consolidated. Ascites and periotonitis was evident in 
the abdominal cavity. Intestines were adhered to each other and the 
abdominal wall. 
Eleven days later a 300 mg. piglet died. By necropsy on the twelfth day, 
the body was badly decomposed and examination revealed little. Both 
intestines were void of food and distended with gas. Twenty-three days 
later, the remaining piglets appeared to be normal. They were sacrificed 
on that day. 
The efficacy of 1-(2,6-dimethylphenyl)-3-methyl-amidinourea hydrochloride 
was determined in naturally occuring "baby pig scours", alone and in 
combination with Neomycin, as follows: 
A. Pre-Treatment 
Litters of newborn pigs were selected at random for treatment. They were 
kept in the farrowing house under good management conditions but with no 
scours prophylaxis. Drug administrator and evaluator were blinded. 
B. Treatment 
Time of birth was recorded. When the first piglet in each litter was 
positively identified for scours, it was treated with one dose of one of 
six regimens: 
1. 1.0 mg. 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride 
2. 1.0 mg. 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride plus 50 
mg. neomycin sulfate 
3. 10.0 mg. 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride 
4. 10.0 mg. 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride 
5. 50 mg. neomycin sulfate 
6. Distilled water 
Each dose was dissolved in 1.1 ml. dH.sub.2 O and administered orally with 
a plunger applicator bottle to which was attached 6 cm. of polyethylene 
tubing. 
As littermates of the affected piglet scoured, they were also treated. At 
approximately six hours after the first piglet scoured, all untreated 
(non-scouring) piglets were treated. 
C. Post-Treatment 
All litters were observed intensively for four days after treatment and 
periodically for the next seven days. All observations were recorded and 
are summarized on the following charts. 
Pen No. 24 
Treatment: 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride (1 mg) 
Birthdate: April 22 
______________________________________ 
PIG 
LET SCOURS TIME COMMENTS 
______________________________________ 
1 Y 1200 
2 Y 1215 
3 Y 1345 
4 N 1730 4/26, died, some food in stomach and 
intestine 
567891011121314 
NNYNNYNNNN 
##STR5## 
4/26, died, no food in GI tract, upper intestine 
pale, lower congested. 4/22, severe diarrhea 4/27, 
died, stomach distended with gas, no food, upper 
intestine pale, lower congested. 
______________________________________ 
Other Observations: 
4/24, one dead, no autopsy 
4/28, two weak 
4/29, above piglets eating 
Summary: 5 scoured, 4 or 5 survived. 
Pen No. 34 
Treatment: 1 mg. 1-(2,6-dimethylphenyl-3-methylamidinourea hydrochloride 
plus 50 mg. neomycin sulfate 
Birthdate: 4/12 
______________________________________ 
PIGLET SCOURS TIME COMMENTS 
______________________________________ 
1 Y 1115 
2 Y 1115 
3 Y 1345 
4 N 1615 
5 N 
6 N all piglets normal 
7 N 
8 ? 
9 N 
10 N 
11 N 
12 N 
______________________________________ 
SUMMARY: 3 scoured, all survived. 
Pen No. 36 
Treatment: 10 mg. 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride 
Birthdate: 4/13 
______________________________________ 
PIG- 
LET SCOURS TIME COMMENTS 
______________________________________ 
1 Y 830 
2 Y 855 scoured again at 1800 
3 Y 855 diarrhea stopped by 1000, scoured 
again at 1800 
4 Y 855 diarrhea stopped by 1000 
5 Y 855 diarrhea stopped by 1000, scoured 
again at 1800 
6 Y 935 diarrhea stopped by 1000 
7 N 1300 
8 N 1300 
______________________________________ 
Other observations: 4/15 no scours, some bloating. Severe, propulsive 
scours before treatment. 
Summary: 6 scoured, all survived. 
Pen No. 35 
Treatment: 10 mg. 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride 
plus 50 neomycin sulfate 
Birthdate: 4/12 
______________________________________ 
PIG- 
LET SCOURS TIME COMMENTS 
______________________________________ 
1 Y 1120 
2 Y 1125 
3 Y 1125 4/15 dead, abdomen distended 
4 Y 1305 stomach 
and intestine full of gas. Stomach 
filled with milk, intestine with soft 
fecal material. Remaining animals 
5 Y 1305 bloated, signs of constipation 
6 Y 1310 
7 Y 1315 
8 N 1625 
9 N 1625 
10 N 1625 
11 N 1625 
______________________________________ 
Other Observations: 
4/14, all piglets apparently normal 
4/16, still bloating, but nursing normally 
4/17, piglets normal 
Summary: 7 scoured, 6 survived. 
Pen No. 30 
Treatment: 50 mg. neomycin sulfate 
Birthdate: 4/12 
______________________________________ 
PIG- 
LET SCOURS TIME COMMENTS 
______________________________________ 
1 Y 1100 
2 Y 1100 4/18, dead, dehydrated, no autoposy- 
"runt" 
3 Y 100 
4 Y 1100 
5 Y 1105 
6 Y 1245 4/14, scours seen again, 945 
7 Y 1245 
8 Y 1250 
9 N 1610 4/15, died, probably crushed by sow. 
No food in stomach. GI tract dis- 
tended with gas, small amount of 
soft material throughout intestines. 
Evidence of soft feces around anus 
and tail. 
10 N 1610 
11 N 1610 
12 N 1610 
13 N 1610 
______________________________________ 
Other Observations: 4/19, all piglets normal 
Summary: 8 scoured, 7 survived. 
Pen No. 1 
Treatment: Distilled Water 
Birthdate: 4/21 
______________________________________ 
PIGLET SCOURS TIME COMMENT 
______________________________________ 
1 Y 1140 
2 Y 1145 
3 Y 1215 
4 Y 1330 
5 Y 1515 
6 Y 1515 
7 Y 1520 
8 Y 1600 
9 N 1730 
10 N 1730 
4/25, dead 
11 N 1730 autopsy - upper part 
of intestine pale, lower part 
congested. 
12 N 1730 
______________________________________ 
Other Observations: 
4/27, one dead, number illegible, autopsy unremarkable 
4/28, two very weak, numbers illegible, one unable to stand 
4/29, one dead, number illegible, dehydrated, autopsy--stomach and 
intestines distended with gas, no food in stomach, small amount hard feces 
in large intestine. 
Summary: 8 scoured, probably 5 survived. 
SUMMARY 
These results from six litters (70 piglets) demonstrate that 
1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride is at least as 
effective as neomycin in stopping scours, though it can also be used in 
combination with neomycin or other medication as an effective treatment or 
preventive for scours in calves, lambs and piglets, particularly when less 
than 10 days old. 
The compositions of the present invention can be prepared in forms suitable 
for administration by compounding an effective single dose amount of a 
compound of Formula I above with known ingredients generally employed in 
the preparation of therapeutic veterinary compositions provided as 
tablets, capsules, lozenges, chewable lozenges, pills, powder, granules, 
suspensions, oil-in-water or water-in-oil emulsions, or other similar 
forms which can be taken orally. Or, the treatment can be accomplished by 
incorporating an effective amount of a compound of Formula I in the animal 
diet as a feed supplement or dissolved in the animal's fluid intake. 
Since the compounds are readily absorbed into the bloodstream from the 
stomach and intestines when taken orally, the preferred method of 
treatment is to give the drug orally which is also the safest and most 
practical route of administration. Optional methods can be used. Where, 
for example, the animal is not eating or cannot swallow or has difficulty 
in swallowing, other methods of administration which permit the drug to be 
absorbed from the gastrointestinal tract or which deliver a solution of 
the drug directly to the bloodstream can be employed. 
The dosage regimens in carrying out the anti-scouring methods utilizing the 
amidinourea compositions of this invention are those which insure maximum 
therapeutic response until improvement is obtained and thereafter the 
minimum effective level which gives relief. Thus, in general, the dosages 
are those that are therapeutically effective in the treatment of scours. 
For calves, lambs, piglets and foals, the average effective dose is 
between about 2 and about 10 mg./kg. of body weight, while for adult 
cattle, a slightly lower total dose is recommended. 
In general, the single oral dose for piglets weighing between about 1 and 5 
lbs. will contain between about 1 mg. and 25 mg. (preferably in the range 
of 5 to 15 mg.). Similar doses of about 1 to 50 mg. are employed for lambs 
of about 5 to 20 lbs. and doses of 5 to 75 mg., preferably 20 to 50 mg. 
for calves of about 10 to 50 lbs. Fractional or multiple doses can of 
course be given bearing in mind that in selecting the appropriate dosage 
in any specific case, consideration must be given to weight, general 
health, age, and other factors which may influence response to the drug. 
The drug response on oral administration usually follows within 10 to 30 
minutes after administration and is maintained for 1 to 4 hours. The drug 
is generally given in single doses 2 to 4 times daily or as required to 
maintain an effective drug level in the blood stream for continuous relief 
of scours. 
Compositions intended for oral use may be prepared according to methods 
known generally in the art, such compositions may contain one or more 
agents selected from the group consisting of sweetening agents, flavoring 
agents, coloring agents, and preserving agents, in order to provide a 
pharmaceutically elegant and palatable preparation. Orally, they may be 
administered in tablets, lozenges, aqueous or oily suspensions, 
dispersible powders or granules, emulsions, hard or soft capsules, or 
syrups or elixers which contain the active amidinourea ingredient in 
admixture with non-toxic pharmaceutically acceptable excipients. 
Excipients which may be, for example, inert diluents, such as calcium 
carbonate, sodium carbonate, lactose, calcium phosphate or sodium 
phosphate; granulating and disintegrating agents, for example, maize 
starch or alginic acid; binding agents, for example, starch, gelatin or 
acacia; and lubricating agents, for example, magnesium stearate, stearic 
acid or talc. The tablets may be uncoated or they may be coated by known 
techniques to make them more effective for example to delay disintegration 
or absorption or to make them more palatable or for other reasons for 
which orally-administered drugs have been previously provided in coated 
form. 
Formulations for oral use may also be presented as hard gelatin capsules 
wherein the active ingredient is mixed with an inert solid diluent, for 
example, calcium carbonate, calcium phosphate or kaolin, or as soft 
gelatin capsules wherein the active ingredient is mixed with an oil 
medium, for example, arachis oil, liquid paraffin or olive oil. 
Aqueous solutions containing the active amidinourea form a further 
embodiment of this invention. Excipients suitable for aqueous suspensions, 
may be employed, if desired. These excipients are suspending agents, for 
example, sodium carboxymethyl-cellulose, methyl-cellulose, 
hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidine, gum 
tragacanth and gum acacia; dispersing or wetting agents may be a naturally 
occurring phosphatide, for example, lecithin; or condensation products or 
an alkylene oxide with fatty acids, for example, polyoxyethylene stearate; 
or condensation products of ethylene oxide with long-chain aliphatic 
alcohols, for example, heptadecaethylenoexy-cetanol; or condensation 
products of ethylene oxide with partial esters derived from fatty acids 
and a hexitol, for example, polyoxyethylene sorbitol mono-oleate; or 
condensation products of ethylene oxide with partial esters derived from 
fatty acids and hexitol anhydrides, for example, polyoxyethylene sorbitan 
monoleate. The said aqueous suspensions may also contain one or more 
preservatives, for example, ethyl, or n-propyl, p-hydroxy benzoate, one or 
more coloring agents, one or more flavoring agents, and one or more 
sweetening agents, such as sucrose. 
Oily suspensions may be formulated by suspending the active ingredient in a 
vegetable oil, for example, arachis oil, olive oil, sesame oil, or coconut 
oil, or in a mineral oil such as liquid paraffin. The oily suspensions may 
contain a thickening agent, for example, beeswax, hard paraffin or cetyl 
alcohol. Sweetening agents, such as those set forth above, and flavoring 
agents may be added to provide a palatable oral preparation. These 
compositions may be preserved by the addition of an anti-oxidant such as 
ascorbic acid. 
Dispersible powders and granules suitable for preparation of an aqueous 
suspension by the addition of water provide the active ingredient in 
admixture with a dispersing or wetting agent, suspending or wetting agents 
and suspending agents are exemplified by those already mentioned above. 
Additional excipients, for example, sweetening, flavoring and coloring 
agents, may also be present. 
The compounds of this invention may also be in the form of oil-in-water 
emulsions. The oily phase may be a vegatable oil, for example, olive oil 
or arachis oils, or a mineral oil, for example, liquid paraffin or 
mixtures of these. Suitable emulsifying agents may be naturally-occurring 
gums, for example, gum acacia or gum tragacanth, naturally-occurring 
phosphatides, for example, soya bean lecithin, and esters or partial 
esters derived from fatty acids and hexitol anhydrides, for example, 
sorbitan mono-oleate. The emulsions may also contain sweetening and 
flavoring agents. 
Syrups and elixers may be formulated with sweetening agents, for example, 
glycerol, sorbitol or sucrose. Such formulations may also contain a 
demulcent, a preservative and flavoring and coloring agents. The 
pharmaceutical compositions may be in the form of a sterile injectionable 
preparation, for example, as a sterile injectable aqueous suspension. This 
suspension may be formulated according to the known art using those 
suitable dispersing or wetting agents and suspending agents which have 
been mentioned above. The sterile injectable preparation may also be a 
sterile injectable solution or suspension in a non-toxic parenterally 
acceptable diluent or solvent, for example, as an aqueous solution 
buffered to a pH of 4.0 to 7.0 and made isotonic with sodium chloride. 
Further, the active amidinourea may be administered alone or in admixture 
with other agents having the same or different pharmacological properties. 
The anti-scour treatment can be administered in combination with 
antibiotics such as neomycin or with other antibacterial or antiviral 
agents, or other adjuvants such as electrolytes and antiemetics. The 
compounds of Formula I can also be used as a preventive measure, in which 
case, the preferred mode of administration is through the diet as a feed 
or water additive. 
For the treatment of scours, the compounds of Formula I, and particularly 
the compounds of Formula II, and the specifically named compounds noted 
above, are administered orally to the infant animals for example with a 
plunger applicator bottle at doses in the order of 0.5 to 25 mg./kg of 
body weight, preferably about 5 to 15 mg/kg administered 1 to 4 times 
daily. Higher doses can be used when tolerated especially in the case of 
larger animals. In general, a dose of about 10 mg. per day is effective in 
relieving symptoms of scours in calves, piglets, lambs and foals. The 
treatments are preferably administered prophylactically or within about 10 
hours (preferably within about 5 hours) after onset of scours. The 
treatments have been found to be especially effective in scouring animals 
less than ten days old.

The veterinary compositions and method of this invention are further 
illustrated by the following examples of therapeutic compositions 
incorporating an effective amidinourea in forms suitable for 
administration to diseased animals. 
EXAMPLE 1 
Therapeutic compositions of the invention are prepared by using known 
techniques for compounding employing either the base or a salt as the 
active ingredient along with the non-toxic excipients chosen in accordance 
with the particular form and properties desired for the therapeutic 
composition. 
Tablets which can be advantageously used for either remedial or 
prophylactic treatments can be provided in a form which provides relief 
when administered at a rate of 2 to 4 tablets per day containing between 
about 5 and 25 mg. of the active ingredient. An exemplary formulation 
which can be utilized is, for example, the following: 
______________________________________ 
1-(2,6-dimethylphenyl)-3-methylamidinourea 
500 mg. 
hydrochloride 
tricalcium phosphate 200 mg. 
talc 50 mg. 
magnesium stearate 10 mg. 
polyvinyl acetate 40 mg. 
______________________________________ 
In addition, there are added protective excipients such as ethylcellulose, 
dibutylphthalate, propylene glycol, wax (white and/or carbauba), 
spermaceti, methylene chloride, and rectified diethyl ether. The 
ingredients are compressed to minimum size to provide a tablet of about 
850 mg. 
EXAMPLE 2 
A lot of tablets each containing 20 mg. of 
1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride is prepared from 
the following types and amounts of ingredients: 
______________________________________ 
1-(2,6-dimethylphenyl)-3-methylamidinourea 
hydrochloride 1 kg. 
dicalcium phosphate 1 kg. 
methylcellulose USP 75 g. 
talc 150 g. 
cornstarch 200 g. 
magnesium stearate 10 g. 
______________________________________ 
The active ingredient and dicalcium phosphate are mixed thoroughly and 
granulated with a 7.5% solution of methylcellulose in water and passed 
through a #8 screen and air-dried. The dried granules are passed through a 
#12 screen and combined with the talc, starch and magnesium stearate with 
thorough mixing after which the composition is compressed into tablets. 
EXAMPLE 3 
A lot of 2-piece hard gelatin capsules, each containing 25 mg. of 
1-(2,6-dimethylphenyl)-3-methylamdinourea hydrochloride are prepared from 
the following types and amounts of ingredients: 
______________________________________ 
1-(2,6-dimethylphenyl)-3-methylamidinourea 
hydrochloride 500 g. 
dicalcium phosphate 500 g. 
talc 150 g. 
magnesium stearate 5 g. 
______________________________________ 
The ingredients are mixed thoroughly and filled into capsules which are 
used for oral administration at the rate of about one every four hours. If 
desired, slow release forms can be provided or delay release forms 
depending on choice of capsules and formulating ingredients. 
EXAMPLE 4 
A sterile solution suitable for interperitoneal injection, and containing 
10 mg. of 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride in 
each, 10 ml. (1:1 wt./volume), is prepared from the following ingredients: 
______________________________________ 
1-(2,6-dimethylphenyl)-3-methylamidinourea 
hydrochloride 10 g. 
benzyl benzoate 100 ml. 
methylparaben 1 g. 
propylparaben 0.5 g. 
cottonseed oil q.s. 500 ml. 
______________________________________ 
EXAMPLE 5 
Tablets for oral use, each containing 25 mg. of 
1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride are prepared from 
the following types and amounts of material: 
______________________________________ 
1-(2,6-dimethylphenyl)-3-methylamidinourea 
hydrochloride 500 g. 
lactose U.S.P. 350 g. 
potato starch U.S.P. 346 g. 
______________________________________ 
The mixture is moistened with an alcoholic solution of 20 g. of stearic 
acid and granulated through a sieve. After drying, the following 
ingredients are added: 
______________________________________ 
potato starch U.S.P. 320 g. 
talc 400 g. 
magnesium stearate 500 g. 
colloidal silicium dioxide 
64 g. 
______________________________________ 
The mixture is thoroughly mixed and compressed into tablets. 
EXAMPLE 6 
Five hundred ampoules each with 2 ml. of solution which contains 15 mg. of 
1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride are prepared from 
the following types and amounts of materials: 
______________________________________ 
1-(2,6-dimethylphenyl)-3-methylamidinourea 
hydrochloride 7.5 g. 
ascorbic acid 1 g. 
sodium bisulphite 0.5 g. 
sodium sulphite 1 g. 
______________________________________ 
EXAMPLE 7 
Capsules are prepared as follows: 
15 g. of 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride, 
3 g. magnesium stearate, 
2 g. of finely divided silica sold under the trademark CAB-O-SIL by Godfrey 
L. Cabot, Inc., Boston, Mass., 
and, 
369 g. of lactose. 
The ingredients are mixed with each other and the mixture is filled in 
gelatin capsules. Each capsule contains 500 mg. of the composition and 
thus, 15 mg. of 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride. 
EXAMPLE 8 
50 g. of 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride, 5 g. of 
propyl p-hydroxybenzoate are dissolved and dilluted to 5000 cc. with twice 
distilled water after the addition of modified Sorensen buffer solution in 
an amount sufficient to adjust the pH value to a pH of 6.0. Sodium 
chloride is dissolved therein in an amount sufficient to render the 
resulting solution isotonic. The final solution is passed through a 
bacteriological filter and the filtrate is autoclaved at 120.degree. C. 
for 15 minutes to yield a parenterally applicable solution which contains 
50 mg. of 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride in 5 
cc. 
By analogous procedures, other amidinoureas can be prepared from the 
corresponding starting materials and formulated for either oral 
administration as injectible or infusible solutions or for rectal 
administration, for example, suppository form. The solid and liquid 
formulations can be dispersed in the feed or dissolved in drinking water 
or the liquid diet.