Safety

A study¹ observed no evidence of toxicity in six calves given amprolium at 200 or 400 mg/kg body weight for four successive days. In addition, studies conducted at Merck Sharp & Dohme Research Laboratories revealed no gross or histologic lesions associated with the administration of 50 mg of amprolium per kg body weight daily for 21 days (ten times the label dosage rate).

Amprolium, the active ingredient in CORID^®, is well tolerated by cattle. The evidence cited suggests that several times the recommended levels of five mg/kg body weight for 21 days for preventive use and 10 mg/kg body weight for five days for therapeutic use can be administered without adverse effect on the animals.

 

Table I:
Summary of Mean Results in Four Trials to Determine Efficacy of CORID in Control of Experimental Coccidiosis in Calves

Treatment	Dosage (mg/kg)	No. Days Treated	Total No. Calves	Oocyst Discharge			Clinical Signs		Weight Gain (lb [kg])
				Total (thousands)	Duration (days)	Peak Production (days)	Diarrhea (No. Days)	Bloody Feces (No. Days)
CORID	25	21	13	4.5*	2.6*	26.1*	2.3*	0*	33.88 (15.4)
CORID	5	21	13	22.6*	3.2*	21.1	2.2*	0.2	34.10 (15.5)
CORID	1	21	3	222.1	6.7	19.7	4.7	1.3	31.90 (14.5)
Untreated Controls	None	—	13**	248.3	7.5	19.8	6.6	1.4	27.50 (12.5)

* Significantly different from untreated controls at P=0.01
** Four of 13 control calves died from coccidiosis. None of the treated calves died.

Efficacy
Controlled Infection Studies – Feed Administration

The results of four trials² showed that CORID effectively controlled coccidiosis in calves. Dosage rates of one, five or 25 mg/kg body weight were used in the trials. CORID was mixed in the grain and given in the morning feeding. The medicated feed was readily consumed by the calves. Medicated feed was given one day before infection and continued for 21 days. The calves were each exposed to 50,000 oocysts of E. bovis. The oocyst inoculum was composed of 90% to 95% E. bovis, and the other species present were E. auburnensis, E. ellipsoidalis, E. cylindrica and E. zurnii. An adaptation of the results of their trial is presented in Table I above.

The data show that CORID at either five or 25 mg/kg body weight was administered to calves once daily in their grain feeding and successfully prevented or controlled the clinical indications of coccidiosis.

 

Table II:
Summary of Weight Data, First and Eighth Weighings (seven-month interval)

Treatment Group	No. of Animals	Mean of First Weighing lbs (kg)	Mean of Eighth Weighing lbs (kg)	Adj. Mean First† Weighing lbs (kg)	Adjusted Mean Cumulative Weight Gain† lbs (kg)
I. Control	5	145.2 (66.0)	550.8 (250.4)	144.9 (65.9)	405.3** (184.2)
II. 500 oocysts	4	146.0 (66.4)	529.8 (240.8)	144.9 (65.9)	382.7 (173.9)
III. 500 oocysts + CORID	5	144.2 (65.5)	570.0 (259.1)	144.9 (65.9)	426.5* (193.9)
IV. 50,000 oocysts	4	145.8 (66.3)	498.0 (226.4)	144.9 (65.9)	351.4 (159.7)
V. 50,000 oocysts + CORID	5	143.8 (65.4)	551.2 (250.5)	144.9 (65.9)	408.5** (185.7)

^† Adjusted by method of Analysts of Covariance.
* Statistically significantly more weight gained than Group II (P< 0.05).

Another study³ was conducted to evaluate the effect of CORID treatment on weight gain of cattle given controlled infections of coccidia. Each day for five days, 23 six-week-old Holstein calves were each given either 500 or 50,000 oocysts of a mixture containing 98% E. bovis with the balance made up of E. zurnii, E. ellipsoidalis and E. auburnensis. Treatment began the day of inoculation and continued for 21 days. The drug was administered as a topdress on the feed. A summary of the results is presented in Table II. The data show that both treated groups gained significantly more weight than their respective infected controls and gained at an equivalent rate compared to the noninfected, nontreated controls. No evidence of compensatory gain was noted within the seven-month period for which observations were made in this trial.

Two additional trials were conducted to the efficacy of CORID used both as a preventive and as a treatment to control naturally infected or induced coccidiosis.⁴ Six- to 12-month-old Hereford calves were experimentally infected with either 50,000 or 100,000 oocysts consisting of a mixture of 94% E. bovis, 4% E. ellipsoidalis, 1% E. auburnensis, 0.5% E. zurnii, 0.4% E. cylindrica and 0.1% E. subspherica. The infection was administered daily for either three or 10 days. Calves in the preventive therapy group received CORID in the feed from the day of inoculation for 21 days; the treatment group received 10 mg/kg body weight treatment in the feed started at Day 13 postinfection and continuing for five days. The results of the two trials are summarized in Table III below.

 

Table III:
Summary of Results in Two Experiments to Determine Effect of CORID Fed in Ration for Coccidiosis in Feeder Calves

Treatment	Dosage (mg/kg)	No. Days Treated	Total No. Calves	Oocyst Discharge			Clinical Signs		Weight Gain (lb [kg])
				Total (thousands)	Duration (days)	Peak Production (days)	Diarrhea (No. Days)	Bloody Feces (No. Days)
Experiment 7
CORID	25	30	20	<0.1**	2.0**	<20.0**	0**	0	212.3 (96.5)
Untreated Controls	None	—	20	< 10	5.1	21.5	2.4	0	205.3 (93.3)
Experiment 8
CORID	10	5	18(1)	1-10*	5.2**	23.8	3(1/17)	1(2/17)**	172.7 (78.5)
CORID	5	21	17(1)	1**	3.3**	26.8**	0	0**	177.3 (80.6)
Untreated Controls	None	—	18(1)	< 10	6.1	20.1	1-2(5/18)	1-2(12/18)	168.1 (76.4)

* Significantly different from untreated controls at (P=0.05)
** Significantly different from untreated controls at (P=0.01)
⁽¹⁾ These groups initially started with 20 calves but some were removed due to respiratory or digestive disturbance not associated with the experimental infection.

The data show that a medicated ration containing CORID effectively controlled clinical coccidiosis and suppressed the development of the coccidial parasites in cattle exposed to oocysts. CORID dosages of five or 25 mg/kg body weight fed for 21 or 30 days, respectively, provided better control than CORID in a dosage of 10 mg/kg body weight fed for only five days. Although cattle treated with CORID showed an improved rate of weight gain in comparison with the controls, the difference was not statistically significant for these relatively mild cases of coccidiosis.

Controlled Infection Studies – Water/Drench Administration

Trials have also studied CORID solution given as a drench for treatment of clinically severe coccidiosis in calves.⁵ Approximately 200,000 sporulated oocysts were administered orally to 10 young Holstein calves; four Holstein calves of approximately the same weight as the inoculated calves served as a control on the environmental exposure to coccidia. The inoculum contained the following species of Eimeria: E. canadensis (60%), E. bovis (24%), E. zurnii (9%), E. ellipsoidalis (4%), E. subspherica (2%), E. bukidnonensis, E. cylindrica and E. auburnensis (less than 1% each).

CORID (9.6% Oral Solution) was administered orally as a drench to six calves. Each calf was given a dosage of 1.5 grams of CORID daily for four days. Treatment was given to groups of two calves each on Days 1 to 4, 8 to 11, or 15 to 18 after inoculation with oocysts. The control calves (inoculated or uninoculated) received no treatment. A summary of the results follows in Table IV below.

 

Table IV:
Therapeutic Efficacy of CORID (Oral Drench - 1.5 G/day) in Bovine Coccidiosis

Average Oocysts/Gram of Feces Days after Inoculation
Days Treated	No. Calves	18	19	20	21	22	23	24	25	Total	% Reduction
1-4	2	5	3	1,474	317	660	1,383	8,153	3,224	15,219	88
8-11	2	—	1	4	962	385	6,023	8,278	12,521	18,174	86
15-18	2	—	—	12	4	33	36	125	20	230	99.8
(Inf.)+	6**	718	4,625	32,309	19,620	24,660	23,096	8,084	11,614	124,726	—
(N.I.C.)+	4	—	241	228	7	517	—	16	—	1,013	—

* Compared to other inoculated controls
** Two calves died on Day 21; death was preceded by syndrome characteristic of severe coccidiosis.
+ Inf. = Infected controls
N.I.C. = Noninfected controls

The data indicate that CORID administered orally to calves once daily for four days on the 15th to 18th days after exposure almost completely prevented the development and passage of oocysts in the feces. When the drug was given similarly for four days on the 1st to 4th or 8th to 11th days after inoculation, oocyst output was drastically reduced and the peak production delayed several days in comparison with the inoculated controls. Although some of the calves treated with CORID had mild to severe diarrhea, none died or had the characteristic symptoms of severe coccidiosis. Two of the control calves died with severe clinical coccidiosis.

Another study reports that CORID was an effective control measure when given in the milk to calves with experimentally induced coccidiosis.⁶ The calves were housed in individual isolation stalls and special precautions were maintained to minimize extraneous exposure to coccidia. At approximately two weeks of age, the calves were inoculated with 50,000 or 100,000 oocysts. More than 90% of the oocysts were E. bovis and the balance represented E. ellipsoidalis, E. auburnensis, and a small number of each of E. zurnii and E. cylindrica.

The treated calves received CORID twice daily in their milk feedings. The dosages administered were 22, 36 or 143 mg/kg body weight per day for 21 days with the initial dose given on the day of inoculation. Other calves were given CORID in a dosage of 143 mg/kg body weight for five days beginning on the 13th day after inoculation. In another group, this same dosage of CORID (143 mg/kg body weight) was given for one day only on the 13th day after exposure to infection with oocysts. A compilation of the results of the trial is presented in Table V below.

 

Table V:
Summary of Mean Results in Six Tests to Determine Effect of CORD on Coccidiosis in Calves

CORID Dosage (mg/kg)	No. Days Treated	Total No. Calves	Oocyst Discharge			Clinical Signs		Weight Gain in 28 Days (lbs [kg])
			Total (thousands)	Duration (days)	Peak Production (days)	Diarrhea (No. days)	Bloody feces (No. days)
143	1-21	6	0**	0.2**	17.0(1)	1.2**	0.2**	31.9* (14.5)
36	1-21	15	7.1**	1.3**	27.2	1.2**	0.1**	31.5* (14.3)
22	1-21	6	4.8**	1.2**	27.5	4.7	0.3	29.9* (13.6)
143	13-18	12	17.5**	2.6**	23.3	3.3**	0.5**	27.1* (12.3)
143	13 (only)	3	97.7	4.0	19.3	4.7	0.3	20.9 (9.5)
None (Inf.)+	—	15	312.0	7.8	19.8	8.6	2.5	18.0 (8.2)
None (N.I.C.)+	—	9	7.0**	2.8**	—	3.1**	0**	23.1 (10.5)

* Significantly different from untreated controls at P=0.05
** Significantly different from untreated controls at P=0.01
⁽¹⁾ One calf had detectable oocysts for one day only
+ Inf. = Infected controls
N.I.C. = Noninfected controls

The results showed that CORID was highly effective in controlling coccidiosis when administered to calves in daily dosages of 22, 36 or 143 mg/kg body weight for 21 days beginning on the day of inoculation with oocysts. CORID was also effective in a dosage of 143 mg/kg body weight given for five days (13 to 18 days after inoculation). However, the same dosage was not effective when given for one day only (13th day after inoculation). The administration of CORID (143 mg/kg body weight) for five days on the 13th to 18th day after infection provided results which were not significantly different from dosages of 23, 36 or 143 mg/kg body weight given daily for 21 days. This observation suggests that CORID mainly affects the later stages in the life cycle of E. bovis. In all trials except the one-day treatment, CORID provided good to excellent control of coccidiosis as revealed by comparing the several criteria in the treated and untreated calves.

Field Efficacy Trials in Feed

CORID was administered in the feed, under field conditions, to over 800 calves of various breeds, sexes and ages in seven different trials at doses varying from five to 66 mg of active material per kg body weight for five to 21 consecutive days, as a preventive or therapeutic treatment. The treatments proved practical to administer, caused no side effects and, depending on the severity of infection present, controlled coccidiosis effectively and reliably. The results of these trials are summarized in the table below.

 

Table VI:
CORID in Cattle
Summary of Field Efficacy and Safety Trials

Investigator & Location of Test	Number Treated	Breed	Sex	Age (months)	Dose (mg/kg)	Comments
D. L. Ferguson, Ph.D. University of Nebraska Test at Agate, Nebraska	185	Hereford	M-F	4-5	5 x 10 days	Coccidiosis controlled.
R. M. Madsen, DVM Omaha, Nebraska Test at Sula, Montana	33	Hereford & Angus	M-F	6	36 x 21 days	Weight improved. Oocyst counts reduced in treated calves.
R. M. Madsen, DVM Omaha, Nebraska Test at Conrad, Montana	62	Cross	F	9	35 x 21 days	Coccidiosis controlled in 5 days.
A. F. Hentschl, DVM Harbor Beach, Michigan Test at Harbor Beach, Michigan	165	Hereford & Angus	Steers	Yearlings	50 x 5 days	Clinical signs of coccidiosis eliminated in 7 days.
G. T. Walters, DVM Novato, California Test at Pasco, Washington	300	Mixed	Steers	Yearlings	10 x 5 days	Coccidiosis controlled and weight improved.
R. M. Madsen, DVM Omaha, Nebraska Test at Corvallis, Montana	31	Hereford	Steers	Weanlings	32 x 21 days	No side effects. Oocyst counts nearly reduced to zero in treated calves.

References

1. Horak R, et al. The use of amprolium in the treatment of coccidiosis in domestic ruminants. J South African Vet MA 1969;40(3):292-299.

2. Slater RL, Hammond DM, Miner ML. Eimeria bovis: development in calves treated with thiamine metabolic antagonist (amprolium) in feed. Trans Amer Microscop Soc 1970;89(1):55-65.

3. Fitzgerald PR, Mansfield ME. Effects of bovine coccidiosis on certain blood components, feed consumption, and body weight changes of calves. Am J Vet Res 1972;33(7):1391-1397(Ref3).

4. Jolley WR, Hammond DM, Miner ML. Amprolium treatment of six to twelve month old calves experimentally infected with coccidia. Proc Helmintol Sol Washington 1971;38(1):117-122.

5. Peardon DL, Bilkovich FR, Todd AC, Hoyt HH. Trials of candidate bovine coccidiostats: efficacy of amprolium, lincomycin, sulfamethazine, chloroquine sulfate, and diphenthane-70. Am J Vet Res 1965;26:683-687.

6. Hammond DM, Fayer R, Miner ML. Amprolium for control of experimental coccidiosis in cattle. Am J Vet Res 1966;27:199-206.