Method for the reduction of heat distress induced nicarbazin toxicity in fowl

There is disclosed a method for the reduction of a toxicity resulting from the use of nicarbazin in fowl during periods of high heat distress. The method involves the administration of phenothiazine during periods of high ambient temperature and/or relative humidity which are concurrent with periods of nicarbabin treatment. The use of phenothiazine during periods of potential heat induced toxicity caused by the administration of nicarbazin results in reduced mortality, higher feed efficiency and higher weight gain than is observed without the use of phenothiazine.

BACKGROUND OF THE INVENTION 
It is generally known that poultry such as chickens, geese, turkeys, quail, 
pheasants and the like are particularly susceptible to poor productivity 
(reduced growth rate, feed efficiency, egg shell quality and high 
mortality) during periods of environmental heat distress (high ambient 
temperatures and high relative humidity). It is also generally well known 
that these heat distress effects are greatly exacerbated if the 
anticoccidial agent nicarbazin (Nicarb) is administered during such heat 
distress periods. 
Heat distress substantially reduces the growth rate of broiler chicks. 
Diets have been altered to reduce this problem via reducing the heat 
increment of the diet with fat supplementation (H. L. Fuller et al; 
"Effect of Heat Increment of the Diet on Feed Intake and Growth of Chicks 
Under Heat Stress", Proc. Maryland Nutr. Conf., pp 58-664, 1973) and 
improved the amino acid balance (P. W. Waldroup et al; "Performance of 
Chicks Fed Diets Formulated to Minimize Excess Levels of Essential Amino 
Acids", Poultry Sci., 55:243-253, 1976). It has also been suggested that 
the decline in growth rate results directly from reduced feed intake (R. 
L. Squibb et al; "Growth and Blood Constitutients of Immature New 
Hampshire Fowl Exposed to Constant Temperatures of 99.degree. C. for 7 
Days", Poultry Sci., 38:220-221, 1959). It has been demonstrated that the 
growth rate of heat stressed broilers can be increased by force feeding at 
a level exceeding ad libitum feed intake (M. O. Smith et al; "Feed Intake 
and Environmental Temperature Effects Upon Growth, Carcass Traits, Ration 
Digestibility, Digestive, Passage Rate and Plasma Parameters in Ad Libitum 
and Force-Fed Broiler Chicks" Poultry Sci., 62:1504 abstr., 1983). 
SUMMARY OF THE INVENTION 
This invention is concerned with the alleviation of heat distress symptoms 
and mortality which occur with the administration of nicarbazin to 
poultry. More particularly, this invention is concerned with the 
administration of phenothiazine to poultry which are also being 
administered nicarbazin during periods of heat distress in order to 
eliminate the toxicity caused by the combination of heat distress and 
nicarbazin. Thus, it is an object of this invention to describe such a 
method to reduce these effects. A further object is to describe the feed 
and water compositions containing nicarbazin and phenothiazine for 
administration to poultry. A still further object is to describe the 
amounts of penothiazine and nicarbazin which are found in the feed and 
water compositions used for the administration of the drugs. Further 
objects will become apparent from a reading of the following description.

DESCRIPTION OF THE INVENTION 
It has been unexpectedly discovered that the well known toxic effects of 
nicarbazin upon poultry subject to heat distress, that is prolonged 
periods of high ambient temperature and/or relative humidity, can be 
alleviated or eliminated if phenothiazine, a known insecticide and 
anthelmintic agent, is administered during the period of nicarbazin 
treatment which occurs during periods of heat distress. The typical 
symptoms of nicarbazin heat distress toxicity of reduced weight gain, 
reduced feed effiency and death are all significantly reduced when 
phenothiazine is used to counteract nicarbazin heat distress toxicity. 
The toxic effects of nicarbazin will begin to be observed during summertime 
conditions when the daily high temperature, as measured inside the poultry 
building, exceeds 28.degree. C. The toxic effects of the combination of 
high temperature, humidity and nicarbazin will vary with age of the bird, 
the genetic make-up and the previous exposure of the bird to high 
temperatures. A brief exposure to temperatures in excess of 30.degree. C. 
may have only a moderate toxic effect upon the bird while a longer 
exposure at 28.degree. C. could have a more severe effect. The method of 
this invention will reduce the heat induced toxicity in both cases. Since 
poultry will generally rely on the mechanism of panting to help dissipate 
body heat, higher levels of relative humidity will reduce the efficiency 
of panting as a cooling mechanism and will increase the toxic effect of 
nicarbazin/heat distress combination. 
Nicarbazin is generally administered to poultry such as chickens, geese, 
turkeys, ducks, quail, pheasant, and the like at levels of from 100 to 150 
ppm in the feed, preferably about 125 ppm. Because it is highly insoluble 
in water, nicarbazin is generally not administered in poultry drinking 
water. 
When phenothiazine is added to the poultry feed in amounts of from 160 to 
10,000 ppm under heat stress conditions, the toxic effects of nicarbazin 
were completely reversed and phenothiazine tested birds were essentially 
indistinguishable from the control birds. Preferably the phenothiazine is 
administered at from 160 to 625 ppm and most preferably at about 320 ppm. 
Phenothiazine, being a basic compound, is capable of forming 
pharmaceutically acceptable acid addition salts with increased water 
solubility. Thus, the phenothiazine can also be readily administered as a 
part of the poultry drinking water. The phenothiazine is generally 
administered in the water ration at levels of from 50 to 1000 ppm. 
Preferably the phenothiazine is administered at from 100 to 500 ppm and 
most preferably at about 250 to 300 ppm. 
The preferred acid addition salts of phenothiazine are those derived from 
hydrohalic acids, preferably hydrochloric, or other mineral acids such as 
nitric, sulfuric, phosphoric and the like. Organic acids such as acetic 
acid are also suitable. 
Specifically, tests were carried out wherein chickens were subjected to 
temperatures with a daily variation of from 24.degree. to 35.degree. C. 
with temperatures exceeding 32.degree. C. for about 6 hours per day. In 
addition, the relative humidity was maintained at from 35 to 50%. In such 
tests, nicarbazin was administered at 0 (control) and 125 ppm and 
phenothiazine was administered at from 0 to 2500 ppm. The addition of 
nicarbazin decreased the number of birds surviving the study by 47%; 
decreased the weight gain by 19%; and decreased feed efficiency by 47%. 
The addition of phenothiazine at all doses of about 160 ppm and higher, 
produced survivability, weight gain and feed effiency which were 
indistinguishable from the control birds. 
The compounds of this invention are orally administered to poultry for the 
control of nicarbazin induced heat stress. Any number of conventional 
methods are suitable for administering the compounds of this invention to 
poultry, as for example, they may be given in the poultry feed. 
Of the various methods of administering the compounds of this invention to 
poultry, they are most conveniently administered as a component of a feed 
composition. The novel compounds may be readily dispersed by mechanically 
mixing the same in finely ground form with the poultry feedstuff, or with 
an intermediate formulation (premix) that is subsequently blended with 
other components to prepare the final poultry feedstuff that is fed to the 
poultry. Typical components of poultry feedstuffs include molasses, 
fermentation residues, corn meal, soybean meal, fish meal, ground and 
rolled oats, wheat shorts and middlings, alfafa, clover and meat scraps, 
together with mineral supplements such as bone meal and calcium carbonate 
and vitamins and amino acid supplementation. 
The following examples are provided that the invention might be more fully 
understood. They should not be contrued as limitations of the inventions. 
EXAMPLE 1 
Trials utilizing 1920 birds have been conducted according to the following 
protocol. Nicarbazin (125 ppm) addition to the basal ration decreased 
(P&lt;0.01) live weight gain (18.6%), survivability (47%), and feed 
efficiency (47%). Feed efficiency values were reduced by nicarbazin 
primarily as a result of its effect upon mortality. Phenothiazine addition 
(312.5, 625, 1250, 2500 ppm) to nicarbazin containing rations returned 
(P&gt;0.1) all production parameters (gain, survival, feed efficiency) to 
control values. No difference was detected (P&gt;0.1) between the 312.5 ppm 
and the 2500 ppm phenothiazine levels for any of the parameters evaluated. 
Phenothiazine was tested for efficacy to ameliorate nicarbazin toxicity 
according to the following treatments. 
______________________________________ 
TRT. Nicarbazin (ppm) 
Phenothiazine (ppm) 
______________________________________ 
Control 0 0 
1 125 0 
2 125 312.5 
3 125 625 
4 125 1250 
5 125 2500 
______________________________________ 
Birds were allotted to treatment such that individual treatment groups 
contained 16 replicates of 6 chicks per replicate. 
Environment: The enviromental chamber was set to oscillate between 
24.degree. C. and 35.degree. C. in a manner simulating a typical summer 
day. Hours in excess of 32.degree. C. averaged approximately 6 hours per 
day. Relative humidity was maintained between 35 and 50%. 
Parameters/Statistical Analysis: Parameters monitored included live weight 
gain, feed consumption, water consumption, feed efficiency and mortality. 
Live weight gain was estimated by the difference between initial and final 
body weights. Feed consumption was recorded for each replicate while water 
consumption was tallied over 8 replicates within a treatment group (2 
observations/trt). Feed efficiency was estimated by dividing total weight 
of birds surviving the study in each replicate by the total feed consumed. 
No effort was made to adjust feed efficiency for mortality as it was 
anticipated that the mortality effects on feed efficiency would be 
significant, adversely affected by treatment and of economic importance to 
the poultry industry. All data were subjected to analysis of variance 
using the General Linear Model of the statistical analysis system. When a 
significant F statistic was indicated by the analysis of variance for 
treatment, means were separated by least squares analyses utilizing the 
model which accounted for the greatest variation in the most efficient 
manner. 
OBJECTIVE 
The objective of the experiment described herein is to refine the dose 
titration of 125 ppm nicarbazin with 4 graded levels of phenothiazine. 
MATERIALS AND METHODS 
Test Animals: Vantress X Arbor Acre male chicks, numbering 1,300 were 
raised on rice hull litter and fed starter ration during the first 3 weeks 
posthatching. This pre-experimental time period was necessary in order to 
bring birds to the age at which they become susceptible to heat distress. 
On the first day of the 4.sup.th week, following an overnight fast, 960 
chicks were selected at random, weighed and randomly allotted to treatment 
groups. 
______________________________________ 
STARTER AND GROWER RATIONS 
INGREDIENT STARTER GROWER 
______________________________________ 
Corn 53.7 56.75 
Soybean meal 40.0 36.0 
Tallow 1.8 3.0 
Dicalcium Phospha 
2.35 2.35 
Calcium Carbomate 
1.2 0.9 
Salt 0.4 0.5 
Vitamin Supplement 
0.3 0.3 
Trace Minerals 0.1 0.1 
d1-Methionine 0.15 0.1 
100.0 100.0 
______________________________________ 
Management: At all times, save for the overnight fast at experiment 
initiation (4 weeks post-hatching), both feed and water were available for 
ad libitum consumption. Rations utilized were formulated to provide at 
least 105% of the requirement for essential nutrients specified by the 
Nutrient Requirement Council with the exception that energy mimicked 
current industry standards. The energy standards established by the NRC 
were used to establish nutrient/calorie ratios. 
Test Drugs: The phenothiazine available to the agricultural industry has an 
8.mu. particle size. However, a 3.mu. particle size is also available by 
special order and was utilized in this study. The smaller particle size 
may be more desirable for enhanced absorption and a lowered effective 
dosage rate. 
The addition of nicarbazin to the basal ration decreased (P&lt;0.01) survival 
(40%), live weight gain (27%) and feed efficiency (46%). Survivial in this 
study for chicks receiving nicarbazin in the absence of phenothiazine 
averaged 40% while survival for heat distressed chicks not fed nicarbazin 
averaged 92% Nicarbazin effects on live body weight gain have been mixed 
in other studies with results ranging from no effect to significant 
reductions. This variation is likely due to the birds previous exposure to 
heat distress and the severity of the stress encountered. In this study 
the birds had no prior exposure to heat distress and were subsequently 
exposed to a significantly elevated ambient temperature with the result 
that weight gains were reduced by 27%. Feed efficiency for birds consuming 
the nicarbazin supplemented ration without phenothiazine was reduced 
(P&lt;0.01) by 46% which is a reflection of both the depressed weight gain 
and survival. No effort was made to adjust feed efficiency values for 
mortality, therefore the feed efficiency values are producer oriented. 
The phenothiazine by nicarbazin interaction as well as the quadratic effect 
of phenothiazine within this interaction was significant (P&lt;0.01) for 
survival, gain and feed efficiency. This interaction may be attributed to 
the slight effect of phenothiazine on the broiler parameters monitored in 
contrast to the large phenothiazine effect in the presence of nicarbazin. 
Phenothiazine additions (312.5, 625, 1250, and 2500) to the basal ration 
containing 125 ppm nicarbazin returned all production parameters to 
control values. No significant differences (P&gt;0.1) were detected between 
the phenothiazine doses in rations containing nicarbazin for survival, 
live weight gain and feed efficiency. Phenothiazine addition to the basal 
ration in the absence of nicarbazin tended (P&lt;0.1) to increase survival at 
the 1250 ppm supplementation level, but only numerically increased 
survival at 2500 ppm. Phenothiazine tended (P&lt;0.1) to enhance growth rate 
in rations without nicarbazin at the 2500 ppm supplementation, level, but 
only numerically enhanced growth rate at the other levels. Feed efficiency 
values parallel survival. Averaging phenothiazine supplementation levels 
over nicarbazin indicated a non-significant F statistic for survival, body 
weight gain, and feed efficiency. 
Conclusion 
The capability of phenothiazine to reduce nicarbazin's toxic effects in 
male broilers during heat distress is sufficient to reduce nicarbazin 
induced heat stress toxicity to control levels. The lowest effective 
phenothiazine dose necessary to elicit a maximal response was not detected 
suggesting that it is equal to or less than 312.5 ppm. 
EXAMPLE 2 
Summary 
One trial utilizing 960 birds was conducted to further refine the dose 
titration of nicarbazin (125 ppm) with graded phenothiazine levels (0, 80, 
160, 320, 640 ppm). All rations evaluated in the study contained 
nicarbazin. Linear effects of phenothiazine supplementation were 
significant (P&lt;0.01) as phenothiazine increased survival from 28% for 
birds consuming ration supplemented with 0 ppm to 60.2% for the 640 ppm 
supplementation level. The 320 ppm phenothiazine level was similar 
(P=0.948) to the 640 ppm level with bird survival at 59.9 and 60.2% 
respectfully. Some signs of toxicity were observed at the 160 ppm dose 
indicating that the minimal effective dose for full heat distress 
protection, lies within the 160 and 320 ppm phenothiazine inclusion 
levels. Results are consistent with Example 1 where the 312.5 and 625 ppm 
phenothiazine levels were judged similar. Gain was not affected by 
phenothiazine level (P&gt;0.1) while feed efficiency paralleled bird 
survival. The high mortality observed in this study occurred on day 4 of 
the assay when the relative humidity increased to 72% as the result of a 
defective humidistat. A nicarbazin free control treatment group was not 
included in this experiment so that treatment replication could be 
maximized. The data do indicate that phenothiazine has efficacy under 
extremely stressful environments and that the minimal effective dose is 
likely between 160 and 320 ppm. 
Objective 
The purpose of this trial was to further refine the dose titration of 125 
ppm nicarbazin with graded levels of phenothiazine in heat distressed 
broilers. 
MATERIALS AND METHODS 
Test Animals: Vantress X Arbor Acre male chicks, numbering 1,300, were 
raised on rice hull litter and fed starter ration during the first 3 weeks 
posthatching. This time period was necessary to bring birds to the age at 
which they become susceptible to heat distress. On the first day of the 
4.sup.th week, following an overnight fast, chicks were weighed and 
randomly allotted to treatment groups. 
Management: At all times, save the overnight fast at experiment initiation, 
both feed and water were available for ad libitum consumption. Rations 
utilized were formulated to provide at least 105% of the requirement for 
essential nutrients specified by the Nutrient Requirement Council with the 
exception that energy mimicked industry standards. The energy standards 
established by the NRC were used to establish nutrient/calorie ratios. 
Test Drug: The phenothiazine marketed to the agricultural industry has an 
8.mu. particle size. However, a 3.mu. particle size is also available by 
special order and was utilized in this study. The smaller particle size 
may be desirable for enhanced absorption and a lowered dosage rate with 
maximal efficacy. 
Treatments and Allocation: Treatment groups consisted of the following 
nicarbazin-phenothiazine combinations: 
______________________________________ 
TRT. Nicarbazin (ppm) 
Phenothiazine (ppm) 
______________________________________ 
1 125 0 
2 125 80 
3 125 160 
4 125 320 
5 125 640 
______________________________________ 
Birds were allotted to treatment such that individual treatment groups 
contained 32 replicates of 6 chicks per replicate. The treatment groups 
evaluated did not include birds fed a nicarbazin free ration in order that 
replication could be maximized to separate phenothiazine supplementation 
levels. 
Environment: The environmental chamber was set to oscillate between 
24.degree. C. and 35.degree. C. in a manner simulating a typical summer 
day. Hours in excess of 32.degree. C. averaged approximately 6 hours per 
day. It was intended that relative humidity be regulated between 45 and 
50%. However, on day 4 of the experiment a defective humidistat remained 
in the "on" position with the result that relative humidity soared to 72%. 
This high level of relative humidity constituted an extremely acute heat 
distress environment with the result that mortality was massive. Based 
upon one previous experience in the environmental chamber where relative 
humidity rose to over 80% with an ambient temperature of just 31.degree. 
C., it would be expected that mortality for birds not consuming nicarbazin 
to also have been dramatically elevated. 
Parameters/Statistical Analysis: Parameters monitored included live weight 
gain, feed consumption, feed efficiency and mortality. Live weight gains 
were estimated by difference between initial and final body weights. Feed 
consumption was recorded for each replicate. Feed efficiency was estimated 
by dividing total weight of birds surviving the study, for each replicate, 
by the total feed consumed. No effort was made to adjust feed efficiency 
for mortality as the mortality effects on feed effiency were significant 
and adversely affected by treatment. All data were subjected to analysis 
of variance using the General Linear Model of the statistical analysis 
system. When a significant F statistic was indicated by the anaylsis of 
variance for treatment, means were separated by least squares analyses 
utilizing the model which accounted for the greatest variation in the most 
efficient manner detected. 
Discussion 
Data collected in this study were consistent with numerous other studies 
where phenothiazine has been observed to ameliorate nicarbazin toxicity 
occurring in broilers during heat distress. In contrast to other 
experiments where the phenothiazine doses evaluated exceeded 300 ppm the 
linear effects of phenothiazine supplementation were significant (P&lt;0.01). 
Phenothiazine increased survival from 28% for birds consuming ration 
supplemented with 0 ppm to 60.2% for the 640 ppm supplementation level. 
The 320 ppm phenothiazine level was similar (P=0.948) to the 640 ppm level 
with bird survival at 59.9 and 60.2% respectfully. Specifically, this 
observation is consistent with Example 1 where the 312.5 and 625 ppm 
phenothiazine levels were also judged similar. Survival, however; was some 
what reduced (P&lt;0.01) in this study for the 80 and 160 ppm doses 
indicating that the minimal effective dose for full heat distress 
protection likely lies within the 160 and 320 ppm phenothiazine inclusion 
levels. Gain was not affected by phenothiazine level (P&gt; 0.1) while feed 
efficiency paralleled bird survival. The high mortality observed in this 
study occurred on day 4 of the assay when the relative humidity increased 
to 72% as the result of a defective humidistat. A nicarbazin free control 
treatment group was not included in this experiment in order that 
treatment replication could be maximized. However, based upon previous 
experience this type of acute heat distress would be expected to also 
significantly increase the mortality of birds consuming nicarbazin free 
rations. 
Conclusion 
Data collected in this study indicate that phenothiazine efficacy under 
extremely stressful environments and that the minimal effective dose for 
full heat distress protection is likely within the 160 and 320 ppm levels.