Figure 1. Effects of Tagamet HB.
R. E. Kosa
D. C. Borger
L. B. Willett 1
The Ohio State University
Department of Animal Sciences
1 For more information, contact at: The Ohio State University, Ohio Agricultural Research and Development Center, 128 Gerlaugh Hall, 1680 Madison Avenue, Wooster, OH 44691; 330-263-3792; willett.2@osu.edu
This study was funded in part by the Ohio Dairy Farmers Federation, Dairy Research Fund.
A number of approaches are being investigated to increase the survival and performance of dairy calves using strategies that can be implemented immediately after birth. Several of these involve treatments that may enhance the absorption of colostral immunoglobulins. Calves are born without sufficient immunoglobulin G (IgG) to effectively resist microbial challenges. New born calves must ingest and absorb IgG within hours of birth to acquire immunity. Less than 50% of consumed IgG is detected in the blood of calves appropriately fed colostrum, suggesting that a portion of the IgG may be degraded in the abomasum. Tagamet HB® (THB; SmithKline Beecham, Philadelphia, Pa.) with the active ingredient cimetidine, is used by humans to reduce the production of gastric secretions. It was hoped that reduced digestive and acid secretions would allow more of the IgG in colostrum to be absorbed. Holstein calves were randomly allotted to four treatment groups: A, 600 mg THB 0.5 postpartum; C2, placebo 0.5 hours postpartum; B, 300 mg THB 0.5 and 7.5 hours postpartum; and C9, placebo 0.5 and 7.5 hours postpartum. Calves were fed a colostrum substitute (Life Boost, Natur's Way Company, Oakland, Nebr.) containing 35 g IgG, 1.5 hours after the last THB or placebo dose. Subsequent feedings were milk replacer (Purina, St. Louis, Mo.) containing <0.4 mg IgG. Blood was collected 0.5 hours after birth, immediately preceding each dose, and at 6, 12, and 24 hours after the first feeding. Serum IgG was determined by ELISA. The health of calves was recorded for six weeks. Neither Tagamet HB treatment protocol influenced serum IgG concentrations when compared to placebo controls, nor were there differences between calves given IgG at two or nine hours postpartum. There was no significant difference between the health of treated calves and those given placebo controls. These results suggested that either abomasal secretions were not destructive to IgG or Tagamet HB is ineffective in newborn calves.
Calves are born with an immature immune defense system and acquire passive immunity by means of the dam's colostrum (Matte et al., 1982). The dam's colostrum, the first milking within 24 hours of calving, is rich in proteins and contains several types of immunoglobulins (Ig). These colostral immunoglobulins provide the calf with passive immunity, the ability to fight infection until the calf develops its own fully functional immune system (Roy, 1980). Therefore, it is important to ensure that the calf is provided with a sufficient amount of immunoglobulins soon after birth. It is also of interest to examine the mechanism of absorption of these immunoglobulins and to determine if methods to increase absorption can be developed.
There has not been definitive research establishing the pH (acid or base) curve of the changing abomasum during the hours after birth. The abomasum was thought to have a fairly basic pH at birth. The cells that secrete hydrochloric acid were thought to not be fully functional but would mature and secrete HCl, causing the pH of the abomasum to drop (Reiter et al., 1980). While these researchers reported the pH at birth to be between six and seven, others reported more acidic conditions of 4.1 (Roy, 1980) to 3.5 (Radostits and Bell, 1970) in the newborn calf.
It is believed that the abomasum of the young calf secretes chiefly rennin, an enzyme that clots the casein in milk. The pH optimum for pepsin has been reported to be in the range of 1.3 (Frandson, 1986) to pH of 2.1 (Roy and Stobo, 1975). It has been well-documented that pepsin cleaves IgG1 into several fragments (Roy, 1990). If pepsin is present in the abomasum of the neonate, especially in significant amounts at an optimum pH, the pepsin would cleave IgG1 before it even reached the small intestinal epithelial cells. It is also possible that a low pH could denature but not cleave IgG, diminishing its ability to provide immunity.
Cimetidine, the active ingredient in Tagamet HB, has been shown to be successful at reducing gastric juice secretion in several species (Binder and Donaldson, 1978). In humans, pepsin secretion was inhibited, though not as drastically as were the acid and the intrinsic factor (Binder and Donaldson, 1978). Tagamet HB has become a major over-the-counter and prescription drug to control indigestion. Cimetidine has also been shown to be effective in reducing gastric secretions in sheep (Hall and Oddy, 1984). Therefore, preliminary experiments were conducted to determine if cimetidine could prevent abomasal secretions that could in turn destroy IgG before it can be absorbed from the intestines of newborn calves. These experiments were conducted using Tagamet HB administered to calves given a uniform source of IgG and sequentially measuring changes in IgG that appeared in blood.
Only calves that were attended at birth were used for this study so that the exact time of birth was known, and there was no chance that the calf could nurse colostrum. Calves were immediately removed from their dam, dried with towels, weighed, navels treated with iodine, and placed in individual pens bedded with wood shavings.
Calves were assigned to one of four treatment groups (three calves per treatment), two control groups, and two groups that received Tagamet HB doses. Group A was given 600 mg of Tagamet HB at 0.5 hours postpartum and was fed colostrum replacer at two hours postpartum. The corresponding control group (C2) was given a placebo at 0.5 hours and was also fed colostrum replacer at two hours. Group B was given 300 mg Tagamet HB at 0.5 and 7.5 hours postpartum and colostrum replacer at nine hours. The corresponding control group (C9) was given placebos at 0.5 and 7.5 hours and colostrum replacer at nine hours.
All calves were given the colostrum replacer called Life Boost (Natur's Way Company, Oakland, Nebr.) for the first feeding, milk replacer (Nurse Chow 100, Purina, St. Louis, Mo.) at the second feeding, and then milk after completion of sampling. All calves were given the same amounts of the colostrum replacer (175 g) and milk replacer (240 g) from the same respective lots. Fresh whole milk was fed at 4% of body weight at each subsequent feeding. Life Boost is 175 g of dehydrated pure bovine colostrum guaranteed to contain at least 35 g of IgG and was given so each calf received the same known amount of IgG. Purina Nurse Chow #100 medicated milk replacer does not contain a significant amount (< 380 mg) of IgG (Gherman, 1997). The milk replacer and Life Boost were prepared in two quarts (1.9 L) of warm water and fed to the calves in a nipple bottle. If the calf did not drink the entire bottle of liquid, the liquid was given by means of an esophageal tube.
Blood samples were collected at 30 minutes postpartum and prior to each dose and feeding. Samples were also taken six hours after the first feeding of colostrum replacer and 12 hours after the milk replacer feeding. Although Group B and C9 calves were not fed until nine hours postpartum and Group A and C2 were fed at two hours postpartum, all calves had blood samples taken at the same number of hours post-feeding and post-dosing. Groups A and C2 had the last sample taken at 26 hours postpartum, while Groups B and C9 did not finish the sampling program until 33 hours postpartum. All calves were fed milk immediately following the last sample collection time.
The serum IgG concentrations of Group A calves, given one 600 mg dose of Tagamet HB at 0.5 hours postpartum and fed IgG at two hours, were not significantly different than those of group C2 calves, given a placebo dose at 0.5 hours postpartum and fed IgG at two hours postpartum. Mean serum concentrations for Groups A and C2 show very similar trends (Figure 1). Both groups showed almost no serum IgG at birth. In both groups, the IgG concentration increased to an average of 560 mg/ml six hours after the first feeding, increased again to an average of 857 mg/ml 12 hours after first feeding, and then began to decrease slightly at 24 hours after the first feeding.
The serum IgG concentrations for Group B calves, which were given 300 mg Tagamet HB at 0.5 hours, 300 mg Tagamet HB at 7.5 hours, and were fed IgG at nine hours, were not significantly different from those of Group C9 calves, which were given placebo doses at 0.5 hours and 7.5 hours, and were fed IgG at nine hours. Mean serum IgG concentrations for the two groups are nearly identical (Figure 1). Both B and C9 groups had near zero (28 and 22 mg/ml respectively) IgG concentrations at 0.5 hours, 7.5 hours, and nine hours postpartum. The concentrations increased to an average of 424 mg/ml at six hours post first feeding, increased again to an average of 730 mg/ml at 12 hours after the first feeding, and then began decreasing at 24 hours after the first feeding.
The serum IgG concentrations for Groups B and C9 were not significantly different from those of Groups A and C2. These data indicated that treated calves, regardless of dose, did not absorb more IgG than placebo control calves. It was also interesting to note that regardless of whether calves were fed at two or nine hours postpartum, the calves still absorbed the same amount of IgG. All calves also exhibited the same trends in IgG absorption, with near zero (19 mg/ml mean for all groups) serum IgG concentrations from birth until feeding, and then with IgG absorption increased after feeding until 12 hours following the first feeding, and then decreased at 24 hours after the first feeding (Figure 1).
Calves are born without an effective immune system and must acquire passive immunity by means of the dam's colostrum to resist microbial challenges (Matte et al., 1982). The colostrum contains many proteins, with IgG as the most abundant immunoglobulin. The IgG is the antibody that provides the calf with protection against disease (Roy, 1980). It has been theorized that in the first 24 hours after birth, the calf has an "open gut" that is open to the absorption of macromolecules from the intestine to the bloodstream. It is theorized that it is this "open gut" that allows the absorption of the necessary IgG (Roy, 1980). It has also been theorized that approximately 12 to 24 hours after birth, the small intestine becomes "closed" to the absorption of macromolecules (Lecce and Morgan, 1962).
In this study, Tagamet HB was administered to neonatal calves to determine its effect on IgG absorption. Cimetidine, the active ingredient in Tagamet HB, reduces the amount of gastric secretion in species such as humans (Binder and Donaldson, 1978) and sheep (Hall and Oddy, 1984). It was theorized prior to this study that IgG is partially destroyed in the abomasum by gastric secretions; therefore, the administration of Tagamet HB might decrease gastric secretions in the calf, resulting in increased absorption of IgG.
It was found that the calves treated with Tagamet HB did not have higher serum IgG concentrations than calves administered placebos, nor did the treated calves have improved health. However, it cannot be determined from this study whether the serum IgG concentrations of treated calves were not higher than those of control calves because the Tagamet HB did not reduce gastric secretions or because the IgG was not being partially destroyed before reaching the small intestine. The treated calves in this study did not exhibit any signs of toxicity, suggesting that Tagamet HB may be safe for newborn calves.
It is interesting to note that the calves fed at nine hours postpartum exhibited the same IgG absorption trend as the calves fed at two hours. All of the calves, both control and treated, had increased serum IgG concentrations through 12 hours after the first feeding, regardless of when the first feeding was given. The data indicated that when feeding was delayed up to nine hours, gut closure did not occur during those nine hours, nor did it occur more rapidly. The findings of the present study seem to disagree with the findings of several other researchers. In a study conducted by Kruse (1970) with 141 newborn calves, it was found that the absorption coefficient was reduced linearly to about half by delaying first feeding of colostrum from two to 20 hours postpartum. It was also found that for each 10 hours the first feeding is delayed, the absorption coefficient is reduced by approximately six units in Red Danish calves and by about eight units in Black and White Danish calves (Kruse, 1970).
However, studies conducted by Stott et al. (1979a) suggested that as colostrum feeding was delayed, gut closure was also delayed. Their study, which used 210 calves, also suggested that age at first feeding had little influence on the rate of IgG absorption up to 12 hours postpartum, although the rate of absorption decreased with age after 12 hours postpartum (Stott et al., 1979b).
Serum IgG concentrations of the calves in the present study seem rather low when compared to those of prior studies. The highest mean IgG concentration in this study was 934 mg/ml at 12 hours following the first feeding of Life Boost for Group C2, which received one placebo dose and was fed IgG at two hours. In the studies conducted by Stott et al. (1979a), calves had serum IgG concentrations of about 5 mg/ml (5,000 mg/ml) at 12 hours following feeding. These calves were fed pooled colostrum which may have had more IgG than the Life Boost used in the present study. Also, serum samples were analyzed by Stott et al. (1979a,b,c) using radial immunodiffusion gel procedures (RID). The present study employed ELISA; thus, the difference in blood analysis techniques may account for some difference in serum IgG concentrations.
Whitaker (1996) also fed calves Life Boost and used the same ELISA techniques developed by Talhouk et al. (1990) at the OARDC that were employed in the present study. The calves in Whitaker's study had IgG concentrations up to 1,000 mg/dl, which were also higher than the concentrations reported in the present study. All of the Life Boost used in the present study came from the same lot as used by Whitaker. It is possible that this lot of Life Boost had less IgG than the 35 g reported, resulting in lower serum IgG concentrations in the calves. A study conducted in 1991-1992 by the United States Department of Agriculture (1993) analyzed the serum IgG of 2,177 calves between 24 to 48 hours of age. The data suggested that more than half of the 53.6% mortality rate of calves with less than 1,000 mg/dl IgG was associated with the decreased IgG absorption. It is important to determine whether use of a dried colostrum product such as Life Boost may be in fact detrimental to the calf's health, as it may not contain enough IgG to allow the calf to reach serum concentrations greater than 1,000 mg/dl.
These results suggested that either abomasal secretions were not destructive to IgG or Tagamet HB is ineffective in newborn calves. Further investigations on modifiers of gastric secretions will depend on the results of other ongoing research relating to the absorption of immunoglobulins and related proteins by newborn calves.
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