Ionophores have limited effects on jejunal glucose absorption and energy metabolism in mice.

Two experiments, Trial 1 (in vitro) and Trial 2 (in vivo), were conducted to examine the effects of ionophores, monensin, laidlomycin, and laidlomycin propionate on whole-animal O2 consumption, organ weights, jejunal glucose absorption, and O2 utilization, as well as growth, feed and water consumption, and feed efficiency. In Trial 1, 30 male Swiss-Webster mice, 8 wk old, were used to measure the in vitro effects of each of the ionophores at concentrations of 1.62 or 16.2 mM. Six combinations of three ionophores at two concentrations resulted in a total of eight treatments. All eight treatments were exposed to jejunal rings from a single mouse for a total of 30 observations per treatment. Jejunal rings were exposed to each ionophore treatment for 15 min. Laidlomycin propionate (16.2 mM) decreased (P < 0.02) glucose absorption, as estimated by H3-3-O-methyl glucose uptake compared with all other treatments, whereas laidlomycin propionate (1.62 mM) increased (P = 0.032) jejunal DM content compared with 16.2 mM laidlomycin propionate. In Trial 2, 40 5-wk-old mice were allotted into four treatments--control and 16.2 mM each of monensin, laidlomycin, and laidlomycin propionate--for a total of 10 observations per treatment. Ionophores were administered via the drinking water for 14 d. No ionophore treatment had any effect on whole-mouse O2 consumption. Monensin increased (P = 0.004) stomach size and decreased (P = 0.049) the efficiency of BW gain compared with controls. Laidlomycin propionate decreased (P = 0.032) the percentage of whole jejunum oxygen consumption due to oubain-sensitive respiration compared with control. The efficiency of intestinal glucose absorption was not changed due to treatment in either trial. Under the conditions of these studies, monensin, laidlomycin, and laidlomycin propionate had minimal and inconsistent effects on jejunal function and energy utilization in mice. This investigation suggests that changes in the energetic requirements of animals treated with ionophores are not an issue in animal production.

Efficacy of laidlomycin propionate for increasing rate and efficiency of gain by feedlot cattle.

One thousand twenty steers and heifers were used in six feeding trials to examine the influence of laidlomycin propionate on feedlot performance and to determine the most efficacious dietary concentrations of that ionophore. Cattle were fed diets ranging in energy content from 1.08 to 1.49 Mcal NEg/kg of DM. Laidlomycin propionate improved rate of gain and feed conversion in both steers and heifers. Improvements in performance were not evident when laidlomycin propionate was fed at only 3 mg/kg. However, both average daily gain and feed conversion were improved by laidlomycin propionate within the range of 6 to 12 mg/kg of DM (P less than .001). Feed consumption was not substantially affected by inclusion of laidlomycin propionate in the diet. Improvements in ADG and feed conversion were greater on lower-energy diets than on higher-energy diets, but both these performance characteristics were improved regardless of the type of diet fed. Average daily gain was maximized with laidlomycin propionate at 6 mg/kg, whereas improvements in feed conversion were sustained through 12 mg/kg. Carcasses of cattle fed diets containing 6 to 12 mg/kg of laidlomycin propionate weighed 7.3 kg more (P less than .001) than carcasses of cattle fed the control diets. Yield grade and quality grade were not affected by laidlomycin propionate (P greater than .05).

Pharmacokinetic and tissue residue characteristics of fenprostalene, a prostaglandin F2 alpha analog, in swine.

Fenprostalene, a prostaglandin F2 alpha analog, can be used to induce parturition in swine. As part of the approval process for that indication, pharmacokinetic characteristics of the absorption and elimination of fenprostalene and the depletion of drug residues from the principal edible tissues of swine were studied. Blood samples, urine, and feces were collected from 8 gilts (body weight, 95 +/- 1.7 kg) for up to 72 hours after a single dose of 0.5 mg of 13,14-[3H]-fenprostalene in polyethylene glycol-400 was administered SC. At intervals of 24, 48, 72, and 168 hours after dosing, 2 gilts each were killed, and samples of liver, kidney, muscle, and abdominal fat were obtained for analysis. The mean (+/- SEM) maximal concentration of fenprostalene radioequivalents in plasma (0.41 +/- 0.05 nanogram-equivalents/ml; n = 8) was observed at 12 hours and decreased biexponentially, with half-lives of approximately 8 hours and 9 days. Mean cumulative recovery (n = 4) of the administered dose by 72 hours was 61.2 +/- 5.9% in urine and 18.5 +/- 2.6% in feces. The highest tissue fenprostalene concentration was in kidneys and liver, probably reflecting the role of those organs in excreting fenprostalene. Rates of depletion of fenprostalene equivalents from the injection site, kidneys, and liver were comparable with those previously observed in cattle. The composition of residue in the liver of 2 gilts slaughtered 12 hours after SC administration of [3H]-fenprostalene was examined in a second study. Results suggested that approximately 4% of the total residue was pharmacologically potent fenprostalene or the carboxylic acid form of fenprostalene.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption and elimination of a prostaglandin F analog, fenprostalene, in lactating dairy cows.

Pharmacokinetic characteristics of the prostaglandin F2 alpha analog, fenprostalene, were studied in five lactating Holstein cows. Blood samples, milk, urine, and feces were collected for up to 7 d following a single subcutaneous injection of 1 mg of 13,14-hydrogen-3-fenprostalene in polyethylene glycol-400. The maximum concentration of tritium in plasma, observed 4 h after injection, equated to .17 ngeq/ml fenprostalene and declined with a fractional disappearance rate of .051 X h-1 to less than .04 ngeq/ml by 48 h. Likewise, milk contained .53 ngeq/ml fenprostalene at 4 h and the concentration declined with a fractional disappearance rate of .069 X h-1 to less than .03 ngeq/ml by 48 h. Milk was a very minor route of elimination of fenprostalene with only .46% of the injected dose recovered over a 7-d sampling. Recovery of tritium in urine accounted for 55% of the total dose and recovery in feces accounted for an additional 43%. Residues from fenprostalene at 7 d after injection were less than .1 ppb in all edible tissues. Differences in the molecular structure, formulation, and route of injection of fenprostalene resulted in a slower rate of absorption and elimination of this analog than previously reported for other prostaglandin products. Nonetheless, the percentage of the injected dose of fenprostalene secreted in milk was not increased appreciably, and no persistent tissue residues of fenprostalene were observed.

Absorption, excretion and tissue residue in feedlot heifers injected with the synthetic prostaglandin, fenprostalene.

Preliminary studies on use of the synthetic prostaglandin, fenprostalene, as an abortifacient had indicated that maximum effectiveness was dependent upon slow delivery. Because both route of administration and formulation control delivery rates, the influences of intramuscular (im) vs subcutaneous (sc) injections, and aqueous acetate buffer (AAB) vs polyethylene glycol-400 (PEG) vehicles on the plasma concentration and urinary excretion of fenprostalene were compared. Feedlot heifers were administered 1 mg injections of [13,14-3H]-fenprostalene. Blood samples and total urine excretion were collected during the following 96 h. The maximum concentration of tritium in plasma occurred at 2 h for AAB-im (.90 ng eq/ml), PEG-im (.75 ng eq/ml) and AAB-sc (.64 ng eq/ml), and then declined throughout 24 h with t 1/2 values of 6.1, 9.4 and 9.2 h, respectively. The peak concentration from PEG-sc was lower (.37 ng eq/ml, P less than .05), observed later (4h, P less than .05) and declined more slowly following peak concentration (t 1/2 = 15.1 h, P less than .05). Consistent with delayed absorption, a smaller fraction (P less than .05) of the total radioactivity excreted in urine was recovered during the first 24 h after injection for PEG-sc (85%) than for PEG-im (95%), AAB-sc (97%) or AAB-im (99%). In a tissue distribution study, plasma, urine and fecal samples were collected and heifers were slaughtered at various times following sc injection of 1 mg of [3H] fenprostalene in PEG. Peak concentrations of tritium in plasma occurred between 4 and 8 h and declined with a t 1/2 of 15.2 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Laidlomycin butyrate--an ionophore with enhanced intraruminal activity.

The polyether ionophore, laidlomycin, and several acyl derivatives were tested for their ability to favorably alter fermentation in two types of in vitro rumen fluid incubations. Dose response data were used to estimate the concentration (microgram/ml) of each ionophore required for either 50% maximal enhancement of propionic acid production (EC50) or 50% maximal inhibition of lactic acid production (IC50). Acylation of laidlomycin with straight-chain acyl groups from two to 12 carbon atoms tended to improve the potency of laidlomycin, especially for inhibiting lactic acid production. Comparative incubations using laidlomycin butyrate, laidlomycin and monensin indicated that both laidlomycin butyrate (EC50 = .3) and monensin (EC50 = .7) were more potent enhancers of propionic acid production than laidlomycin (EC50 = 2.0; P less than .05). Laidlomycin butyrate (IC50 = .3) was a more potent inhibitor of lactic acid production than either laidlomycin (IC50 = 1.8) or monensin (IC50 = 1.3; P less than .05). In a continuous culture experiment, three chemostats each received laidlomycin butyrate or monensin at the rate of .5 micrograms/ml of effluent/d while two flasks remained as control. Propionic acid production was increased (P less than .01) from 22.9 mmol/d in control flasks to 30.5 and 33.7 mmol/d in flasks treated with monensin and laidlomycin butyrate, respectively. Concomitant decreases in production rates of acetic, butyric and isovaleric acids also were observed (P less than .01). Thirty-six steers were used in a 56-d trial to evaluate effects of laidlomycin butyrate and monensin, at 33 mg/kg of diet, on feedlot performance.(ABSTRACT TRUNCATED AT 250 WORDS)

Synthesis and evaluation of ureido- and vinylureidopenicillins as inhibitors of intraruminal lactic acid production.

A series of 14 vinylureidopenicillins and a series of 9 ureidopenicillins were prepared by reaction of 6-aminopenicillanic acid with vinyl isocyanates and isocyanates. These compounds were evaluated for their potential to protect ruminants against lactic acidosis. The compounds were tested for inhibition of in vitro ruminal lactic and propionic acid production, and six compounds inhibited lactic acid production to less than 10% of control at doses of 0.31 microgram/mL or lower, whereas they did not inhibit propionic acid production at doses greater than 10 micrograms/mL. The most active compounds also were screened for general antibacterial activity and were found to be weakly active against Gram-positive bacteria. The structure--activity relationships are discussed for both series. Triethylammonium 6-[3[2-(4-tert-butylphenyl)vinyl]ureido]penicillanate (4) was chosen for evaluation as an inhibitor of intraruminal lactic acidosis in vivo.

Effect of intraruminal urea administration on glucose metabolism in dairy steers.

Isotope dilution techniques were used to study steady-state glucose kinetics in four rumen-fistulated Holstein steers and to study the effect of rapid absorption of ammonia from the rumen on glucose metabolism. Steers were fed a high-concentrate diet at hourly intervals from automatic feeders. Plasma glucose specific activity curves following single intravenous injection of [2-3H]glucose were used to construct a two-compartment model of the glucose pool with inflow and outflow from compartment one. Primed continuous infusion of [2-3H]glucose was used to determine the steady-state turnover rate of glucose and to monitor changes in the rates of inflow and outflow of glucose from the glucose pool following a single dosage of urea (0.4 g/kg body weight) into the rumen. Compartment sizes of the glucose pool were 65.6 and 33.5 g for compartments 1 and 2, respectively. Glucose turnover rate during steady-state was 15.4 mg/minute/kg body weight 0.75 and transfer rate of glucose between compartments was 17.9 mg/minute/kg body weight 0.75. Concentrations of rumen ammonia-nitrogen, plasma ammonia-nitrogen and plasma urea-nitrogen were 6.1, 0.5 and 4.0 mg/100 ml, respectively, before urea dosage. Rumen ammonia-nitrogen, plasma ammonia-nitrogen increased after urea dosage and reached peak concentrations, 170.0 and 1.2 mg/100 ml, respectively, approximately 120 minutes after urea dosage. Plasma urea-nitrogen increased linearly throughout the 4-hour sampling period and reached 12.0 mg/100 ml at end of the experiment. Concentration of glucose in plasma increased from 98.2 mg/100 ml before urea dosage to 114.6 mg/100 ml at 100 minutes after urea dosage. Estimates of glucose production and utilization indicated that the increased concentration of glucose in plasma in all steers was due, at least partially, to a decrease in the rate of glucose utilization. A rapid rate of glycogenolysis which resulted in a marked increase in the plasma glucose concentration also was evident in one steer.

Milk production, nitrogen utilization and glucose synthesis in lactating cows infused postruminally with sodium caseinate and glucose.

Four lactating Holstein cows were used in a 4 X 4 Latin Square design to determine the effects of postruminally administering sodium caseinate and/or glucose on milk production, milk composition, nitrogen utilization, amino acid utilization by the lactating mammary gland and glucose turnover rate. An 8.5% increase in milk yield and a 13.3% increase in milk protein production were obtained during infusion of sodium caseinate. No significant production responses were attributed to abomasal infusion of glucose. Arterial concentrations of most essential amino acids were increased during infusion of sodium caseinate. Uptake of phenylalanine, methionine and lysine by the mammary gland most closely paralleled their output in milk. The relative concentrations of methionine, lysine and phenylalanine in arterial plasma were considerably less than their concentrations in milk which resulted in a large percentage extraction of these amino acids by the mammary gland. If the availability of essential amino acids to the mammary gland, per se, was limiting the synthesis of milk protein, methionine, lysine and phenylalanine may have been the three amino acids most limiting. Measurements of glucose entry rate showed a trend toward increased glucose flux when either glucose, sodium caseinate or glucose plus sodium caseinate were infused abomasally. The similarity in glucose entry rates obtained during infusion of glucose and sodium caseinate suggest that the increase in milk production was not due totally to increased glucose flux resulting from sodium caseinate infusion.

Metabolism of arginine and ornithine in the cow and rabbit mammary tissue.

Amino acid uptake by the bovine mammary gland was determined by arteriovenous difference. Extraction of arginine from the plasma by the lactating bovine mammary gland was in excess of requirements for milk protein synthesis. Ornithine and citrulline also were extracted by the gland but are not in milk protein. Incubations of slices of lactating mammary tissue from cows and rabbits indicate that nonessential amino acids, especially proline and glutamate, are the major end products of arginine and ornithine metabolism in the lactating mammary gland.

Milk production and nitrogen utilization in response to postruminal infusion of sodium caseinate in lactating cows.

Five lactating, rumen-fistulated Holstein cows were used to obtain additional information concerning the effects of postruminal infusion of sodium caseinate on milk production and amino acid utilization. A 7-day continuous abomasal infusion of approximately 450 g/day of sodium caseinate was preceded and followed by 7-day infusions of an isonitrogenous-isocaloric solution of glucose, monosodium glutamate, and urea. Total collections of milk, urine, and feces were obtained during the last 5 days of each infusion period. On the last day of each period, arterial and mammary venous blood samples were obtained for analysis of plasma free amino acids. During infusion of sodium caseinate, milk production, milk protein (N times 6.38) production, and efficiency of nitrogen utilization for milk crude protein production were increased. Arterial plasma concentrations of free histidine, isoleucine, phenylalanine, valine, and total essential amino acids were elevated above control levels during infusion of sodium caseinate, while ornithine and tryrosine were decreased. Calculation of the relative concentration of essential amino acids in arterial plasma and in milk protein indicated that methionine and lysine were least abundant in plasma relative to their requirement for milk protein synthesis. A high precentage extraction from arterial plasma by the mammary gland also suggested that methionine and lysine may have been the essential amino acids in most critical supply for milk protein synthesis. Calculation of uptake to output ratios of individual plasma amino acids by the mammary gland suggested that significant quantities of extracted arginine, isoleucine, leucine, threonine, and valine were utilized in pathways other than direct incorporation into milk protein.