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Abstract

Objective

To compare the effect of oral and IV administrations of flunixin meglumine on the endotoxin-induced inflammatory response in heifers.

Design

The study was conducted in 2 experimental sets in which heifers were exposed to low IV doses of Escherichia coli endotoxin. Within each set, heifers were allocated to 3 treatment groups; pretreatment with flunixin meglumine orally and IV prior to endotoxin administration, or endotoxin administration only. The dose of flunixin used was the recommended therapeutic dose in cattle.

Animals

11 clinically normal heifers weighing from 400 to 640 kg.

Procedure

A permanent cannula was inserted into the jugular vein on the day prior to the experiment. Blood samples were collected regularly during the experiment and analyzed for the content of prostaglandin F metabolite, Cortisol, blood mononuclear cells, and polymorphonuclear neutrophilic leukocytes and rectal temperature was measured.

Results

Endotoxin administration caused clinical signs and hematologic changes characteristic of endotoxemia in cattle. Flunixin administered orally prior to experimentally induced endotoxemia exerted an effect equal to that after its IV administration. Significant increases in rectal temperature and prostaglandin F metabolite concentrations after administration of endotoxin were abrogated when the heifers were pretreated with flunixin, irrespective of route of administration. Cortisol concentrations were lower after pretreatment with flunixin. However, flunixin did not prevent the decrease in blood mononuclear cells and polymorphonuclear neutrophilic leukocytes seen after endotoxin administration.

Conclusion

Owing to no major difference in the inflammatory response between oral and IV flunixin dosing, flunixin granules may be an alternative to parenteral use in bovine practice.

Free access
in American Journal of Veterinary Research

SUMMARY

A high-performance liquid chromatography method was developed for determination of flunixin in bovine plasma. The extraction procedure was easily performed and made it possible to detect low concentrations of flunixin with high accuracy. The limit of quantitation was 7 ng/ml (relative standard deviation = 18%, n = 10). The analytic method permits processing of 60 samples/d. Flunixin, as well as the internal standard (diclofenac sodium), belong to the group of nonsteroidal anti-inflammatory drugs, which are known to have a high degree of binding to plasma proteins. Therefore, an evaluation of several buffer systems was undertaken to optimize analytic conditions.

Cattle were given 2.2 mg of flunixin meglumine/kg of body weight. In experiment 1, single injections were administered IV to 1 cow and IV and IM to 1 heifer (7 days apart), and pharmacokinetic variables were calculated. The IV data were best described by a two-compartment model. The half-life after single IV or IM administration was around 4.0 hours. In experiment 2, the decreasing flunixin concentration was determined after the last of either 4 IM injections daily (n = 3 cows) or 2 IM injections daily (n = 3 cows) administered during a 14-day postpartum period. The half-life, determined between 48 and 96 hours after the last dose, was approximately 26 hours in both groups, and flunixin could be detected in plasma up to 8 days, on average.

The protein binding of flunixin was studied, using the method of equilibrium dialysis. Flunixin was found to have a high degree of protein binding (ie, 99.4 ± 0.2%) at a flunixin concentration in plasma of 3 to 24 μg/ml. Differences in protein binding between cattle were not found.

Free access
in American Journal of Veterinary Research

Abstract

Objective

To determine the relative role of endogenous prostaglandin F (pgf secretion in cloprostenol-induced abortion in mares that no longer require luteal progesterone secretion for maintenance of pregnancy, and to evaluate the ability of a prostaglandin cyclooxygenase inhibitor (flunixin meglumine) to prevent cloprostenol-induced abortion.

Design

The effect of flunixin meglumine on pgf secretion and outcome of pregnancy was compared between mares treated with cloprostenol only and mares treated with cloprostenol plus flunixin meglumine.

Animals

Five pregnant mares, aged 4 to 15 years, of light-horse type.

Procedure

Cloprostenol (250 μg) was administered at 24-hour intervals to 5 pregnant mares. Flunixin meglumine (500 mg, iv) was administered at 8-hour intervals starting 15 minutes before the first cloprostenol administration. Hourly blood samples were analyzed for 15-ke-todihydro-pgf , progesterone, and estrogen concentrations. Previously reported data on cloprostenol-induced abortion in 6 pregnant mares treated daily with cloprostenol only were used as historic controls.

Results

The mean (± sem) interval from first cloprostenol administration to fetal expulsion 56.4 (± 13.7) hours and number of cloprostenol administrations 3.2 (± 0.6) in the 5 flunixin meglumine-treated mares were not significantly different, compared with values for 6 pregnant mares treated daily with cloprostenol only, 48.6 (± 5.6) hours and 2.8 (± 0.2) cloprostenol administrations. Flunixin meglumine did not inhibit endogenous pgf secretion. Prostaglandin F secretion rates on the day before and day of fetal expulsion were similar in both groups.

Conclusion

Flunixin meglumine at a dosage of 500 mg/animal, administered iv every 8 hours, is ineffective in modulating uterine pgf secretion during cloprostenol-induced abortion.

Clinical Relevance

Flunixin meglumine is ineffective in the modulation of prostaglandin-induced uterine pgf secretion and, therefore, does not offer a viable alternative for the prevention of abortion in mares at risk of abortion because of systemic illness.

Free access
in American Journal of Veterinary Research

Abstract

Objectives

To determine the role of progesterone in the regulation of endogenous prostaglandin F (PGF) secretion during cloprostenol-induced abortion and to investigate use of progestins to prevent prostaglandin-associated abortion.

Animals

16 pregnant mares.

Procedure

To induce abortion, cloprostenol (250 μg/d) was administered daily until fetal expulsion or for up to 5 days. In experiment 1, 8 mares, 98 to 153 days’ pregnant, received progesterone (300 mg/d) at 24-hour intervals for 5 days, starting 18 hours after the first cloprostenol administration. In experiment 2, 8 mares, 93 to 115 days’ pregnant, received altrenogest (44 mg/d) at 24-hour intervals, starting 12 hours after the first cloprostenol administration. Historic control mares, 82 to 102 days’ pregnant, received cloprostenol (250 μg/d) daily until fetal expulsion.

Results

In control mares, fetal expulsion occurred after 2 to 3 cloprostenol administrations and was associated with significant increases in PGF secretion. Abortion did not occur in 5 of 8 progesterone-treated mares and 8 of 8 altrenogest-treated mares, and endogenous PGF secretion was inhibited, compared with values in aborting mares.

Conclusion

Circulating progestogen concentrations may have a role in the outcome of pregnancy during prostaglandin-induced abortion. Altered prostaglandin secretion may be a reflection of a direct effect of progesterone or may be caused by the abortion process.

Clinical Relevance

Progestogens might be useful for prevention of abortion in mares in which pregnancy is at risk owing to diseases that are associated with excess prostaglandin secretion. (Am J Vet Res 1996;57:1331-1337)

Free access
in American Journal of Veterinary Research

SUMMARY

The role of prostaglandin F (pgf ) in embryonic loss following induced endotoxemia was studied in mares that were 21 to 44 days pregnant. Thirteen pregnant mares were treated with a nonsteroidal anti-inflammatory drug, flunixin meglumine, to inhibit the synthesis of pgf caused by Salmonella typhimurium endotoxin given iv. Flunixin meglumine was administered either before injection of the endotoxin (group 1, -10 min; n = 7), or after endotoxin injection into the mares (group 2, 1 hour, n = 3; group 3, 2 hours, n = 3); 12 pregnant mares (group 4) were given only S typhimurium endotoxin.

In group 4, the secretion of pgf , as determined by plasma 15-keto-13,14-dihydro-pgf concentrations, was biphasic, initially peaking at 30 minutes followed by a second, larger peak approximately 105 minutes after the endotoxin was given iv. When flunixin meglumine was administered at −10 minutes, synthesis of pgf was inhibited for several hours, after administration of flunixin meglumine at 1 hour, the second secretory surge of pgf was blocked, and administration of the drug at 2 hours did not substantially modify the secretion of pgf .

Plasma progesterone concentrations were unchanged after endotoxin injections were given in group 1. In group 2, progesterone values decreased < 2 ng/ml and remained low for several days. In group 3 and group 4, progesterone concentrations decreased to values < 0.5 ng/ml by 48 hours after endotoxin injections were given. Pregnancy continued in all 7 mares in group 1; in group 2, pregnancy continued in 2 of 3 mares; and in group 3, none of the 3 mares was pregnant by 4 days after endotoxin administration.

The abortifacient effect of endotoxemia in mares < 2 months pregnant is mediated indirectly through the secretion of pgf ; compromised luteal activity and inadequate progesterone secretion are the primary causes of fetal death. Although flunixin meglumine administration can be used to prevent loss of pregnancy in cases of endotoxemia, it must be initiated at an early stage of the endotoxemia, that is, when clinical signs are often not yet apparent.

Free access
in American Journal of Veterinary Research

SUMMARY

The role of decreased luteal activity in embryonic loss after induced endotoxemia was studied in mares 21 to 35 days pregnant. Fourteen pregnant mares were treated daily with 44 mg of altrenogest to compensate for the loss of endogenous progesterone secretion caused by prostaglandin F (pgf ) synthesis and release following intravenous administration of Salmonella typhimurium endotoxin. Altrenogest was administered daily from the day of endotoxin injection until day 40 of gestation (group 1; n = 7), until day 70 (group 2; n = 5), or until day 50 (group 3; n = 2).

In all mares, secretion of pgf , as determined by the plasma 15-keto-13,14-dihydro-pgf concentrations, followed a biphasic pattern, with an initial peak at 30 minutes followed by a second, larger peak at 105 minutes after endotoxin injection. Plasma progesterone concentrations decreased in all mares to values < 1 ng/ml within 24 hours after endotoxin injection.

In group 1, progesterone concentrations for all mares were < 1 ng/ml until the final day of altrenogest treatment. In 6 of 7 mares in group 1, the fetuses died within 4 days after the end of treatment, with progesterone concentrations < than 1 ng/ml at that time. In the mare that remained pregnant after the end of treatment, plasma progesterone concentration was 1.6 ng/ml on day 41 and increased to 4.4 ng/ml on day 44.

In group 2, all mares remained pregnant, even though plasma progesterone concentrations were < 1 ng/ml in 4 of 5 mares from the day after endotoxin injection until after the end of altrenogest treatment. One group-2 mare appeared to develop a secondary corpus luteum before day 70, with progesterone concentrations greater than 1 ng/ml from day 36 through day 70.

Daily altrenogest administration consistently prevented pregnancy loss, which usually follows induced endotoxemia. Altrenogest administration offers a reliable and practical treatment for the prevention of fetal loss following endotoxemia in mares < 2 months pregnant.

One group-3 mare remained pregnant, and in the other mare, fetal death was diagnosed 8 days after endotoxin administration, although this mare was still being treated with altrenogest. In that case fetal death was believed to be unrelated to the treatment.

Free access
in American Journal of Veterinary Research