Endotoxin-induced bovine mastitis: arachidonic acid metabolites in milk and plasma and effect of flunixin meglumine

Arachidonic acid metabolites (AAM) were measured in milk and plasma during the course of acute endotoxin-induced mastitis in 12 lactating cows. Mastitis was induced by intramammary challenge exposure with 10 micrograms of Escherichia coli (026:B6) endotoxin. Endotoxin was injected into the teat cistern via the teat canal of a single randomly selected rear quarter of each cow. Concentrations of prostaglandin (PG) F2 alpha and thromboxane (Tx) B2 in fat-free unextracted milk and of 15-keto-13,14-dihydro-PGF2 alpha in plasma were measured by radioimmunoassay. Total production of AAM in milk was determined by measuring quarter milk production. The AAM were compared in 6 cows administered flunixin meglumine (1.1 mg/kg of body weight) and in 6 cows administered saline solution. Concentrations of TxB2 in milk were significantly (P less than 0.001) increased during the early course of acute mastitis in endotoxin-treated quarters of cows not administered flunixin meglumine. Peak concentrations of TxB2 in milk occurred at 8 hours after endotoxin inoculation. Flunixin meglumine treatment produced significant (P less than 0.05) reductions in milk TxB2 and plasma 15-keto-13,14-dihydro-PGF2 alpha concentrations. Concentrations of PGF2 alpha in milk and total PGF2 alpha and TxB2 production per quarter per milking were not significantly influenced by endotoxin challenge or by flunixin meglumine treatment.     

Efficacy of flunixin meglumine for the treatment of endotoxin-induced bovine mastitis

The clinical effect of flunixin meglumine administration was determined in cows with acute mastitis induced by intramammary administration of endotoxin. In 12 lactating cows, 10 micrograms of Escherichia coli 026:B6 endotoxin were administered via a teat cannula into the teat cistern of single randomly selected rear quarters. Cows were challenge exposed as pairs. One cow in each pair was administered parenteral flunixin meglumine (6 cows) and 1 cow per pair was administered saline solution (6 cows). Multiple doses (7) of 1.1 mg of flunixin meglumine/kg of body weight or saline solution were administered at 8-hour intervals beginning 2 hours after endotoxin. Cow and quarter clinical signs as well as milk somatic cell concentrations, bovine serum albumin, electrical conductivity, and milk production were determined before and for 14 days after endotoxin inoculation. Intramammary endotoxin produced signs characteristic of acute coliform mastitis. Quarter and systemic abnormalities occurred and milk production was reduced by approximately 50% at 12 hours after endotoxin. Flunixin meglumine therapy significantly (P less than or equal to 0.05) reduced rectal temperatures and quarter signs of inflammation and improved clinically graded depression when compared with these signs in saline solution-treated controls. Milk production and laboratory indicators of inflammation in milk were not significantly (P greater than 0.05) different for flunixin meglumine vs saline solution controls. The clinical response observed was consistent with the antipyretic, analgesic, and anti-inflammatory properties of flunixin meglumine.     

Endotoxin-induced hematologic and blood chemical changes in ponies: effects of flunixin meglumine, dexamethasone, and prednisolone

To evaluate the effect of certain drugs on hematologic changes, blood chemical values, and survival in endotoxin shock, anesthetized ponies were given (IV) endotoxin (Escherichia coli O55:B5) and then treated as follows: Group A ponies--given a saline infusion at 5 minutes and at 3 hours after they were given endotoxin; group B ponies--given flunixin meglumine at 5 minutes and at 3, 6, 9, and 24 hours after they were given endotoxin; group C ponies--treated with dexamethasone; and group D ponies--treated with prednisolone at 5 minutes and at 3, 9, and 24 hours after they were given endotoxin. Anesthesia was maintained for 4 hours, after which time the ponies were allowed to recover. Throughout the experiment, samples of blood were collected for blood gas, hematologic, and blood chemical values. The endotoxin effects were seen in the 4 groups: lactic acidosis, prolonged coagulation times, leukopenia, hemoconcentration, and elevated blood chemical values. Although none of the treatments prevented the effects of endotoxin, changes were less severe and survival times were longer in ponies treated with flunixin meglumine.     

Endotoxin-induced abortion in early pregnant gilts and its prevention by flunixin meglumine

The objective of the study was to examine the effect of endotoxin on early pregnancy in gilts and to test the potential of flunixin meglumine (FM), a cyclooxygenase inhibitor, to counteract abortifacient action of the endotoxin. Ten gilts at 30 days gestation were used in the experiment. Eight were injected with lipopolysaccharide (LPS) of Salmonella typhimurium, while 2 were treated with 500 micrograms cloprostenol (CP). Six of the LPS-injected gilts were treated with a total of 4 mg/kg body weight FM in 2 different dose regimens. Clinical observations were recorded and plasma levels of 15-keto-13, 14-dihydro-PGF2 alpha, progesterone and estrone sulfate (ES) were determined with radioimmunoassay. LPS induced typical signs of endotoxemia and a monophasic fever in all LPS-treated gilts. No antipyretic effect of FM was observed. The CP-treated gilts aborted within 34 h as did the gilts treated by LPS only. Of the 6 LPS + FM-treated gilts, 1 aborted within 34 h, while 5 maintained gestation. These were aborted about a week later by CP and the aborted fetuses anatomically examined. Two of the litters were lost (devoured by the dams), 2 showed no signs of earlier death and 1 showed extensive fetal death. The PGF2 alpha metabolite concentrations increased at least 10 fold immediately after the LPS injection. Progesterone plasma concentration decreased rapidly. A 5-10 fold increase in the plasma metabolite levels accompanied all abortions. CP caused no immediate change in the PGF2 alpha metabolite levels, but the abortion-related response was similar to that in LPS-injected gilts. In the FM-treated gilts, the LPS-induced PGF2 alpha metabolite response was rudimentary and the progesterone decrease temporary in nonaborting gilts. The elevated concentrations of ES decreased within 48 h in gilts aborting at 30 days gestation, while in nonaborting gilts a slow, graduate decrease of ES occurred within 3-5 days of the LPS injection. These results indicate that FM apparently suppressed LPS-induced prostaglandin synthesis and thus prevented luteolysis and abortion in early pregnant gilts.     

Comparison of carprofen and flunixin meglumine asadjunctive therapy in bovine respiratory disease

In an open, controlled, multi-centre clinical field trial, seven ‘naturally occurring’ outbreaks of acutefebrile (rectal temperature ≥ 39·5°C) respiratory disease in housed calves were treated with a single antimicrobial agent, and either the non-steroidal anti-inflammatory drug (NSAID) carprofen (n=95) or flunixin meghunine (n=92) on an alternate basis. Carprofen was administered as a single subcutaneous injection at a mean dosage of 1·4 mg kg⁻¹ (range 1·2 to 1·9 mg kg⁻¹) body weight on the first day and flunixin meglumine by intravenous injection at a mean dosage of 2·0 mg kg⁻¹ (range 1·2 to 2·6 mg kg⁻¹) body weight on the first 3 consecutive days. All calves were examined clinically immediately prior to initial treatment and on three occasions up to 1 week after the end of treatment. There were no statistically significant differences between NSAID groups in reduction of clinical parameters between examinations, or in overall efficacy. This trial demonstrated that a single dose of carprofen was equally effective as three daily closes of flunixin meglumine as adjunctive therapy to antimicrobial treatment in acute respiratory disease in calves.     

新兽药氟尼辛葡甲胺的解热镇痛作用

通过小鼠醋酸扭体法、家兔蛋白胨致热法对氟尼辛葡甲胺的解热、镇痛作用进行了研究。结果表明,氟尼辛葡甲胺具有明显的解热、镇痛作用。和对照组相比,氟尼辛葡甲胺4个剂量组（1.25、2.5、5、10 mg/kg）对醋酸所致的小鼠扭体反应均有极强的抑制作用,抑制率最高达100%。2.5 mg/kg的氟尼辛葡甲胺镇痛率即达82.7%,明显强于双氯芬酸钠（65.4%）和安乃近（58.7%）。对蛋白胨所致家兔发热的解热效果,氟尼辛葡甲胺高剂量组（4 mg/kg）优于安乃近组（0.2 g/kg）（P〈0.05）和氨基比林组（0.2 g/kg）（P〈0.01）。中剂量氟尼辛葡甲胺组（2 mg/kg）作用稍逊于安乃近组,但差异不显著。低剂量氟尼辛葡甲胺组（1 mg/kg）作用与氨基比林组相当。     

Pharmacokinetics of flunixin meglumine in dogs

The pharmacokinetics of flunixin meglumine, a potent nonsteroidal anti-inflammatory agent, were studied in 6 intact, awake dogs. Plasma samples were obtained up to 12 hours after IV administration of flunixin meglumine. Flunixin concentration was determined, using high performance liquid chromatography. Plasma data best fit a 2-compartment model. Distribution half-life was 0.55 hour; elimination half-life was 3.7 hours; volume of distribution (area) was 0.35 L/kg; volume of distribution at steady state was 0.18 L/kg; volume of the central compartment was 0.079 L/kg; and total body clearance was 0.064 L/hr/kg. Flunixin concentrations obtained over a 6-hour period in 3 dogs with septic peritonitis did not differ significantly from those obtained from healthy dogs.     

Pharmacokinetics of flunixin meglumine in donkeys, mules, and horses

OBJECTIVE: To compare serum disposition of flunixin meglumine after i.v. administration of a bolus to horses, donkeys, and mules. ANIMALS: 3 clinically normal horses, 5 clinically normal donkeys, and 5 clinically normal mules. PROCEDURE: Blood samples were collected at time zero (before) and 5, 10, 15, 30, and 45 minutes, and at 1, 1.25, 1.5, 1.75, 2, 2.5, 2.75, 3, 3.5, 4, 4.5, 5, 5.5, 6, and 8 hours after i.v. administration of a bolus of flunixin meglumine (1.1 mg/kg of body weight). Serum was analyzed in duplicate by the use of high-performance liquid chromatography for determination of flunixin meglumine concentrations. The serum concentration-time curve for each horse, donkey, and mule were analyzed separately to estimate noncompartmental pharmacokinetic variables RESULTS: Mean (+/-SD) area under the curve for donkeys (646 +/- 148 minute x microg/ml) was significantly less than for horses (976 +/- 168 minute x microg/ml) or for mules (860 +/- 343 minute x microg/ml). Mean residence time for donkeys (54.6 +/- 7 minutes) was significantly less than for horses (110 +/- 24 minutes) or for mules (93 +/- 30 minutes). Mean total body clearance for donkeys (1.78 +/- 0.5 ml/kg/h) was significantly different from that for horses (1.14 +/- 0.18 ml/kg/h) but not from that for mules (1.4 +/- 0.5 ml/kg/h). Significant differences were not found between horses and mules for any pharmacokinetic variable. CONCLUSION AND CLINICAL RELEVANCE: Significant differences exist with regard to serum disposition of flunixin meglumine in donkeys, compared with that for horses and mules. Consequently, flunixin meglumine dosing regimens used in horses may be inappropriate for use in donkeys.     

Efficacy and pharmacokinetics of enrofloxacin and flunixin meglumine for treatment of cows with experimentally induced Escherichia coli mastitis

The efficacy of flunixin alone and together with enrofloxacin in treatment of experimental Escherichia coli mastitis was compared using six cows. The cross-over study design was used. Pharmacokinetics of flunixin and enrofloxacin were also studied in these diseased cows. The response of each cow was similar after the first and second challenge and the individual reaction seemed to explain the severity of clinical signs. The most important predictive factor for outcome of E. coli mastitis was a heavy drop in milk yield. Treatment with enrofloxacin and flunixin enhanced elimination of bacteria, but the difference from those receiving flunixin alone was not significant. Two cows, which had received no antimicrobial treatment (Group 1), were killed on day 4 postchallenge. One cow was killed after the first and the other after the second challenge. Cows receiving combination therapy produced 0.9 L more milk per day during the study period than cows which had only received flunixin (P < 0.05). Based on our findings, antimicrobial treatment might be beneficial in the treatment of high-yielding cows in early lactation. The absorption of enrofloxacin was delayed after subcutaneous administration, the mean apparent elimination half-life being about 23 h, whereas after i.v. administration elimination t(1/2) was only 1.5 h. The majority of the antimicrobial activity in milk originated from the active metabolite, ciprofloxacin, which could be measured throughout the 120-h follow-up period after the last subcutaneous administration. No differences were present in the pharmacokinetic parameters of flunixin between treatment groups: mean elimination half-life was 5.7-6.2 h, volume of distribution 0.43-0.49 L/kg and clearance 0.13-0.14 L h/kg. No flunixin or merely traces were detected in milk: one of the three cows had a concentration of 0.019 mg/L 8 h after administration.     

氟尼辛葡甲胺对血液内毒素的影响

为研究氟尼辛葡甲胺对血液内毒素的影响,本实验选择预产期相近的长大母猪20头,随机分为实验组和对照组各10头。实验组母猪于分娩前15 d直至断奶,每1 000 kg日粮中添加1 kg高热血毒清(含10%氟尼辛葡甲胺),对照组不添加高热血毒清。采用鲎试验法检测内毒素、使用全自动生化分析仪测定肝功能、通过临床症状评估发病率。结果显示:实验组母猪和仔猪血液内毒素含量均极显著低于对照组(p0.01);实验组母猪便秘发生率、子宫内膜炎发生率、仔猪腹泻发生率和仔猪死亡率极显著低于对照组(p0.01);实验组母猪分娩前3 d至分娩后2 d的体温显著低于对照组(p0.05);实验组各日龄仔猪血清丙氨酸氨基转移酶和天门冬氨酸氨基转移酶均显著低于对照组(p0.05),γ-谷氨酰转移酶极显著低于对照组(p0.01)。本研究结果表明氟尼辛葡甲胺具有较强的抗内毒素作用,可以改善仔猪肝功能,为控制内毒素对猪的不良作用提供实验依据。     

Pharmacokinetics of flunixin meglumine in the cow

Plasma levels of flunixin were measured in heifers after a single intravenous injection (1.1 mg kg-1), using high performance liquid chromatography. Plasma concentration versus time curves were best described by a two compartment model. The distribution phase (alpha) half-life was 0.294 hours, the elimination phase (beta) half-life was 8.12 hours and the volume of distribution was 1050 ml kg-1.     

Disposition and excretion of flunixin meglumine in horses

The disposition of flunixin meglumine administered IV at a dosage of 1.1 mg/kg was described by a 2-compartment model; the alpha and beta half-lives (t1/2) were 0.61 and 1.5 hours, respectively. When administered IV at a rate of 2.2 mg/kg, the disposition was best described by a 3-compartment model, and the alpha, beta, and lambda t1/2 were 0.16, 1.52, and 6.00 hours, respectively. The zero-time plasma concentrations after flunixin meglumine was administered at 1.1 and 2.2 mg/kg were 9.3 +/- 0.76 and 21.5 +/- 7.4 mg/L, respectively. The bioavailability after oral administration of 1.1 mg/kg was 85.8%. The absorption t1/2 was 0.57 hours, with a peak concentration of 2.50 +/- 1.25 mg/L. The cumulative urinary recoveries for IV and oral administrations were 61.0% and 63.3%, respectively, of the dose for the 12-hour collection period. The final asymptotic points of urine excretion after IV and oral administrations were 406.4 +/- 65.5 and 357.7 +/- 53.5 mg, respectively, which represented 75.5 and 77.5% of the drug accounted for between 30 and 35 hours after administration. Flunixin meglumine was rapidly excreted in urine over a 2- to 4-hour period after drug administration and was highly bound to protein in plasma.     

Pharmacokinetic interactions of flunixin meglumine and enrofloxacin in dogs

OBJECTIVE: To examine pharmacokinetic interactions of flunixin meglumine and enrofloxacin in dogs following simultaneously administered SC injections of these drugs. ANIMALS: 10 Beagles (4 males and 6 females). PROCEDURE: All dogs underwent the following 3 drug administration protocols with a 4-week washout period between treatments: flunixin administration alone (1 mg/kg, SC); simultaneous administration of flunixin (1 mg/kg, SC) and enrofloxacin (5 mg/kg, SC); and enrofloxacin administration alone (5 mg/kg, SC). Blood samples were collected from the cephalic vein at 0.5, 0.75, 1, 1.5, 2, 3, 5, 8, 12, and 24 hours following SC injections, and pharmacokinetic parameters of flunixin and enrofloxacin were calculated from plasma drug concentrations. RESULTS: Significant increases in the area under the curve (32%) and in the elimination half-life (29%) and a significant decrease (23%) in the elimination rate constant from the central compartment of flunixin were found following coadministration with enrofloxacin, compared with administration of flunixin alone. A significant increase (50%) in the elimination half-life and a significant decrease (21%) in the maximum plasma drug concentration of enrofloxacin were found following coadministration with flunixin, compared with administration of enrofloxacin alone. CONCLUSIONS AND CLINICAL RELEVANCE: The observed decrease in drug clearances as a result of coadministration of flunixin and enrofloxacin indicates that these drugs interact during the elimination phase. Consequently, care should be taken during the concomitant use of flunixin and enrofloxacin in dogs to avoid adverse drug reactions.     

The pharmacokinetics of flunixin meglumine in the sheep

Flunixin meglumine was administered intravenously and intramuscularly in sheep and the pharmacokinetics of the drug studied. Plasma concentrations of flunixin were measured by high performance liquid chromatography. The decline in plasma- flunixin concentration with time was best fitted by a triexponential equation. The pharmacokinetics following intravenous administration of 1.0 mg/kg indicate that flunixin has a rapid distribution half-life (t_½π= 2.3 min), a slow body clearance rate (Cl_b= 0.6 ml/kg/min) and an elimination half-life of 229 min. Similarly, at 2.0 mg/kg, flunixin is rapidly distributed from the plasma, t_½π= 2.7 min, has a slow body clearance rate (C/b = 0.7 mk/lg/min) and an elimination half-life of 205 min.
Following intramuscular injection flunixin is rapidly and well absorbed from the injection site. It had a mean maximum concentration ( C _max) of ≫5.9 μg/ml when administered at a dose rate of 1.1 mg/kg, and a relative bioavailability of 70%. Plasma concentrations increase proportionally to dose over the range 1.1 mg/kg-2.2 mg/kg when administered by the intramuscular route.     

The effect of breed and sex on sulfamethazine,enrofloxacin, fenbendazole and flunixin meglumine pharmacokinetic parameters in swine

Drug use in livestock has received increased attention due to welfare concerns and food safety. Characterizing heterogeneity in the way swine populations respond to drugs could allow for group‐specific dose or drug recommendations. Our objective was to determine whether drug clearance differs across genetic backgrounds and sex for sulfamethazine, enrofloxacin, fenbendazole and flunixin meglumine. Two sires from each of four breeds were mated to a common sow population. The nursery pigs generated (n = 114) were utilized in a random crossover design. Drugs were administered intravenously and blood collected a minimum of 10 times over 48 h. A non‐compartmental analysis of drug and metabolite plasma concentration vs. time profiles was performed. Within‐drug and metabolite analysis of pharmacokinetic parameters included fixed effects of drug administration date, sex and breed of sire. Breed differences existed for flunixin meglumine (P‐value<0.05; Cl, Vd_ss) and oxfendazole (P‐value<0.05, AUC_0→∞). Sex differences existed for oxfendazole (P‐value < 0.05; T_max) and sulfamethazine (P‐value < 0.05, Cl). Differences in drug clearance were seen, and future work will determine the degree of additive genetic variation utilizing a larger population.     

Interactions between erythromycin,flunixin meglumine,levamisole and plant secondary metabolites towards bovine gastrointestinal motility—in vitro study

Continued ingestion of plant secondary metabolites by ruminants can provoke pharmacological interactions with pharmaceutical agents used in animals. As some drugs and phytocompounds affect smooth muscle activity, the aim of this study was to verify the possible interaction between selected pharmaceutical agents and plant secondary metabolites towards bovine gastrointestinal motility. The interactions between phytocompounds—apigenin, quercetin, hederagenin, medicagenic acid—and medicines—erythromycin, flunixin meglumine and levamisole—were evaluated on bovine isolated abomasal and duodenal specimens obtained from routinely slaughtered cows. The obtained results confirmed the contractile effect of all three drugs used solely. Hederagenin and medicagenic acid (0.001 μM) enhanced the contractile effect of levamisole. Hederagenin additionally increased the impact of erythromycin. Both saponins (100 μM) showed synergistic effects with all tested pharmaceuticals. Apigenin and quercetin (0.001 μM) intensified the contractile response induced by erythromycin and levamisole. Moreover, both flavonoids (100 μM) showed an antagonistic interaction with all tested drugs which in that situation were devoid of the prokinetic effect. To conclude, plant metabolic metabolites such as saponins and flavonoids are potent modifiers of the effect of drugs towards gut motility. The synergy observed between phytocompounds and selected medicines can be beneficial in the treatment of cows with hypomotility disorders.