Pharmacokinetics and pharmacodynamics of intravenous and transdermal flunixin meglumine in meat goats

The aim of this study was to determine the pharmacokinetics and prostaglandin E₂ (PGE₂) synthesis inhibiting effects of intravenous (IV) and transdermal (TD) flunixin meglumine in eight adult female Boer goats. A dose of 2.2 mg/kg was administered intravenously (IV) and 3.3 mg/kg administered TD using a cross‐over design. Plasma flunixin concentrations were measured by LC‐MS/MS. Prostaglandin E₂ concentrations were determined using a commercially available ELISA. Pharmacokinetic (PK) analysis was performed using noncompartmental methods. Plasma PGE₂ concentrations decreased after flunixin meglumine for both routes of administration. Mean λ_z‐HL after IV administration was 6.032 hr (range 4.735–9.244 hr) resulting from a mean V_z of 584.1 ml/kg (range, 357.1–1,092 ml/kg) and plasma clearance of 67.11 ml kg^?1 hr^?1 (range, 45.57–82.35 ml kg^?1 hr^?1). The mean C_max, T_max, and λ_z‐HL for flunixin following TD administration was 0.134 μg/ml (range, 0.050–0.188 μg/ml), 11.41 hr (range, 6.00–36.00 hr), and 43.12 hr (15.98–62.49 hr), respectively. The mean bioavailability for TD flunixin was calculated as 24.76%. The mean 80% inhibitory concentration (IC₈₀) of PGE₂ by flunixin meglumine was 0.28 μg/ml (range, 0.08–0.69 μg/ml) and was only achieved with IV formulation of flunixin in this study. The PK results support clinical studies to examine the efficacy of TD flunixin in goats. Determining the systemic effects of flunixin‐mediated PGE₂ suppression in goats is also warranted.     

Pharmacokinetics and pharmacodynamics of intravenous and transdermal flunixin meglumine in alpacas

The aim of this study was to determine the pharmacokinetics and prostaglandin E₂ (PGE₂) synthesis inhibiting effects of intravenous (IV) and transdermal (TD) flunixin meglumine in eight, adult, female, Huacaya alpacas. A dose of 2.2 mg/kg administered IV and 3.3 mg/kg administered TD using a cross‐over design. Plasma flunixin concentrations were measured by LC‐MS/MS. Prostaglandin E₂ concentrations were determined using a commercially available ELISA. Pharmacokinetic (PK) analysis was performed using noncompartmental methods. Plasma PGE₂ concentrations decreased after IV flunixin meglumine administration but there was minimal change after TD application. Mean t_1/2λz after IV administration was 4.531 hr (range 3.355 to 5.571 hr) resulting from a mean Vz of 570.6 ml/kg (range, 387.3 to 1,142 ml/kg) and plasma clearance of 87.26 ml kg^?1 hr^?1 (range, 55.45–179.3 ml kg^?1 hr^?1). The mean C_max, T_max and t_1/2λz for flunixin following TD administration were 106.4 ng/ml (range, 56.98 to 168.6 ng/ml), 13.57 hr (range, 6.000–34.00 hr) and 24.06 hr (18.63 to 39.5 hr), respectively. The mean bioavailability for TD flunixin was calculated as 25.05%. The mean 80% inhibitory concentration (IC₈₀) of PGE₂ by flunixin meglumine was 0.23 µg/ml (range, 0.01 to 1.38 µg/ml). Poor bioavailability and poor suppression of PGE₂ identified in this study indicate that TD flunixin meglumine administered at 3.3 mg/kg is not recommended for use in alpacas.     

Adverse reactions to fentanyl transdermal patches in calves: a preliminary clinical and pharmacokinetic study

Objective

To describe adverse reactions and measure plasma fentanyl concentrations in calves following administration of a fentanyl transdermal patch (FTP).

中药透皮吸收的研究进展

中药透皮吸收因无首过清除、血药浓度稳定等优点已成为经皮给药研究的热点和重点之一,与此相应的透皮吸收促渗剂、促渗方法也取得较大的发展.本文介绍了中药透皮吸收机理、透皮吸收药物的研究现状及促渗剂和促渗方法研究,简要分析了中药透皮吸收中存在的问题.     

Effect of flunixin meglumine treatment during and after embryo transfer on the pregnancy rate in cattle

This study aimed to determine the effect of flunixin meglumine treatment during and after the transfer of in vivo produced embryos to Angus (cows) and Holstein (cows and heifers) breeds of cattle on pregnancy rate. Holstein cows were used as donors in the study. A double dose of prostaglandin F2α was administered to the recipient animals for synchronization. Uterine flushing was performed in donors on day 7 after artificial insemination. A total of 295 transferable embryos were obtained. These embryos were transferred to Angus cows (n = 85), Holstein heifers (n = 80) and Holstein cows (n = 130). After the transfer, these animals were divided into three subgroups. The first subgroup (TI) was administered flunixin meglumine during embryo transfer, and the second subgroup (TII) was administered flunixin meglumine both during embryo transfer and on days 8 and 9 after the transfer. The third subgroup (TIII) was not administered anything and it was considered the control group. Pregnancy examination of the recipients was performed on days 30–35 after the transfer using real-time ultrasonography. The pregnancy rates after embryo transfer were found to be 43.52% in Angus cows, 42.5% in Holstein heifers, and 24.61% in Holstein cows (p < .05). When the animals were not classified according to breed, the pregnancy rates in subgroups TI, TII and TIII were found to be 29.29%, 45.10% and 29.79%, respectively (p < .05). In addition, the pregnancy rates were higher in TII and TIII subgroups of Angus cows and Holstein heifers compared to that of Holstein cows (p < .05). As a result, the pregnancy rates obtained after embryo transfer in Angus cows and Holstein heifers were found to be higher than that in Holstein cows. In addition, it was concluded that the administration of flunixin meglumine during and during/after embryo transfer has a positive effect on pregnancy rates in Angus cows and Holstein heifers.     

The pharmacokinetics of transdermal flunixin meglumine in Holstein calves

This study describes the pharmacokinetics of topical and intravenous (IV) flunixin meglumine in Holstein calves. Eight male Holsteins calves, aged 6 to 8 weeks, were administered flunixin at a dose of 2.2 mg/kg intravenously. Following a 10‐day washout period, calves were dosed with flunixin at 3.33 mg/kg topically (transdermal). Blood samples were collected at predetermined times from 0 to 48 h for the intravenous portions and 0 to 72 h following topical dosing. Plasma drug concentrations were determined using liquid chromatography with mass spectroscopy. Pharmacokinetic analysis was completed using noncompartmental methods. The mean bioavailability of topical flunixin was calculated to be 48%. The mean AUC for flunixin was determined to be 13.9 h × ug/mL for IV administration and 10.1 h × ug/mL for topical administration. The mean half‐life for topical flunixin was 6.42 h and 4.99 h for the intravenous route. The C_max following topical application of flunixin was 1.17 μg/mL. The time to maximum concentration was 2.14 h. Mean residence time (MRT) following IV injection was 4.38 h and 8.36 h after topical administration. In conclusion, flunixin when administered as a topical preparation is rapidly absorbed and has longer half‐life compared to IV administration.     

Pharmacokinetics of multiple doses of transdermal flunixin meglumine in adult Holstein dairy cows

A transdermal formulation of the nonsteroidal anti‐inflammatory drug, flunixin meglumine, has been approved in the United States and Canada for single‐dose administration. Transdermal flunixin meglumine was administered to 10 adult Holstein cows in their second or third lactation at the label dose of 3.33 mg/kg every 24 hr for three total treatments. Plasma flunixin concentrations were determined using high‐pressure liquid chromatography with mass spectroscopy (HPLC ‐MS ). Pharmacokinetic analysis was completed on each individual animal with noncompartmental methods using computer software. The time to maximum drug concentration (T max) was 2.81 hr, and the maximum drug concentration was 1.08 μg/ml. The mean terminal half‐life (T½) was determined to be 5.20 hr. Clearance per fraction absorbed (Cl/F) was calculated to be 0.294 L/hr kg^?1, and volume of distribution of fraction (V z/F ) absorbed was 2.20 L/kg. The mean accumulation factor was 1.10 after three doses. This indicates changes in dosing may not be required when giving multiple doses of flunixin transdermal. Further work is required to investigate the clinical efficacy of transdermal flunixin after multiple daily doses.     

促渗剂促进药物透皮吸收机理的研究进展

综述了促渗剂促进药物透皮吸收机理的研究概况,着重介绍了氮酮、油酸和萜烯等常用促渗剂的促渗机理研究进展,并提出透皮吸收机理研究发展趋势,为该领域进一步深入研究提供参考.     

Clinical efficacy of diclofenac sodium and flunixin meglumine as adjuncts to antibacterial treatment of respiratory disease of calves

Objective To compare the efficacy of the non-steroidal antiinflammatory drugs, diclofenac sodium and flunixin meglumine as adjuncts to the antibiotic treatment of bovine respiratory disease (BRD). Procedure We randomly allocated 80 Holstein calves with BRD to three groups. All the calves received a dose of 2.5 mg/kg tulathromycin by single subcutaneous injection and two of the groups received, in addition, either 2.5 mg/kg diclofenac sodium as a single intramuscular injection (diclofenac group, n = 30) or 2.2 mg/kg flunixin meglumine as an intravenous injection on the first three consecutive days after tulathromycin administration (flunixin group, n = 30). All calves were given a clinical score prior to initial treatment (day 0) and after treatment (days 1, 2, 3, 7 and 14) by observing appetite, demeanour, rectal temperature, the rate and type of respiration, presence or absence of coughing, and nasal discharge. Results During the first 48 h, improvement of adverse signs of respiratory disease, such as pyrexia and elevated respiratory rate, and of a high clinical index score was significant in the two adjunct groups compared with the calves receiving antibiotic alone. The reduction in pyrexia was greatest in the diclofenac group. There were no statically significant differences between treatment groups with regard to eventual perceived recovery from respiratory disease in 14 days. Conclusion In this trial, a single intramuscular dose of diclofenac sodium was equally effective as three intravenous injections of flunixin meglumine given on consecutive days as adjunctive therapy for BRD.     

Behavioral and performance response associated with administration of intravenous flunixin meglumine or oral meloxicam immediately prior to surgical castration in bull calves

The objective of this study was to determine the effects of flunixin meglumine or meloxicam on behavioral response and performance characteristics associated with surgical castration in crossbred bulls. Intact male Bos taurus calves (n = 252; averaging 176 kg) were randomly allocated into one of three treatment groups within pen: control (CON), flunixin meglumine (FLU; 2.2 mg/kg intravenous injection), or meloxicam (MEL; 2.0 mg/kg per os). The individual animal was the experimental unit. Calves were individually weighed on days 0 and 14 of the trial to evaluate performance outcomes. On study day 0, treatments were administered, according to their random allocation, immediately prior to surgical castration using the Henderson tool method. Visual analog scale (VAS) assessment and categorical attitude score (CAS) were collected on days −1, 0 (6 h post-castration), 1, 2, 3, and 4 in the study. The VAS was assigned using a 100 mm horizontal line with “normal” labeled at one end of the line and “moribund” at the other end of the horizontal line. The masked observer assigned a mark on the horizontal line based upon the observed severity of pain exhibited by that individual animal. The CAS was assigned by the same observer using five different categories with a score of 0 being “normal”. Average daily gain tended (P = 0.09) to be associated with the treatment group, and MEL had a greater (P = 0.04) average daily gain through day 14 compared with CON. A significant (P < 0.01) treatment by day interaction was indicated for VAS score, and MEL had lower VAS scores on days 0, 1, 2, and 3 post-castration compared with CON; FLU had lower VAS scores on days 0 and 1 compared with CON. A significant treatment by day interaction was not present (P = 0.25) for CAS. The FLU had lesser percent CAS ≥1 (17.5%; P = 0.05) compared with CON (29.4%); MEL has lesser percent CAS ≥1 observations (14.9%; P = 0.01) compared with CON. The median VAS increased as CAS was more severe. Results indicated MEL and FLU calves temporally improved behavioral responses following surgical castration with positive numerical trends for a 14 d average daily gain (ADG). The VAS system appeared to be an effective method of subjective evaluation of pain in beef calves in this study. Route of administration, duration of therapy, and low relative cost make oral meloxicam a reasonable analgesic treatment in calves when administered at the time of surgical castration.     

Effect of morphine and flunixin meglumine on isoflurane minimum alveolar concentration in goats

OBJECTIVE: To determine the effect of morphine and flunixin meglumine on isoflurane (ISO) minimum alveolar concentration (MAC) in goats. STUDY DESIGN: Prospective, randomized experimental study. ANIMALS: Five adult, wether goats from 1 to 3 years in age, and weighing 24-65 kg. METHODS: Anesthesia was induced using ISO, which was delivered via a mask. Goats were intubated and ventilated to maintain an end-tidal carbon dioxide concentration between 25 and 30 mm Hg (3.3-4 kPa). End-tidal ISO concentration was measured using an infrared analyzer. The baseline ISO MAC that prevented purposeful movement in response to clamping a claw was determined. Following baseline MAC determination, each goat received one of the following four treatments intravenously (IV): morphine (2 mg kg(-1)), flunixin (1.5 mg kg(-1)), flunixin (1.5 mg kg(-1)) plus morphine (2 mg kg(-1)) or saline, and the MAC was re-determined. Goats were studied at weekly intervals, and each goat received each treatment in a randomized fashion. RESULTS: The baseline ISO MAC for the control treatment was 1.43%. Morphine reduced the MAC by 29.7%. Flunixin did not significantly decrease the MAC nor did it potentiate the effect of morphine on MAC. The quality of recovery was good in all cases. CONCLUSIONS: Morphine (2 mg kg(-1), IV) significantly reduced the ISO MAC in goats and did not adversely affect the quality of recovery. CLINICAL RELEVANCE: The use of morphine, at the dose studied, in association with ISO anesthesia, will allow a clinically significant reduction in the concentration of ISO required to maintain general anesthesia in goats.     

Pharmacokinetics of transdermal flunixin in sows

The objective of this study was to describe the pharmacokinetics (PK) of flunixin in 12 nonlactating sows following transdermal (TD) flunixin (3.33 mg/kg) and intravenous (IV; 2.20 mg/kg) flunixin meglumine (FM) administration using a crossover design with a 10‐day washout period. Blood samples were collected postadministration from sows receiving IV FM (3, 6, 10, 20, 40 min and 1, 3, 6, 12, 16, 24, 36, and 48 hr) and from sows receiving TD flunixin (10, 20, 40 min and 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, and 72 hr). Liquid chromatography and mass spectrometry were used to determine plasma flunixin concentrations, and noncompartmental methods were used for PK analysis. The geometric mean ± SD area under the plasma concentration–time curve (AUC) following IV injection was 26,820.59 ± 9,033.88 and 511.83 ± 213.98 hr ng/ml for TD route. Mean initial plasma concentration (C₀) was 26,279.70 ± 3,610.00 ng/ml, and peak concentration (C_max) was 14.61 ± 7.85 ng/ml for IV and TD administration, respectively. The percent mean bioavailability of TD flunixin was 1.55 ± 1.00. Our results demonstrate that topical administration is not an efficient route for delivering flunixin in mature sows.     

Plasma and urine pharmacokinetics of intravenously administered flunixin in greyhound dogs

Medication control in greyhound racing requires information from administration studies that measure drug levels in the urine as well as plasma, with time points that extend into the terminal phase of excretion. To characterize the plasma and the urinary pharmacokinetics of flunixin and enable regulatory advice for greyhound racing in respect of both medication and residue control limits, flunixin meglumine was administered intravenously on one occasion to six different greyhounds at the label dose of 1 mg/kg and the levels of flunixin were measured in plasma for up to 96 hr and in urine for up to 120 hr. Using the standard methodology for medication control, the irrelevant plasma concentration was determined as 1 ng/ml and the irrelevant urine concentration was determined as 30 ng/ml. This information can be used by regulators to determine a screening limit, detection time and a residue limit. The greyhounds with the highest average urine pH had far greater flunixin exposure compared with the greyhounds that had the lowest. This is entirely consistent with the extent of ionization predicted by the Henderson–Hasselbalch equation. This variability in the urine pharmacokinetics reduces with time, and at 72 hr postadministration, in the terminal phase, the variability in urine and plasma flunixin concentrations are similar and should not affect medication control.     

Flunixin对猪肝微粒体细胞色素P450酶系的影响

采用cocktail探针药物法研究了氟尼辛葡甲铵对猪肝微粒体细胞色素（CY）P450酶系的作用.将12头猪随机分为2组,试验组每日肌肉注射氟尼辛葡甲铵1次,对照组给予等体积的生理盐水,连续给药10 d.通过高效液相色谱法检测探针药物的代谢率,评价各组CYP450酶的活性水平.结果显示,试验组的氨苯砜代谢减慢,消除半衰期t1/2延长;而氯唑沙宗代谢加快,t1/2缩短.说明氟尼辛葡甲铵对猪的CYP3A4具有抑制作用,而对CYP2E1存在诱导效应.     

Effect of flunixin meglumine on Escherichia coli heat-stable enterotoxin-induced diarrhea in calves

In a study to evaluate the effect of flunixin meglumine on secretory diarrhea, 11 calves were assigned to 3 groups: group 1 (n = 3) served as controls, group-2 calves (n = 4) were given 2.2 mg of flunixin meglumine/kg, IM at 7 AM and 3 PM, and group-3 calves (n = 4) were given 2.2 mg of flunixin meglumine/kg, IM at 7 AM, 11 AM, and 3 PM. All calves were given approximately 200 micrograms of heat-stable Escherichia coli enterotoxin (STa) orally at 8 AM. Mean cumulative fecal output for groups 1, 2, and 3 was 1,331.0 +/- 317.2 g, 1,544.3 +/- 154.4 g, and 785.5 +/- 276.5 g, respectively. There was a significant (P less than 0.05) reduction in mean fecal output in group-3 calves, compared with that in groups 1 and 2. Calves in group 2 tended to have a delay, but not a reduction, in their fecal output. At 12 hours, hemoconcentration was significantly (P less than 0.05) greater in group-1 calves than in group-2 or group-3 calves.     

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.     

Intravenous pharmacokinetics of moxifloxacin following simultaneous administration with flunixin meglumine or diclofenac in sheep

In this study, the pharmacokinetics of moxifloxacin (5 mg/kg) was determined following a single intravenous administration of moxifloxacin alone and co-administration with diclofenac (2.5 mg/kg) or flunixin meglumine (2.2 mg/kg) in sheep. Six healthy Akkaraman sheep (2 ± 0.3 years and 53.5 ± 5 kg of body weight) were used. A longitudinal design with a 15-day washout period was used in three periods. In the first period, moxifloxacin was administered by an intravenous (IV) injection. In the second and third periods, moxifloxacin was co-administered with IV administration of diclofenac and flunixin meglumine, respectively. The plasma concentration of moxifloxacin was assayed by high-performance liquid chromatography. The pharmacokinetic parameters were calculated using a two-compartment open pharmacokinetic model. Following IV administration of moxifloxacin alone, the mean elimination half-life (t_1/2β), total body clearance (Cl_T), volume of distribution at steady state (V_dss) and area under the curve (AUC) of moxifloxacin were 2.27 hr, 0.56 L h⁻¹ kg⁻¹, 1.66 L/kg and 8.91 hr*µg/ml, respectively. While diclofenac and flunixin meglumine significantly increased the t_1/2β and AUC of moxifloxacin, they significantly reduced the Cl_T and V_dss. These results suggest that anti-inflammatory drugs could increase the therapeutic efficacy of moxifloxacin by altering its pharmacokinetics.     

金属硫蛋白在奶牛公犊体内的代谢规律研究

采用放射性¹²⁵Ｉ标记金属硫蛋白（¹²⁵Ｉ-MT）的同位素示踪技术,对金属硫蛋白在奶牛公犊体内吸收、排泄、存留和分布等代谢规律进行了研究。结果表明,在灌喂¹²⁵Ｉ-MT 11ｈ 后,牛血液中放射性活度达最大值（0.6235×10^-２ mCi）。在灌喂后３ｈ开始从粪中检测到¹²⁵Ｉ-MT,33ｈ达最大值（6.4673×10^-２ mCi）,¹²⁵Ｉ-MT在粪中排出时间相对集中在29～37ｈ;牛粪中¹²⁵Ｉ-MT的排出率为24.1776％。在灌喂后１ｈ便在尿中检测到¹²⁵Ｉ-MT,在灌喂后21ｈ尿中放射性活度达最大值（6.1845×10^-2 mCi）,尿中MT 的排出率为31.7460％。¹²⁵Ｉ-MT富集量以及ＭＴ 含量在牛组织器官间具有显著差异（P＜0.05或P＜0.01）。¹²⁵Ｉ-MT在各组织器官中的存留率大小依次为：肌肉、肝、皮、骨、小肠、大肠、真胃、肺、心、肾和脾;在各组织器官中的总存留率为7.9854％;MT 在各组织器官中的含量高低依次为：心、肝、肺、脾、大肠、真胃、小肠、肾、皮、肌肉和骨。     

代乳粉在犊牛早期断奶技术中应用的试验研究

22头体重相近的荷斯坦犊牛随机分为2组,试验组饲喂代乳料,对照组饲喂新鲜牛奶。经60d的饲喂试验发现,试验组增重比对照组多5.3kg/头,且差异极显著(P<0.01),日增重比对照组提高了88.3g/d,差异极显著(P<0.01)。