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.     

Identification and characterization of the enzymes responsible for the metabolism of the non‐steroidal anti‐inflammatory drugs,flunixin meglumine and phenylbutazone,in horses

The in vivo metabolism and pharmacokinetics of flunixin meglumine and phenylbutazone have been extensively characterized; however, there are no published reports describing the in vitro metabolism, specifically the enzymes responsible for the biotransformation of these compounds in horses. Due to their widespread use and, therefore, increased potential for drug–drug interactions and widespread differences in drug disposition, this study aims to build on the limited current knowledge regarding P450‐mediated metabolism in horses. Drugs were incubated with equine liver microsomes and a panel of recombinant equine P450s. Incubation of phenylbutazone in microsomes generated oxyphenbutazone and gamma‐hydroxy phenylbutazone. Microsomal incubations with flunixin meglumine generated 5‐OH flunixin, with a kinetic profile suggestive of substrate inhibition. In recombinant P450 assays, equine CYP3A97 was the only enzyme capable of generating oxyphenbutazone while several members of the equine CYP3A family and CYP1A1 were capable of catalyzing the biotransformation of flunixin to 5‐OH flunixin. Flunixin meglumine metabolism by CYP1A1 and CYP3A93 showed a profile characteristic of biphasic kinetics, suggesting two substrate binding sites. The current study identifies specific enzymes responsible for the metabolism of two NSAIDs in horses and provides the basis for future study of drug–drug interactions and identification of reasons for varying pharmacokinetics between horses.     

消癖散及水提物与醇提物体外透皮特性的 比较研究

[摘要〕目的通过对消疲散散剂、水提物与醇提物的体外透皮试验研究,比较不同提取工艺的经皮渗透特性,为 剂型设计、药理、毒理试验及临床研究提供依据〔方法以有效成分大黄素累积透皮百分率为测定指标,高效液相色谱 法定量,用改良的Franz扩散池及离体兔皮进行体外透皮实验,比较该方散剂及水提物与醇提物透皮速度、透皮百分 率与皮肤储量的差别、结果透皮速度由快至慢、皮肤储量由高到低,散剂、透皮总量由多至少依次为:醇提物>水提 物>散剂、结论醇提物透皮速度最快.皮肤储量最多.透皮总量最多、     

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.     

Pain management in horses and farm animals

Objective: This review discusses the different analgesic drugs and routes of administration used in large animals for acute pain management. General guidelines and doses are given to assist in choosing techniques that provide effective analgesia. Etiology: Noxious stimuli are perceived, recognized, and localized by specialized sensory systems located at spinal and supraspinal levels. Diagnosis: Localizing the source of the noxious stimulus as well as understanding the behavioral aspects and physiological changes that result from such insult is important to adequately diagnose and treat pain. Pain assessment is far from being definite and objective; not only are there species differences, but also individual variation. In addition, the behavioral and physiological manifestations vary with the acute or chronic nature of pain. Therapy: Pain management should include (1) selecting drugs that better control the type of pain elicited by the insult; (2) selecting techniques of analgesic drug administration that act on pathways or anatomical locations where the nociceptive information is being processed or originating from; (3) combining analgesic drugs that act on different pain pathways; and (4) provide the best possible comfort for the animal. Prognosis: Providing pain relief improves the animal's well being and outcome; however, interpreting and diagnosing pain remains difficult. Continuing research in pain management will contribute to the evaluation of the pathophysiology of pain, pain assessment, and newer analgesic drugs and techniques.     

Plasma fentanyl concentrations in awake cats and cats undergoing anesthesia and ovariohysterectomy using transdermal administration

Objective To measure the plasma fentanyl concentrations achieved over time with transdermal fentanyl patches in awake cats and cats undergoing anesthesia and ovariohysterectomy. Study design Randomized prospective experimental study. Animals Twenty‐four purpose‐bred cats. Methods Cats were randomly assigned to three groups for Part I of a larger concurrent study. Group P received only a 25 μg hour^?1 transdermal fentanyl patch. Group P/A received the patch and anesthesia. Group A received only anesthesia. After a minimum 1‐week washout period, the cats were randomly reassigned to two groups for Part II of the larger study. Group P/A/O received the patch, anesthesia and ovariohysterectomy. Group A/O received anesthesia and ovariohysterectomy. Patches were left in place for 72 hours and plasma samples were obtained for fentanyl analysis while the patches were in place, and for 8 hours after patch removal for cats in Group P, P/A, and P/A/O. Results The 25 μg hour^?1 transdermal fentanyl patches were well tolerated by the cats in this study (mean body weight of 3.0 kg) and no overt adverse effects were noted. Mean plasma fentanyl concentrations over time, mean plasma fentanyl concentrations at specific times (8, 25, 49, and 73 hours after patch placement), time to first detectable plasma fentanyl concentration, time to reach maximum plasma fentanyl concentration, maximum plasma fentanyl concentration, mean plasma fentanyl concentration from 8 to 73 hours, elimination half‐life, and total area under concentration (AUC) were not statistically different among the groups. Conclusions Halothane anesthesia and anesthesia/ovariohysterectomy did not significantly alter the plasma fentanyl concentrations achieved or pharmacokinetic parameters measured, when compared with awake cats. There was a high degree of individual variability observed both within and between groups of cats in parameters measured. Clinical significance The high degree of variability observed suggests that careful observation of cats with fentanyl patches in place is required to assess efficacy and any potential adverse effects. Anesthesia and anesthesia/ovariohysterectomy do not appear to alter plasma fentanyl concentrations achieved by placement of a 25 μg hour^?1 transdermal fentanyl patch when compared to cats not undergoing these procedures.     

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.     

Pharmacokinetics of Flunixin Meglumine After Intravenous and Intramuscular Administration in Pigs

Pharmacokinetics of flunixin meglumine （FM） was investigated in 14 healthy pigs following single intravenous （i.v.） and intramuscular （i.m.） administration of the drug at the dosage of 2.2 and 1.1 mg kg-1. Blood samples were collected at different intervals after administration, and concentrations of FM were determined by HPLC method with a limit of detection of 0.1μg mL-1. The FM concentration-time data were fitted to a two-compartment open model after single i.v. dosing in pigs. The main pharmacokinetic parameters were as follows： tl/2a, 0.49 ± 0.03 and 0.58±0.07 h; tl/2β, 6.28±0.13 and 7.37 ±0.59 h; V/F, 0.01 ±0.001 and 0.01 ±0.002 L kg-1; CL, 0.01 ± 0.002 and 0.01 ± 0.002 L h-l; AUC, 237.73 ± 52.46 and 147.71 ± 36.76μg h-1 mL-1. The drug concentration-time data were fitted to a two-compartment model with first-order absorption after single i.m. administration in pigs. The main pharmacokinetic parameters were as follows： t1/2α, 0.90± 0.07 and 0.86±0.10 h; t1/2β, 8.79±0.85 and 9.60±0.10 h; V/F, 0.02±0.004 and 0.02±0.003 L kg-1; CL, 0.01±0.002 and 0.01 ±0.003 L h-l; AUC, 174.63 ± 45.84 and 112.42 ± 31.19 pg h-1 mL 1. The results of the present study showed that FM was rapidly absorbed, extensively distributed, and slowly eliminated in pigs. The drug was completely absorbed after single i.m. administration and a good bioavailability in pigs.     

Pathophysiology of experimental bovine endotoxicosis: endotoxin induced synthesis of prostaglandins and thromboxane and the modulatory effect of some non-steroidal anti-inflammatory drugs.

Endotoxin-induced synthesis of thromboxane A2 (TXA2), prostacyclin (PGI2) and prostaglandin E2 (PGE2) was studied in 3 cows after intravenous E. coli endotoxin (055:B5-0.025 mg/kg b.w.) administration. Blood sampling and monitoring of clinical signs were performed from 2 h prior to until 6 h after endotoxin challenge. Blood samples were analyzed for stable hydrolysis products of TXA2 (TXB2), PGI2 (6-keto PGF) and PGE2 (bicyclic PGE2), biochemical and haematological parameters. In a similar experimental design the efficacy of the non-steroidal anti-inflammatory drugs (NSAID) flunixin meglumine (FM) and phenylbutazone (PB) in suppressing eicosanoid synthesis and clinical signs in response to endotoxin challenge was investigated. Two groups of cows, each comprising 2 animals, were treated with FM and PB prior to endotoxin challenge. It was observed that plasma concentrations of TXB2, 6-keto PGF and bicyclic PGE2 increased rapidly after endotoxin challenge. Concentrations were significantly elevated for hours and were correlated to the severity of clinical signs of endotoxicosis. Pretreatment with NSAID suppressed mediator production and alleviated clinical signs. The experiments suggest a certain pathophysiological role of TXA2, PGI2 and PGE2 for the early systemic ill-effects of bovine endotoxicosis.