Pharmacokinetics and anti-inflammatory effects of flunixin meglumine as a sole agent and in combination with phenylbutazone in exercised Thoroughbred horses.
- 作者列表："Knych HK","Arthur RM","McKemie DS","Baden RW","Seminoff K","Kass PH
BACKGROUND:Flunixin meglumine (FM) and phenylbutazone (PBZ) are potent anti-inflammatory agents and as such their potential to mask injuries that would otherwise keep a horse from training or racing is concerning. A common practice in racetrack medicine in the USA is to administer the two drugs within close proximity (24 hours apart) of each other, raising the concern of pharmacokinetic interactions and enhanced anti-inflammatory effects. OBJECTIVES:Describe the pharmacokinetics and effects of PBZ on the clearance of FM when administered in close proximity as well as effects on inflammatory mediators. STUDY DESIGN:Two-way randomised balanced crossover experiment. METHODS:Twelve Thoroughbred exercised horses received 500 mg FM IV alone or in combination with 2 g of IV PBZ 24 hours later. Blood and urine samples were collected prior to and for up to 120 hours post-drug administration. Whole blood samples were collected at various times and challenged with lipopolysaccharide or calcium ionophore to induce ex vivo synthesis of eicosanoids. Concentrations of FM, PBZ and eicosanoids were measured using LC-MS/MS and noncompartmental pharmacokinetic analysis performed on concentration data. RESULTS:Flunixin meglumine clearance was significantly increased when horses received PBZ 24 hours post-administration (P = .03). No other differences in pharmacokinetic parameters were noted between groups. Thromboxane B2 was significantly suppressed, relative to baseline for 96 hours post-FM administration. Subsequent administration of PBZ prolonged the suppression. Prostaglandin E2 was decreased for 24 hours following administration of FM with subsequent administration of PBZ prolonging the suppression until 120 hours. PGF2alpha concentrations were decreased for up to 168 hours post-FM administration. FM administration significantly decreased 15-HETE. MAIN LIMITATIONS:Small sample size and lack of a phenylbutazone-only treatment group. CONCLUSIONS:Administration of PBZ post-FM administration increased FM clearance. The anti-inflammatory effects of FM appear to be prolonged when PBZ is administered 24 hours post-administration.
背景: 氟尼辛葡甲胺 (FM) 和保泰松 (PBZ) 是有效的抗炎剂，因此它们可能掩盖否则会阻止马训练或比赛的损伤。美国赛马场医学的常见做法是在彼此紧密接近 (间隔24小时) 的情况下施用两种药物，引起了对药代动力学相互作用和增强的抗炎作用的关注。 目的: 描述在近距离给药时PBZ的药代动力学和对FM清除的影响以及对炎症介质的影响。 研究设计: 双向随机平衡交叉实验。 方法: 12匹纯种马在24小时后单独接受500 mg FM IV或与2g IV PBZ组合。在给药前和给药后120小时收集血液和尿液样品。在不同时间收集全血样品并用脂多糖或钙离子载体激发以诱导类花生酸的离体合成。使用lc-ms/MS测量FM、PBZ和类花生酸的浓度，并对浓度数据进行非室药代动力学分析。 结果: 当马在给药后24小时接受PBZ时，氟尼辛葡甲胺清除率显著增加 (P = .03)。在药代动力学参数中没有注意到组之间的其他差异。相对于FM给药后96小时的基线，血栓烷B2被显著抑制。随后给予PBZ延长了抑制。在给予FM后24小时降低前列腺素E2，随后给予PBZ将抑制延长至120小时。在FM施用后，pgf2α 浓度降低达168小时。FM给药显著降低15-hete。 主要限制: 样本量小，缺乏仅含保泰松的治疗组。 结论: FM给药后PBZ给药增加了FM清除率。当给药后24小时给予PBZ时，FM的抗炎作用似乎延长。
METHODS::The ATP binding-cassette superfamily corresponds the mostly transmembrane transporters family found in humans. These proteins actively transport endogenous and exogenous substrates through biological membranes in body tissues, so they have an important role in the regulation of many physiological functions necessary for human homeostasis, as well as in response regulation to several pharmacological substrates. The development of multidrug resistance has become one of the main troubles in conventional chemotherapy in different illnesses including cancer, being the increased efflux of antineoplastic drugs the main reason for this multidrug resistance, with a key role of the ABC superfamily. Likely, the interindividual variability in the pharmacological response among patients is well known, and may be due to intrinsically factors of the disease, genetic and environmental ones. Thus, the understanding of this variability, especially the genetic variability associated with the efficacy and toxicity of drugs, can provide a safer and more effective pharmacological treatment, so ABC genes are considered as important regulators due to their relationship with the reduction in pharmacological response. In this review, updated information about transporters belonging to this superfamily was collected, the possible role of these transporters in cancer, the role of genetic variability in their genes, as well as some therapeutic tools that have been tried to raise against main transporters associated with chemoresistance in cancer.
METHODS:BACKGROUND:Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD). RESEARCH DESIGN AND METHODS:The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120. RESULTS:A total of 98 patients were randomly allocated to the early-start (donepezil-to-donepezil) and delayed-start (placebo-to-donepezil) groups. Mean (SD) of the baseline MMSE was 27.6 (2.0) and 28.0 (2.1), respectively. MMSE change at week 120 was better in the early-start group than in the delayed-start group, but the difference was not significant. The MMSE declined in apolipoprotein ε4 carriers, but not in non-carriers, and the factor interaction (intervention × ε4 genotype) was highly significant (P < 0.001). Analyzed with the interaction, the difference was significant (group difference 1.95 [0.33 to 3.57], P = 0.018). The MMSE decline slope in phase 1 was significantly better in the early-start group than in the delayed-start group (P = 0.048). CONCLUSIONS:Cognitive function deteriorated in ε4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.
METHODS::Since the discovery of dental pulp stem cells, a lot of teams have expressed an interest in dental pulp regeneration. Many approaches, experimental models and biological explorations have been developed, each including the use of stem cells and scaffolds with the final goal being clinical application in humans. In this review, the authors' objective was to compare the experimental models and strategies used for the development of biomaterials for tissue engineering of dental pulp with stem cells. Electronic queries were conducted on PubMed using the following terms: pulp regeneration, scaffold, stem cells, tissue engineering and biomaterial. The extracted data included the following information: the strategy envisaged, the type of stem cells, the experimental models, the exploration or analysis methods, the cytotoxicity or viability or proliferation cellular tests, the tests of scaffold antibacterial properties and take into account the vascularization of the regenerated dental pulp. From the 71 selected articles, 59% focused on the "cell-transplantation" strategy, 82% used in vitro experimentation, 58% in vivo animal models and only one described an in vivo in situ human clinical study. 87% used dental pulp stem cells. A majority of the studies reported histology (75%) and immunohistochemistry explorations (66%). 73% mentioned the use of cytotoxicity, proliferation or viability tests. 48% took vascularization into account but only 6% studied the antibacterial properties of the scaffolds. This article gives an overview of the methods used to regenerate dental pulp from stem cells and should help researchers create the best development strategies for research in this field.