HPLC-MS/MS法同时测定鸡肉中40种糖皮质激素和9种非甾体抗炎药物残留

建立了高效液相色谱-串联质谱法(HPLC-MS/MS)同时测定鸡胸肉中40种糖皮质激素和9种非甾体抗炎药物残留。样品用90%乙腈-水溶液(V/V,含0.1%甲酸溶液)提取,经Oasis PRIME HLB固相萃取柱净化,浓缩后采用Waters Acquity UPLC BEH C18色谱柱(2.1 mm×100 mm×1.7 μm)分离,以0.1%甲酸溶液和乙腈为流动相进行梯度洗脱。采用电喷雾正离子模式,以多反应监测模式进行质谱检测。结果表明,在2~100 μg/L范围内,鸡肉中49种兽药残留的线性关系良好,线性相关系数均大于0.996,回收率为60.2%~111.7%,相对标准偏差(n=6)均在1.3%~12.0%之间,检出限为0.1~0.5 μg/kg,定量限为0.3~1.5 μg/kg。该方法操作简单、灵敏度高、准确性好,可同时测定鸡肉中的糖皮质激素和非甾体抗炎药物残留。     

Extended delivery of non-steroidal anti-inflammatory drugs through contact lenses loaded with Vitamin E and cationic surfactants

The purpose of this study is to extend drug release from ACUVUE Oasys® and ACUVUE TruEye® silicone hydrogel contact lenses by incorporation of vitamin E in conjunction with a cationic surfactant. In ACUVUE Oasys® and ACUVUE TruEye®, the release of ketorolac tromethamine and flurbiprofen sodium is extended from hours to several days for 11% and 21% vitamin E, (weight of vitamin E / weight of dry lens) but with a considerable reduction in the amount of drug released. Cetalkonium chloride and stearylamine increased the drug loading capacity which was otherwise compromised by the addition of vitamin E in the contact lenses. In the case of diclofenac sodium, a sustained release over 150 h for both contact lenses can be achieved. It was found that the release-time-increase factor due to vitamin E has a linear dependence with the octanol-water partition coefficient of the drug in ACUVUE Oasys®. The results in this study show that contact lenses loaded with vitamin E in conjunction with cationic surfactants achieved sustained release of non-steroidal anti-inflammatory drugs (NSAIDs) within the therapeutic window.     

Physicochemical studies of binary eutectic of ibuprofen and ketoprofen for enhanced transdermal drug delivery

Methods: The thermodynamic, eutectic, and crystalline properties of ibuprofen and ketoprofen binary mixtures were investigated using differential scanning calorimetry (DSC) and X-ray powder diffractometry (XRPD). Results: The DSC studies showed that melting point (61°C), enthalpy (11.3 kJ/mol), and entropy of fusion (33.7 J/K/mol) of the binary eutectic were significantly lower than those of the individual anti-inflammatory drugs (NSAIDs). Due to the melting-point depression and enhanced skin lipid solubility, the steady-state flux of ibuprofen and ketoprofen from preparations of the binary eutectic increased as compared to pure NSAIDs using shed snakeskin as a model membrane. The NSAID membrane flux values were calculated by flux ratio equations based on drug thermodynamic data, and compared to experimental values obtained from permeation studies. Conclusion: The proposed flux ratio equations correctly predicted flux increase.     

Ozonation of NSAID: A Biodegradability and Toxicity Study

This work deals with the biodegradability and toxicity of three non-steroidal anti-inflammatory drugs (NSAID) (diclofenac, ibuprofen and naproxen) treated by ozonation. The results show that the total removal of 200 mg L^?1 of diclofenac and 100 mg L^?1 of naproxen is possible using an ozone dose of 0.20 and 0.04 g L^?1, respectively. For 200 mg L^?1 of ibuprofen, 90% removal is achieved using an ozone dose of 2.3 g L^?1. The BOD₅/COD ratio, the Zahn-Wallens test and EC₅₀ toxicity test (Microtox) are chosen as biological and toxicity indicators of NSAID intermediates. The evolution of BOD₅/COD ratio during 1 hour of treatment is evaluated and the results show that ozonation improves the biodegradability for the three NSAID treated solution. The Zahn-Wellens test for diclofenac and ibuprofen solutions shows that biological mineralization, after 28 days, is higher for diclofenac than for ibuprofen solution. According to the Microtox test, the treatment with ozone removes the toxicity of the naproxen solution. Taking into account the results obtained with the biocompatibility tests it could be assumed that ozonation is an adequate treatment for removal NSAID in aquatic medium, and the ozonated effluents could be post-treated in a biological wastewater facility.     

木瓜提取物预防非甾体抗炎药诱导的小鼠肠黏膜损伤

为了研究木瓜提取物对非甾体抗炎药(NSAID)引起的小鼠小肠黏膜损伤的预防作用,应用灌胃方式连续6d给与木瓜提取物,在第5 d给与双氯芬酸钠5 mg/mL连续两天灌胃,建立NSAID诱导小肠黏膜损伤模型。检测小肠黏膜通透性及观察小肠黏膜病变情况,检测葡萄糖转运蛋白(GRP-78)、CHOP、肿瘤坏死因子α(TNF-α)、Toll受体4(TLR4)及NLRP的表达水平。FITC-DT测定结果显示正常组相对荧光值(Relative fluorescence value,RFU)为682.7±105.4、模型组2008.3±496.1、木瓜低剂量组为1097.8±501.1、木瓜高剂量组为737.5±275.5;与正常组相比,模型组小鼠小肠黏膜明显损伤及通透性增加;与模型组相比,不同剂量木瓜提取物处理小鼠后能明显减轻小肠黏膜损伤,其机制与木瓜提取物调节肠道组织的内质网应激(GRP78和CHOP)、降低肠道炎症反应(TLR4和TNF-α)有关。提示木瓜提取物能通过调节TLR4-内质网应激预防NSAID对小鼠小肠黏膜的损伤。     

The effects of periparturient administration of flunixin meglumine on the health and production of dairy cattle

Research on the assessment and management of pain in cows following difficult or assisted calving is still limited, especially on the effects of analgesics intended to mitigate this pain. The purpose of this study was to assess the effects of flunixin meglumine on the health and production of Holstein cows after calving. In total, 34 flunixin-treated and 38 placebo-treated animals were enrolled in a precalving treatment trial. A total of 633 animals given flunixin and 632 animals administered a placebo were enrolled in a postcalving treatment trial. In both cases, animals were randomly assigned to treatment, and researchers were blind to treatment condition until after analysis. A total of 1,265 animal records were analyzed for milk production for the first 14 d in milk and health outcomes for the first 30 d in milk. Animals treated with flunixin meglumine before calving had a significantly increased risk of stillbirth. Animals treated immediately after calving had increased odds of having a retained placenta and, in turn, increased risk of a high temperature, decreased milk production, and an increased risk of developing metritis. The administration of flunixin meglumine within 24 h of parturition is not recommended in dairy cattle.     

Method to study the effect of blend flowability on the homogeneity of acetaminophen

The aim of this study was to develop an enteric-coated multiunit dosage form containing aceclofenac, a nonsteroidal anti-inflammatory drug. The pellets were prepared by using extrusion/spheronization method, and the core pellets were coated with a pH-sensitive poly(meth) acrylate copolymer (Eudragit L100-55) to achieve site-specific drug release. The formulated pellets were characterized for percentage yield, size distribution, surface morphology studies, drug content, and flow properties. In vitro dissolution test was used for comparison of drug release profiles of various coated pellets. The practical yield was found to be 90–95%. The particle size of enteric-coated pellets was found to be in the range of 0.59–0.71 mm. The pellets were spherical in shape and surfaces of pellets were found to be rough and showing micropores. Enteric-coated pellets showed good flow properties and in vitro dissolution profile. Dissolution tests were carried out in a USP type II dissolution apparatus in media-simulating pH conditions of the gastrointestinal tract. The release of the aceclofenac from formulated pellets was established to be minimum in the pH 1.2 (<5%) for a period of 2 h, and at pH 6.8, it shows the maximum release (85 ± 5% release within 1 h) which indicates gastric resistance of the formulated pellets. The 20% wt/wt enteric-coated pellets were compared to that of marketed product (tablets), it was observed that pellets showed better release profile. The study concluded that the formulated multiparticulate dosage forms can be used as an ideal drug delivery system for the aceclofenac.     

The study of dual COX-2/5-LOX inhibitors by using electronic-topological approach based on data on the ligand–receptor interactions

Structural and electronic factors influencing selective inhibition of cyclooxygenase-2 and 5-lipoxygenase (COX-2/5-LOX) were studied by using Electronic-Topological Method combined with Neural Networks (ETM–NN), molecular docking, and Density Functional Theory (DFT) in a large set of molecules. The results of the ETM–NN calculations allowed for the selection of pharmacophoric molecular fragments, which could be taken as a basis for a system capable of predicting the COX-2/5-LOX inhibitory activity. For the more effective extraction of the pharmacophoric molecular fragments, docking of molecules into the active sites of the two enzymes was carried out to get data on the ligand–receptor interaction. To make an assessment of these interactions, stabilization energies were calculated by using Natural Bond Orbital (NBO) analysis. Docking and data on the electronic structures of active sites of enzymes helped to reveal effectively the peculiarities of the ligand–receptor binding. The system for the selective COX-2/5-LOX inhibitory activity prediction that has been developed as the result of the ETM–NN study recognized correctly 93% of compounds as highly active ones. Thus, this system can be successfully used for carrying out computer screening and synthesis of potent inhibitors of COX-2/5-LOX with diverse molecular skeletons.     

Photocatalytic degradation of non-steroidal anti-inflammatory drugs with TiO2 and simulated solar irradiation

The aim of this work is to evaluate and compare the degradation achieved for three non-steroidal anti-inflammatory drugs (NSAIDs) by heterogeneous TiO2 photocatalytic means in aqueous solution at laboratory scale. The selected pharmaceutical compounds were diclofenac (DCF), naproxen (NPX) and ibuprofen (IBP). These compounds were used in their sodium salt chemical form. Previous experiments (adsorption, photolysis and thermodegradation) were developed to evaluate non-catalytic degradation for each NSAID. Photocatalytic experiments were carried out in a Xe-lamp reactor in order to study the influences of different operational conditions (catalyst load, temperature and dissolved oxygen concentration). These results showed that the optimum amount of TiO2, to achieve maximum degradation, of IBP was 1g/L. In contrast, the maximum degradation for DCF or NPX was observed at a TiO2 loading of 0.1g/L. Temperature had a significant effect only for NPX degradation, achieving almost 99% phototransformation. No significant differences were observed for DCF and IBP at 20, 30 and 40 degrees C. Dissolved oxygen concentration was an important parameter to increase the degradation for NPX and IBP. However, it was observed that its rate of mineralization did not increase. Intermediate metabolites were detected in all cases. Hydroxyl metabolites were the most important residual compounds after the photocatalytic treatment of IBP. The inhibition percentage of bioluminescence from Vibro fischeri--as a toxicity parameter--increased during the irradiation time due to the residual concentration of the hydroxyl metabolites generated. However, after 120 min, in experiments with 40 mg/L of dissolved oxygen, a decrease of the % inhibition was observed. Only photocatalytic treatment of IBP drives to a satisfactory biodegradability index BOD5/COD (between 0.16 and 0.42) and, only in this case, a post-biological treatment could be suggested.     

Effects of local or systemic administration of meloxicam on mammary gland inflammatory responses to lipopolysaccharide-induced mastitis in dairy cows

Nonsteroidal anti-inflammatory drugs (NSAID) are commonly used in combination with antimicrobial mastitis treatments to reduce pain. Little is known about whether meloxicam, an NSAID designed for the preferential inhibition of cyclooxygenase-2 over cyclooxygenase-1, affects the mammary immune response. The objective of this study was to analyze the mammary immune response to intramammary (local) or intravenous (systemic) administration of meloxicam with or without immune activation by lipopolysaccharide (LPS). We challenged 108 quarters of 30 cows with or without a low or high dose of LPS from Escherichia coli (0.1 or 0.2 µg/quarter), with or without meloxicam via intramammary administration (50 mg/quarter) or intravenous injection (0.5 mg/kg of body weight; ~300 mg/cow). Intramammary administration of meloxicam alone did not trigger an acute inflammatory response, verified by unchanged somatic cell count (SCC) and lactate dehydrogenase (LDH), BSA, and IgG concentrations in milk, which are normally augmented during mastitis due to an opening of the blood–milk barrier. Similarly, intramammary meloxicam did not change the mRNA abundance of inflammatory factors in mammary gland tissue. As expected, quarters challenged with either dose of LPS showed increased leukocyte infiltration (SCC); increased LDH, BSA, IgG, Na, and Cl concentrations; and diminished K concentrations in milk. In contrast to our hypothesis, the addition of intramammary or intravenous meloxicam did not reduce these markers of mastitis in milk. Instead, intramammary meloxicam appeared to accelerate the SCC response to LPS, but only at the lower LPS dose. Moreover, the mRNA expression of inflammatory factors in mammary tissue was not modified by the intramammary application of meloxicam compared with the contralateral quarters that were challenged with LPS only. We demonstrated for the first time that intramammary meloxicam at a dose of 50 mg/quarter did not trigger an immune response in the mammary glands of dairy cows. At the doses we used, meloxicam (intramammary or systemic) did not lower inflammatory responses. The intramammary administration of meloxicam seemed to stimulate leukocyte recruitment into the milk in quarters challenged with a low dose of LPS. The integrity of the blood–milk barrier was not protected by meloxicam in LPS-stimulated quarters. This study provides the first indications that meloxicam does not limit the inflammatory response in the mammary gland, although it does not impair the mammary immune system.