Effect of pre-administered flurbiprofen axetil on the EC50 of propofol during anesthesia in unstimulated patients: a randomized clinical trial / Efeito da pré‐ administração de flurbiprofeno axetil na CE50 do propofol durante anestesia em pacientes não estimulados: estudo clínico randomizado

Abstract Background and objectives Preoperative use of flurbiprofen axetil (FA) is extensively adopted to modulate the effects of analgesia. However, the relationship between FA and sedation agents remains unclear. In this study, we aimed to investigate the effects of different doses of FA on the median Effective Concentration (EC50) of propofol. Methods Ninety-six patients (ASA I or II, aged 18-65 years) were randomly assigned into one of four groups in a 1:1:1:1 ratio. Group A (control group) received 10 mL of Intralipid, and groups B, C and D received 0.5 mg.kg−1, 0.75 mg.kg−1 and 1 mg.kg−1 of FA, respectively, 10 minutes before induction. The depth of anesthesia was measured by the Bispectral Index (BIS). The "up-and-down" method was used to calculate the EC50 of propofol. During the equilibration period, if BIS ≤ 50 (or BIS > 50), the next patient would receive a 0.5 µg.mL−1-lower (or -higher) propofol Target-Controlled Infusion (TCI) concentration. The hemodynamic data were recorded at baseline, 10 minutes after FA administration, after induction, after intubation and 15 minutes after intubation. Results The EC50 of propofol was lower in Group C (2.32 µg.mL−1, 95% Confidence Interval [95% CI] 1.85-2.75) and D (2.39 µg.mL−1, 95% CI 1.91-2.67) than in Group A (2.96 µg.mL−1, 95% CI 2.55-3.33) (p = 0.023, p = 0.048, respectively). There were no significant differences in the EC50 between Group B (2.53 µg.mL−1, 95% CI 2.33-2.71) and Group A (p > 0.05). There were no significant differences in Heart Rate (HR) among groups A, B and C. The HR was significantly lower in Group D than in Group A after intubation (66 ± 6 vs. 80 ± 10 bpm, p < 0.01) and 15 minutes after intubation (61 ± 4 vs. 70 ± 8 bpm, p < 0.01). There were no significant differences among the four groups in Mean Arterial Pressure (MAP) at any time point. The MAP of the four groups was significantly lower after induction, after intubation, and 15 minutes after intubation than at baseline (p < 0.05). Conclusion High-dose FA (0.75 mg.kg−1 or 1 mg.kg−1) reduces the EC50 of propofol, and 1 mg.kg−1 FA reduces the HR for adequate anesthesia in unstimulated patients. Although this result should be investigated in cases of surgical stimulation, we suggest that FA pre-administration may reduce the propofol requirement when the depth of anesthesia is measured by BIS.

Resumo Justificativa e objetivos A administração pré‐operatória de Flurbiprofeno Axetil (FA) é amplamente usada para a modulação da analgesia. No entanto, a relação entre FA e fármacos sedativos permanece obscura. Neste estudo, nosso objetivo foi investigar os efeitos de diferentes doses de FA na Concentração Efetiva mediana (CE50) do propofol. Métodos Noventa e seis pacientes (ASA I ou II, com idades de 18-65 anos) foram alocados aleatoriamente em quatro grupos na proporção de 1:1:1:1. Dez minutos antes da indução, o Grupo A (grupo controle) recebeu 10 mL de Intralipid, enquanto os grupos B, C e D receberam FA na dose de 0,5 mg.kg‐1; 0,75 mg.kg‐1 e 1 mg.kg‐1, respectivamente. A profundidade da anestesia foi medida pelo Índice Bispectral (BIS). O método up‐and‐down foi usado para calcular a CE50 do propofol. Durante o período de equilíbrio, se o valor do BIS fosse ≤ 50 ou BIS > 50, o próximo paciente tinha a infusão de propofol ajustada para uma concentração alvo‐controlada 0,5 µg.mL‐1 inferior ou superior, respectivamente. Os dados hemodinâmicos foram registrados no início do estudo, 10 minutos após a administração de FA, após a indução, após a intubação e 15 minutos após a intubação. Resultados A CE50 do propofol foi menor no Grupo C (2,32 µg.mL‐1, Intervalo de Confiança de 95% [95% IC] 1,85-2,75) e D (2,39 µg.mL‐1, 95% IC 1,91-2,67) do que no Grupo A (2,96 µg.mL‐1; 95% IC 2,55-3,33) (p = 0,023, p = 0,048, respectivamente). Não houve diferenças significantes na CE50 entre o Grupo B (2,53 µg.mL‐1, 95% IC 2,33-2,71) e o Grupo A (p > 0,05). Não houve diferenças significantes na Frequência Cardíaca (FC) entre os grupos A, B e C. A FC foi significantemente menor no grupo D do que no grupo A após a intubação (66 ± 6 vs. 80 ± 10 bpm, p < 0,01) e 15 minutos após a intubação (61 ± 4 vs. 70 ± 8 bpm, p < 0,01). Não houve diferenças significantes entre os quatro grupos na Pressão Arterial Média (PAM) em qualquer momento. A PAM dos quatro grupos foi significantemente menor após a indução, após a intubação e 15 minutos após a intubação do que na linha de base (p < 0,05). Conclusão FA em altas doses (0,75 mg.kg‐1 ou 1 mg.kg‐1) reduz a CE50 do propofol, e 1 mg.kg‐1 de FA reduz a FC durante níveis adequados de anestesia em pacientes não estimulados. Embora esse resultado deva ser investigado na presença de estimulação cirúrgica, sugerimos que a pré‐administração de FA pode reduzir a necessidade de propofol durante anestesia cuja profundidade seja monitorada pelo BIS.

Efficacy of preoperative nonsteroidal anti-inflammatory drug and the re-dilation technique in minimizing miosis after femtosecond laser in cataract surgery / Eficácia do AINE pré-operatório e da técnica de re-dilatação em minimizar a miose na cirurgia de catarata com laser de femtosegundo

ABSTRACT Purpose: To assess the efficacy of using a nonste­roidal anti-inflammatory drug preoperatively and of applying the re-dilation technique when necessary to minimize pupil size variation when comparing the degree of mydriasis before femtosecond laser pretreatment with that at the beginning of phacoemulsification. Methods: This retrospective study included patients who underwent cataract surgery using the LenSx (Alcon Laboratories, Inc., Fort Worth, TX). Our routine dilating regimen with flurbiprofen, tropicamide, and phenylephrine was used. The re-dilation technique was applied on eyes that manifested with a pupillary diameter that was smaller than the programmed capsulotomy diameter after laser pretreatment. The technique consists of overcoming pupillary contraction by instilling tropicamide and phenylephrine before phacoemulsification. Pupil size was assessed before femtosecond laser application and at the beginning of phacoemulsification. Results: Seventy-five eyes (70 patients) were included. Nine (12%) eyes underwent the re-dilation technique. There was no significant difference in mean pupillary diameter and mean pupillary area between the two studied surgical time points (p=0.412 and 0.437, respectively). The overall pupillary area constriction was 2.4 mm2. Immediately before opening the wounds for phacoemulsification, none of the eyes presented with a pupillary diameter <5 mm, and 61 (85.3%) eyes had a pupillary diameter >6 mm. Conclusion: Preoperative administration of nonsteroidal anti-inflammatory drug and the re-dilation technique resulted in no significant pupil size variation in eyes that were pretreated with the femtosecond laser, when comparing the measurements made before the laser application and at the beginning of phacoemulsification. This approach can avoid the need to proceed with cataract extraction with a constricted pupil.

RESUMO Objetivo: Avaliar a eficácia do uso de anti-inflamatório não-esteróide no pré-operatório e aplicação da técnica de re-dilatação quando necessária para minimizar a variação do tamanho pupilar ao comparar o grau de midríase antes do tra­tamento com laser de femtosegundo no início da facoemulsificação. Métodos: Esse estudo retrospectivo incluiu pacientes que foram submetidos à cirurgia de catarata usando o LenSx (Alcon Laboratories, Inc., Fort Worth, TX). Nosso regime de di­latação de rotina com flurbiprofeno, tropicamida e fenilefrina foi usado. A técnica de re-dilatação doi aplicada em olhos que se manifestaram com um diâmetro pupilar menor do que o diâmetro da capsulotomia programado após o pré-tratamento a laser. A técnica consiste em superar a contração pupilar pela instilação de tropicamida e fenilefrina antes da facoemulsificação. O tamanho pupilar foi avaliado antes da aplicação do laser de femtosegundo e no inicio da facoemulsificação. Resultados: Setenta e cinco olhos (70 pacientes) foram incluídos. Nove (12%) olhos foram submetidos à técnica de re-dilatação. Não houve diferença significativa no diâmetro pupilar médio e na área pupilar média entre os dois tempos cirúrgicos estudados (p=0,412 e 0,437, respectivamente). A constrição global da área pupilar foi de 2,4 mm2. Imediatamente antes de abrir as incisões para a facoemulsificação, nenhum dos olhos apresentava diâmetro pupilar <5 mm e 61 (85,3%) olhos apresentavam um diâmetro pupilar >6 mm. Conclusões: O administração pré-operatória de anti-inflamatório não-esteróide e da técnica de re-dilatação resultaram em uma variação significativa do tamanho pupilar em olhos que foram pré-tratados com laser de femtosegundo, comparando as medidas realizadas antes da aplicação do laser e no inicio da facoemulsificação. Essa abordagem pode evitar a necessidade de prosseguir com a extração da catarata com uma pupila contraída.

Effect of Flurbiprofen Axetil on Low-frequency Fluctuation Amplitude of Resting-state Functional Magnetic Resonance Imaging in Trigeminal Neuralgia / 中国医学科学院学报

Objective To observe the changes of brain function in patients with trigeminal neuralgia after administration of flurbiprofen axetil by using the resting-state functional magnetic resonance imaging(fMRI)and based on the amplitude of low-frequency fluctuation(ALFF). Methods Resting fMRI data of 20 patients with trigeminal neuralgia before and after treatment with flurbiprofen axetil were collected by 1.5T magnetic resonance imaging system.The resting fMRI data were pretreated by Statistical Parametric Mapping and DPABI(a toolbox for Data Processing and Analysis for Brain Imaging)software,and the difference of low-frequency oscillation amplitude of brain spontaneous activity before and after treatment with flurbiprofen axetil was analyzed by ALFF. Results The Visual Analogue Scale of pain intensity after flurbiprofen axetil injection was significantly lower than that before administration,and the pain relieved significantly(P=0.000).The ALFF values of right dorsolateral prefrontal lobe,bilateral medial prefrontal lobe,and right middle cingulate gyrus in patients treated with flurbiprofen axetil at rest were significantly lower than those before administration(P=0.000). Conclusions The analgesic effect of flurbiprofen axetil is exerted on the central system.This agent can inhibit the abnormal brain function caused by chronic pain stimulation and thus reduce pain.However,the specific mechanism needs further investigations.

Development of fast dissolving tablets of flurbiprofen by sublimation method and its in vitro evaluation

Flurbiprofen belongs to Biopharmaceutical Classification System (BCS) class II drugs which are poorly soluble in water. The objective of present research work was to prepare fast dissolving tablets of Flurbiprofen using varying concentrations of three different sublimating agents to improve the dissolution rate. Seven formulations were prepared containing different concentrations of camphor, ammonium bicarbonate and thymol as sublimating agent along with primogel as a superdisintegrant. Tablets were manufactured by direct compression method. The prepared tablets were evaluated for pre-compression and post-compression parameters result, For all formulations result was within official limits. FTIR studies revealed that there were no interactions between the drug and the excipients used. From in vitro drug release studies it was concluded that the formulations F6 and F7 containing 10% and 15% of thymol showed fast drug release of 100.00% and 100.84% respectively in 30 minutes. Formulations containing camphor (F2 & F3) and ammonium bicarbonate (F4 & F5) as sublimating agents showed a drug release of less than 80%, while the control formulation F1 having no sublimating agent showed 49.14% of drug release in 30 minutes. Thus thymol can successfully be used to formulate fast dissolving tablets of flurbiprofen by sublimation method with much better dissolution profile

Solubility and dissolution enhancement of flurbiprofen by solid dispersion using hydrophilic carriers

ABSTRACT The intent of the current work is to study the effect of polyethylene glycol 8000 and polyethylene glycol 10000 as hydrophilic carriers on dissolution behaviour of flurbiprofen. In the present study, solvent evaporation method was used to prepare flurbiprofen solid dispersions and evaluated for physico-chemical properties, drug-carrier compatibility studies and dissolution behaviour of drug. Solubility studies showed more solubility in higher pH values and formulations SD4 and SD8 were selected to prepare the fast dissolving tablets. FTIR and DSC study showed no interaction and drug was dispersed molecularly in hydrophilic carrier. XRD studies revealed that there was change in the crystallinity of the drug. The results of In vitro studies showed SD8 formulation confer significant improvement (p<0.05) in drug release, Q20 was 99.08±1.35% compared to conventional and marketed tablets (47.31±0.74% and 56.86±1.91%). The mean dissolution time (MDT) was reduced to 8.79 min compared to conventional and marketed tablets (25.76 and 22.22 min.) indicating faster drug release. The DE (% dissolution efficiency) was increased by 2.5 folds (61.63%) compared to conventional tablets (23.71%). From the results, it is evident that polyethylene glycol solid dispersions in less carrier ratio may enhance the solubility and there by improve the dissolution rate of flurbiprofen.

Investigation of the parameters affecting the release of flurbiprofen from chitosan microspheres

ABSTRACT Flurbiprofen (FLB), a NSAID, widely used for preventing pain generally for arthritis or dental problems. In this study, FLB loaded chitosan microspheres were prepared by ionotropic gelation method. In this method, microspheres were formed by dropping chitosan solutions containing FLB into sodium alginate solutions including sodium tripolyphosphate (TPP). A variety of formulation parameters like drug:polymer ratio, drug concentration, polymer's molecular weight, polymer concentration, pH and the concentration of TPP solutions, drying method and stirring time were analyzed. The dissolution studies were performed in a shaking water bath in pH 7.4 phosphate buffer saline (PBS) at 37 °C. Laser diffractometer was used for particle size analysis, and scanning electron microscope (SEM) was used for morphological properties. Drug loading and loading efficiency were calculated by using UV spectrophotometer. The particles obtained were spherical with 0.7-1.3 mm size range, and the loading efficiency was approximately 21-79%. The dissolution studies conducted revealed that drug:polimer ratio and the polymer type and concentration affected the drug release from microspheres. It was observed that increasing the polymer concentration, polymer's molecular weight and TPP concentration decreased the FLB release from microspheres, which was according to Higuchi kinetics.

case of nodular posterior scleritis mimicking choroidal mass

The aim of this study is to report clinical and imaging findings, and treatment outcomes of a patient with nodular posterior scleritis. A 41-year-old woman was diagnosed as nodular posterior scleritis in the light of clinical and imaging findings. At first admission best corrected visual acuity was 20/50 in her right eye. Fundus examination revealed an amelanotic subretinal mass under the superior temporal arcade associated with subretinal fluid surrounding it. B-scan ultrasonography, optical coherence tomography, fluorescein angiography, and indocyanine green angiography findings confirmed the diagnosis. As treatment, nepafenac eye drops 3 times a day, and flurbiprofen tablet 100 mg twice a day were prescribed. After 4 weeks of treatment, the ocular pain was relieved, BCVA improved to 20/20, and subretinal mass totally regressed. Although the diagnosis of nodular posterior scleritis may be confusing, it has to be kept in mind in patients with a subretinal/choroidal mass. Multimodal fundus imaging may be helpful in differential diagnosis. The condition is usually curable with non-steroidal anti-inflammatory drugs and/or systemic steroids

Do Different Cyclooxygenase Inhibitors Impair Rotator Cuff Healing in a Rabbit Model? / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The effect of selective and non-selective cyclooxygenase (COX) inhibitors on tendon healing was variable. The purpose of the study was to evaluate the influence of non-selective COX inhibitor, ibuprofen and flurbiprofen axetil and selective COX-2 inhibitor, celecoxib on the tendon healing process in a rabbit model.</p><p><b>METHODS</b>Ninety-six New Zealand rabbits were used as rotator cuff repair models. After surgery, they were divided randomly into four groups: ibuprofen (10 mg·kg-1·d-1), celecoxib (8 mg·kg-1·d-1), flurbiprofen axetil (2 mg·kg-1·d-1), and control group (blank group). All drugs were provided for 7 days. Rabbits in each group were sacrificed at 3, 6, and 12 weeks after tendon repair. Tendon biomechanical load failure tests were performed. The percentage of type I collagen on the bone tendon insertion was calculated by Picric acid Sirius red staining and image analysis. All data were compared among the four groups at the same time point. All data in each group were also compared across the different time points. Qualitative histological evaluation of the bone tendon insertion was also performed among groups.</p><p><b>RESULTS</b>The load to failure increased significantly with time in each group. There were significantly lower failure loads in the celecoxib group than in the control group at 3 weeks (0.533 vs. 0.700, P = 0.002), 6 weeks (0.607 vs. 0.763, P = 0.01), and 12 weeks (0.660 vs. 0.803, P = 0.002), and significantly lower percentage of type I collagen at 3 weeks (11.5% vs. 27.6%, P = 0.001), 6 weeks (40.5% vs. 66.3%, P = 0.005), and 12 weeks (59.5% vs. 86.3%, P = 0.001). Flurbiprofen axetil showed significant differences at 3 weeks (failure load: 0.600 vs. 0.700, P = 0.024; percentage of type I collagen: 15.6% vs. 27.6%, P = 0.001), but no significant differences at 6 and 12 weeks comparing with control group, whereas the ibuprofen groups did not show any significant difference at each time point.</p><p><b>CONCLUSIONS</b>Nonsteroidal anti-inflammatory drugs can delay tendon healing in the early stage after rotator cuff repair. Compared with nonselective COX inhibitors, selective COX-2 inhibitors significantly impact tendon healing.</p>

Formulation and in vitro evaluation of mucoadhesive controlled release matrix tablets of flurbiprofen using response surface methodology

The objective of the current study was to formulate mucoadhesive controlled release matrix tablets of flurbiprofen and to optimize its drug release profile and bioadhesion using response surface methodology. Tablets were prepared via a direct compression technique and evaluated for in vitro dissolution parameters and bioadhesive strength. A central composite design for two factors at five levels each was employed for the study. Carbopol 934 and sodium carboxymethylcellulose were taken as independent variables. Fourier transform infrared (FTIR) spectroscopy studies were performed to observe the stability of the drug during direct compression and to check for a drug-polymer interaction. Various kinetic models were applied to evaluate drug release from the polymers. Contour and response surface plots were also drawn to portray the relationship between the independent and response variables. Mucoadhesive tablets of flurbiprofen exhibited non-Fickian drug release kinetics extending towards zero-order, with some formulations (F3, F8, and F9) reaching super case II transport, as the value of the release rate exponent (n) varied between 0.584 and 1.104. Polynomial mathematical models, generated for various response variables, were found to be statistically significant (P<0.05). The study also helped to find the drug's optimum formulation with excellent bioadhesive strength. Suitable combinations of two polymers provided adequate release profile, while carbopol 934 produced more bioadhesion.

O objetivo do presente estudo foi formular comprimidos mucoadesivos de flurbiprofeno, de liberação controlada, e otimizar o perfil da liberação do fármaco e a bioadesão, utilizando a metodologia de superfície de resposta. Prepararam-se os comprimidos via técnica de compressão direta, que foram avaliados in vitro quanto aos parâmetros de dissolução e da força bioadesiva. Planejamento com componente central para dois fatores em cinco níveis cada foi empregado para esse estudo. Carbopol 934 e carboximetilcelulose sódica foram tomados como variáveis independentes. Efetuaram-se estudos de espectroscopia por transformada de Fourier (FTIR) para observar a estabilidade do fármaco durante a compressão direta e para avaliar a interação a fármaco-polímero. Aplicaram-se vários métodos cinéticos para avaliar a liberação do fármaco dos polímeros. Gráficos de superfície de contorno e de resposta foram efetuados para retratar a relação entre as variáveis dependentes e a resposta. Os comprimidos mucoadesivos de flurbiprofeno apresentaram cinética de liberação não-fickiana, estendendo para ordem zero, para algumas formulações (F3, F8 e F9), alcançando transporte super caso II, à medida que o valor do expoente (n) de taxa de liberação variou entre 0,584 e 1,104. Modelos matemáticos polinomiais, gerados por diversas variáveis de resposta, foram estatisticamente, significativos (P<0,05). O estudo também auxiliou a encontrar a formulação ótima do fármaco, com excelente força de bioadesão. Combinações adequadas dos dois polímeros resultaram em perfis de liberação adequado, sendo que o Carbopol 934 produziu mais adesão.

Formulation, Evaluation and Pharmacokinetics of Flurbiprofen Fast Dissolving Tablets.

Aim: The intent of present study is to formulate fast dissolving tablets of flurbiprofen using different superdisintegrants to improve the dissolution and bioavailability. Place and Duration of Study: Jyothishmathi Institute of Pharmaceutical Sciences, Karimnagar, Andhra Pradesh, India, between January 2011 and December 2012. Methodology: Flurbiprofen fast dissolving tablets were prepared using different superdisintegrants and characterized for different physical parameters, DSC, FTIR studies, in vitro dissolution studies and in vivo pharmacokinetics to prove the enhancement of bioavailability. Results: From the in vitro dissolution studies, the percent drug release in 15 min (Q15) was found to be 91.46±1.42% in case of optimized formulation where as the conventional tablets prepared by similar manner showed 22.92±0.47% in 15 min. The initial dissolution rate and dissolution efficiency for optimized formulation was 6.10%/min and 53.44 but it was 1.53%/min and 10.96 in conventional tablets. They increased by 4.0 folds when compared to conventional tablets. From the pharmacokinetic evaluation, the optimized fast dissolving tablets produced peak plasma concentration (Cmax) as 11433.32 ng/ml at 2 h Tmax, but they were found to be 8792.64 ng/ml at 3 h Tmax, in case of conventional tablets. The area under the curve for the optimized fast dissolving and conventional tablets were found to be 42691.23 and 30727.14 ng-h/ml. Conclusion: In summary, formulation of fast dissolving tablets using superdisintegrants was a good approach to enhance the dissolution and absorption rates of flurbiprofen.

Intestinal absorption kinetics of flurbiprofen in rats / 药学学报

To study the in situ intestinal absorption kinetics of flrubiprofen in rats, the absorption of flurbiprofen in small intestine (duodenum, jejunum and ileum) and colon of rats was investigated using in situ single-pass perfusion method and the drug content was measured by HPLC. The effects of drug concentration on the intestinal absorption were investigated. The K(a) and P(app) values of flurbiprofen in the small intestine and colon had no significant difference (P > 0.05). Drug concentration (4.0, 10.0 and 16.0 mg x L(-1)) had no significant influence on the K(a) values (P > 0.05). However, when concentration was 4.0 mg x L(-1) and 10.0 mg x L(-1), significant effect on the P(app) values (P < 0.05) was found, but significant effect on the P(app) values was not shown between 10.0 mg x L(-1) and 16.0 mg x L(-1) (P > 0.05). The K(a) and P(app) values of flurbiprofen on the perfusion flow rate had significant difference (P < 0.05). Flurbiprofen could be absorbed at all segments of the intestine in rats and had no special absorption window. The absorption of flurbiprofen complies with the facilitated diffusion in the general intestinal segments, and accompany with the cytopsistransport mechanism probably. The perfusion flow rate had significant effect on the K(a) and P(app).

Flurbiprofen toxicity in 2 dogs / 대한수의학회지

Two dogs were presented with melena, vomiting and depression after accidental swallowing of candy form of Strepsils (flurbiprofen), which is one of non-steroidal anti-inflammatory drugs used in human medicine for controlling a sore throat. These dogs had common signs of anemia induced by gastrointestinal ulceration and hemorrhage with azotemia and leukocytosis. The dogs were treated with blood transfusion, fluid therapy, proton-pump inhibitor, antiemetics, mucus protectant and antibiotic. Although most of clinical signs of two dogs were resolved, azotemic problem with evidence of renal injury have remained.

Alzheimer's Disease: Clinical Trials and Future Perspectives / 대한정신약물학회지

Alzheimer's disease is increasingly common in elderly population with a large socioeconomic burden. Current available drugs for Alzheimer's disease are acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor antagonist. Much effort is directed towards not just symptomatic treatments but disease-modifying treatments. Several drugs with differing targets and mechanisms of action are under development for the treatment of Alzheimer's disease. Phase III trials of dimebon, Ginkgo biloba, non-steroidal anti-inflammatory drugs, phenserine, statins, semagacestat, tarenflurbil, tramiprosate, valproate, xaliproden have been completed without demonstrating adequate efficacy. Encouraging results would be expected from ongoing phase III trials of bapineuzumab and solanezumab. The clinical trials for the disease-modifying treatment of Alzheimer's disease have resulted in both promise and disappointment.

Flurbiprofen axetil promotes neuroprotection by activation of cerebral peroxisome proliferator-activated receptor gamma after focal cerebral ischemia in rats / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Our previous papers indicate that flurbiprofen axetil (FA), a cyclooxygenase inhibitor, is a promising therapeutic strategy for cerebral ischemia in rats. This study aimed to investigate whether FA could promote a neuroprotective effect by activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) after focal cerebral ischemia in rats.</p><p><b>METHODS</b>Totally 48 male Sprague-Dawley (SD) rats were randomly assigned into six groups (n = 8 in each group): animals in group ischemia/reperfusion (I/R) only received 120-minute transient middle cerebral artery occlusion (tMCAO); animals in group I/R + FA were administered FA (10 mg/kg) by caudal vein just after 120-minute tMCAO; animals in group I/R + FA + GW9662 were administered GW9662 (a PPAR-γ inhibitor, 1 mg/kg) intraperitoneally 30 minutes before cerebral ischemia onset and FA (10 mg/kg) by caudal vein just after 120-minute tMCAO; animals in group I/R + GW9662 were administered GW9662 (1 mg/kg) intraperitoneally 30 minutes before cerebral ischemia onset; animals in group I/R + DMSO were administered 3% DMSO (vehicle of GW9662, 1 ml/kg) intraperitoneally 30 minutes before cerebral ischemia onset; animals in sham group experienced the identical surgery apart from the insertion of the nylon filament. The neurologic deficit score (NDS) were performed at 72 hours after reperfusion, and then mean brain infarct volume percentage (MBIVP) was determined with 2,3,5-triphenyltetrazolium chloride (TTC) 10 g/L staining.</p><p><b>RESULTS</b>NDS was significantly increased in group I/R + FA (12.0 (10.0 - 15.0)), group I/R + FA + GW9662 (10.0 (8.0 - 12.0)), and in group I/R + FA + DMSO (12.0 (9.0 - 14.0)) at 72 hours after reperfusion compared with those in group I/R (7.5 (6.0 - 10.0)). NDS was conspicuously different between group I/R + FA (12.0 (10.0 - 15.0)) and group I/R + FA + GW9662 (10.0 (8.0 - 12.0)). MBIVP in group I/R ((45.82 - 8.83)%) was significantly greater than that in group I/R + FA ((23.52 - 9.90)%), group I/R + FA + GW9662 ((33.17 - 7.15)%); MBIVP in group I/R + FA ((23.52 - 9.90)%) was significantly smaller than that in group I/R + FA + GW9662 ((33.17 - 7.15)%).</p><p><b>CONCLUSIONS</b>FA confers the neuroprotective effect on tMCAO in rats and the selective PPAR-γ antagonist GW9662 attenuates the effect of FA. FA could promote a neuroprotective effect by, or in part, activation of PPAR-γ after focal cerebral ischemia in rats.</p>

Preemptive analgesic effects of flurbiprofen axetil in patients undergoing radical resection of esophageal carcinoma via the left thoracic approach / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Systemic non-steroidal anti-inflammatory drugs have been evaluated for their possible preemptive analgesic effects. The efficacy of flurbiprofen axetil for preemptive analgesia in patients undergoing radical resection of esophageal carcinoma via the left thoracic approach needs further investigation. The aim of this study was to research the preemptive analgesic effects of flurbiprofen axetil in thoracic surgery, and the influence of preoperative administration on postoperative respiratory function.</p><p><b>METHODS</b>This randomized, double-blind, controlled trial enrolled 60 patients undergoing radical resection of esophageal carcinoma via the left thoracic approach. Anesthesia management was standardized. Each patient was randomly assigned to receive either 100 mg flurbiprofen axetil intravenously 15 minutes before incision (PA group) or intravenous normal saline as a control (C group). Postoperative analgesia was with sufentanil delivered by patient-controlled analgesia pump. Postoperative sufentanil consumption, visual analog scale pain scores, plasma levels of interleukin-8, and oxygenation index were measured.</p><p><b>RESULTS</b>Compared with the preoperative baseline, postoperative patients in the PA group had no obvious increase in pain scores (P > 0.05), but patients in the C group had significantly increased pain scores (P < 0.05). Pain scores in the C group were significantly higher at 24 hours postoperatively than preoperatively. Intergroup comparisons showed lower visual analog scale scores at 2 - 24 hours postoperatively in the PA group than the C group (P < 0.05). Sufentanil consumption and plasma interleukin-8 levels at 2 and 12 hours postoperatively were significantly lower in the PA group than the C group (P < 0.05). The oxygenation index at 2 and 12 hours postoperatively was significantly higher in the PA group than the C group (P < 0.05).</p><p><b>CONCLUSIONS</b>Intravenous flurbiprofen axetil appears to have a preemptive analgesic effect in patients undergoing radical resection of esophageal carcinoma via the left thoracic approach, and appears to contribute to recovery of respiratory function and to reduction of the postoperative inflammatory reaction.</p>

Ion-sensitive nanoemulsion-in situ gel system for ophthalmic delivery of flurbiprofen axetil / 药学学报

The aim of the study is to prepare flurbiprofen axetil nanoemulsion-in situ gel system (FBA/NE-ISG) and observe its ocular pharmacokinetics, rheological behavior, TEM images, irritation and cornea retention. Production of nanoemulsion was based on high-speed shear and homogenization process, and then mixed with gellan gum to prepare FBA/NE-ISG. Rheological study showed that FBA/NE-ISG possesses strong gelation capacity and its viscosity and elastic modulus increases by 2 Pa*s and 5 Pa respectively when mixed with artificial tear at the ratio of 40 : 7. TEM images suggested no significant changes in particle morphology of the pre and post gelation. Good ocular compatibility of FBA/NE-ISG was testified by the irritation test based on histological examination. In vivo fluorescence imaging system was applied to investigate the characteristics of cornea retention, and the results indicated that the nanoemulsion-in situ gel (NE-ISG) prolonged the cornea retention time significantly since K(NE-ISG) (0.008 5 min(-1) was much lower compared with flurbiprofen sodium eye drops (FB-Na, 0.03% w/v) of which the K(Eye drops) was 0.105 2 min(-1), indicated that the cornea retention time of NE-ISG was prolonged significantly. Pharmacokinetics of FBA/NE-ISG in rabbit aqueous humor was studied by cornea puncture, the MRT (12.3 h) and AUC(0-12h) (126.8 microg x min x mL(-1)) of FBA/NE-ISG was 2.7 and 2.9 times higher than that of the flurbiprofen sodium eye drops respectively, which meant that the ocular bioavailability was improved greatly by the novel preparation. Therefore, FBA/NE-ISG can enhance the ocular bioavailability by prolonging drug corneal retention significantly. What's more, encapsulated by emulsion droplets prodrug flurbiprofen (FBA) instead of flurbiprofen (FB) can reduce the ocular irritation.

Population pharmacokinetic modeling of flurbiprofen / 药学学报

The paper is to report the establishment of a population pharmacokinetic model for flurbiprofen (FP), an active metabolite of flurbiprofen axetil (FA). 246 FP serum concentration and clinical data were perspectively collected from 23 general anaesthesia patients receiving FA intravenously before operation in Dentofacial Surgery and Otorhinolaryngology Department of the First Affiliated Hospital of Fujian Medical University. Population pharmacokinetic data analysis was performed using NONMEM software. The measure of Bootstrap was applied for internal validation, while Visual Predictive check was adopted for external validation. The data of FP correspond with two-compartment model. The body weight (WT) had conspicuous effect on clearance and volume of central compartment, while sex, age and daily dose of administration had no marked effect on pharmacokinetic parameter of FP. The basic model was described as follows: CL (L x h(-1)) = 1.28x EXP(ETA(1)), V1 (L) = 5.03x EXP(ETA(2)), Q (L x h(-1)) = 8.5 x EXP(ETA(3)), V2 (L) = 4.39 x EXP(ETA(4)). The final model was described as follows: CL (L x h(-1)) = 1.32 x (WT/60) x EXP(ETA(1)), V1 (L) = 5.23 x (WT/60) x EXP(ETA(2)), Q (L x h(-1)) = 8.45 x EXP(ETA(3)), V2 (L) = 4.37 x EXP(ETA(4)). The population typical value of CL, V1, Q and V2 were: 1.32 L x h(-1), 5.23 L, 8.45 L x h(-1) and 4.37 L, respectively. Bootstrap and visual predictive check show that the final model of FP is stable, effective and predictable. A novel population pharmacokinetic model is developed to estimate the individual pharmacokinetic parameter for patients intravenous injecting FA in terms of patients' characteristics and dosing history, and to design a prior dosage regimen.

Postoperative analgesia with fentanyl combined with flurbiprofen axetil following gynecologic surgery for turnor / 南方医科大学学报

<p><b>OBJECTIVE</b>a To observe the analgesic effect of fentanyl combined with flurbiprofen axetil for postoperative analgesia after gynecologic surgery.</p><p><b>METHODS</b>One hundred and forty patients undergoing gynecologic surgery were randomized equally into two groups to receive postoperative patient controlled intravenous analgesia (PCIA) with fentanyl (1.6-1.8 mg) plus tropisetron (5 mg/100 ml) (group I), or with fentanyl (0.8-1.0 mg) and flurbiprofen axetil (200 mg) plus tropisetron (5 mg/100 ml) (group II), at the PCIA rate of 2 ml/h, bolus dose of 1 ml, and lock time of 15 min. At 6 h (T1), 12 h (T2), 24 h (T3), and 48 h (T4) after the operation, the analgesic effect was evaluated with the Prine-Henry score (PHS), and the side effects were recorded. The coagulation function of the patients was assessed with thrombelastography before (T0) and 48 h (T4) after the operation, and the time of gastrointestinal function recovery was recorded.</p><p><b>RESULTS</b>The fentanyl dose was significantly less in group II than in group I (P<0.05). At the time points of T1 and T2, the PHS in group II was significantly lower than that in group I (P<0.05), but comparable between the two groups at T3 and T4 (P>0.05). Significant higher incidences of the adverse effects such as nausea, dizziness and lethargy was noted in group I than in group II (P<0.05). Compared with that at T0, the parameter K was significantly delayed at T4 in both groups (P<0.05). The two groups showed similar time of gastrointestinal function recovery after the operation (P>0.05).</p><p><b>CONCLUSION</b>Flurbiprofen axetil combined with fentanyl for postoperative analgesia can significantly reduce fentanyl dose and the incidence of adverse effects associated with fentanyl without obviously affecting the coagulation and gastrointestinal functions.</p>

Effect of preemptive analgesia with flurbiprofen axetil on patient-controlled intravenous analgesia with tramadol in patients undergoing postburn plastic surgery / 南方医科大学学报

<p><b>OBJECTIVE</b>To observe the preemptive analgesic effect of flurbiprofen axetil for post-operative pain relief.</p><p><b>METHODS</b>Sixty ASA class I or II patients undergoing postburn plastic surgery were randomly assigned into two groups to receive intravenous administration of 100 mg flurbiprofen axetil (group F, n=30) and 10 ml intravenous saline (group C, n=30) 30 min before surgery. After the operation, all the patients received patient-controlled intravenous analgesia (PCIA) with tramadol for pain relief. The postoperative analgesic effect was assessed by visual analog scales (VAS) at 1, 2, 4, 8, 12 and 24 h after surgery, with tramadol requirements and the adverse effects were recorded.</p><p><b>RESULT</b>At 1, 2, 4, and 8 h after the operation, the patients in group F showed significantly lowered VAS scores as compared with the patients in group C (P<0.05). The requirement of tramadol was also significantly less in group F than in group C (182.9-/+37.4 vs 227.3-/+49.8 mg, P<0.05). No significant difference was found in the adverse effects between the two groups.</p><p><b>CONCLUSION</b>Flurbiprofen axetil can produce preemptive analgesia and reduce the tramadol dose during postoperative PCIA in patients undergoing postburn plastic operations.</p>

Topical emulsions stabilized by silica nanoparticles: in vitro release and anti-inflammatory studies of flurbiprofen and diclofenac sodium

Simple and multiple emulsions have a wide range of pharmaceutical applications. Therefore, the stabilization of such emulsions is a challenge to ensure a stable formulation along the period of storage, usage and at the same time to conserve the efficacy of the incorporated medicament. Simple o/w and multiple w/o/w emulsions were prepared using castor and paraffin oils as oil phases and stabilized solely by silica nanoparticles of well-controlled surface properties. Two non-steroidal ant-inflammatory drugs, namely flurbiprofen and diclofenac sodium were incorporated in the stabilized simple and multiple emulsions, respectively. The stability of emulsions and the in vitro release of the drugs from the prepared emulsions were studied. In addition, the anti-inflammatory activity of the drugs from these liquid formulations was assessed using carageenan-induced hindpaw edema in rats. The results indicated that the prepared liquid emulsions, which stabilized with silica nanoparticles, were highly stable. The in vitro release of flurbiprofen and diclofenac sodium from these simple and multiple emulsions showed higher rates compared with those preapred from paraffin oil due to their lower viscosities. The results revealed also that the percentage of oil has a pronounced effect on the in vitro release rates of the drugs from the emulsions. Furthermore, topical flurbiprofen and diclofenac sodium emulsions exhibited a potent local anti-inflammatory activity compared with the orally adminstered drugs in the suspension form and this activity reached its peak [57-84%] 3 hrs after carrageenan injection and persisted for 5 hrs, the period of study